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Sample records for actinium-225 self-immolative tumor-targeted

  1. Production of Actinium-225 via High Energy Proton Induced Spallation of Thorium-232

    Energy Technology Data Exchange (ETDEWEB)

    Harvey, James T.; Nolen, Jerry; Vandergrift, George; Gomes, Itacil; Kroc, Tom; Horwitz, Phil; McAlister, Dan; Bowers, Del; Sullivan, Vivian; Greene, John

    2011-12-30

    The science of cancer research is currently expanding its use of alpha particle emitting radioisotopes. Coupled with the discovery and proliferation of molecular species that seek out and attach to tumors, new therapy and diagnostics are being developed to enhance the treatment of cancer and other diseases. This latest technology is commonly referred to as Alpha Immunotherapy (AIT). Actinium-225/Bismuth-213 is a parent/daughter alpha-emitting radioisotope pair that is highly sought after because of the potential for treating numerous diseases and its ability to be chemically compatible with many known and widely used carrier molecules (such as monoclonal antibodies and proteins/peptides). Unfortunately, the worldwide supply of actinium-225 is limited to about 1,000mCi annually and most of that is currently spoken for, thus limiting the ability of this radioisotope pair to enter into research and subsequently clinical trials. The route proposed herein utilizes high energy protons to produce actinium-225 via spallation of a thorium-232 target. As part of previous R and D efforts carried out at Argonne National Laboratory recently in support of the proposed US FRIB facility, it was shown that a very effective production mechanism for actinium-225 is spallation of thorium-232 by high energy proton beams. The base-line simulation for the production rate of actinium-225 by this reaction mechanism is 8E12 atoms per second at 200 MeV proton beam energy with 50 g/cm2 thorium target and 100 kW beam power. An irradiation of one actinium-225 half-life (10 days) produces {approx}100 Ci of actinium-225. For a given beam current the reaction cross section increases slightly with energy to about 400 MeV and then decreases slightly for beam energies in the several GeV regime. The object of this effort is to refine the simulations at proton beam energies of 400 MeV and above up to about 8 GeV. Once completed, the simulations will be experimentally verified using 400 MeV and 8 Ge

  2. Programmable Microcapsules from Self-Immolative Polymers

    Energy Technology Data Exchange (ETDEWEB)

    Esser-Kahn, Aaron P. [Beckman Inst. for Advanced Science and Technology, Univ. of Illinois, Urbana, IL (United States); Sottos, Nancy R. [Beckman Inst. for Advanced Science and Technology, Univ. of Illinois, Urbana, IL (United States); White, Scott R. [Beckman Inst. for Advanced Science and Technology, Univ. of Illinois, Urbana, IL (United States); Moore, Jeffrey S. [Beckman Inst. for Advanced Science and Technology, Univ. of Illinois, Urbana, IL (United States)

    2010-01-01

    For the autonomous repair of damaged materials, microcapsules are needed that release their contents in response to a variety of physical and chemical phenomena, not just by direct mechanical rupture. Herein we report a general route to programmable microcapsules. This method creates core-shell microcapsules with polymeric shell walls composed of self-immolative polymer networks. The polymers in these networks undergo a head-to-tail depolymerization upon removal of the triggering end group, leading to breakdown of the shell wall and subsequent release of the capsule’s liquid interior. We report microcapsules with shell walls bearing both Boc and Fmoc triggering groups. The capsules release their contents only under conditions known to remove these triggering groups; otherwise, they retain their contents under a variety of conditions. In support of the proposed release mechanism, the capsule shell walls were observed to undergo physical cracking upon exposure to the triggering conditions.

  3. Self-immolation and the exchange of self and others

    DEFF Research Database (Denmark)

    Sobisch, Jan-Ulrich

    2012-01-01

    On the recent self-immolations as a form of Tibetan protest, the Dalai Lama's statement on it, and its relation to some doctrinal aspects such as karma and the bodhisattvas' ability to exchange of Self and other.......On the recent self-immolations as a form of Tibetan protest, the Dalai Lama's statement on it, and its relation to some doctrinal aspects such as karma and the bodhisattvas' ability to exchange of Self and other....

  4. Self-immolation in Iran, risk factors and prevention strategies

    Directory of Open Access Journals (Sweden)

    Shahram Mami

    2015-04-01

    Full Text Available Background: approximately 1,500 to 2,000 people die due to self-immolation every year in Iran. This phenomenon is more pronounced in young women who comprise an active and reproductive segment of the population which can lead to numerous negative consequences in the individual, family, and community. However, since self-immolation is a preventable public health issue, the healthcare system is required to take seriously into account. Methods: In this narrative review, several online databases, including PubMed, PsycINFO, Google Scholar, ISI, Scopus as well as offline resources, including textbooks and theses were searched for the published information about the risk and protective factors of self-immolation. An attempt was made to analyze and identify the epidemiologic patterns and prevention strategies of this phenomenon briefly. Results: Our review revealed that the phenomenon of self-immolation is particularly frequent among young women in Iran and adjustment disorder is the most common risk factor for self-immolation. Conclusion: This study shows that self-immolation is a significant health problem in some parts of Iran, suggesting that the health care system and authorities should be more attentive to this public health challenge. Furthermore, low-cost precautionary and preventive measures including counseling services can manage this phenomenon and should be of high priority for health officials.

  5. LaPO4 Nanoparticles Doped with Actinium-225 that Partially Sequester Daughter Radionuclides

    Energy Technology Data Exchange (ETDEWEB)

    Woodward, Jonathan [ORNL; Kennel, Steve J [ORNL; Stucnkey, Alan [University of Tennessee, Knoxville (UTK); Osborne, Dustin [University of Tennessee, Knoxville (UTK); Wall, Jonathan [University of Tennessee, Knoxville (UTK); Rondinone, Adam Justin [ORNL; Standaert, Robert F [ORNL; Mirzadeh, Saed [ORNL

    2011-01-01

    Nanoscale materials have been envisioned as carriers for various therapeutic drugs, including radioisotopes. Inorganic nanoparticles (NPs) are particularly appealing vehicles for targeted radiotherapy because they can package several radioactive atoms into a single carrier and can potentially retain daughter radioisotopes produced by in vivo generators such as actinium -225 (225Ac, t1/2=10 d). Decay of this radioisotope to stable bismuth-209 proceeds through a chain of short-lived daughters accompanied by the emission of four -particles that release >27 MeV of energy. The challenge in realizing the enhanced cytotoxic potential of in vivo generators lies in retaining the daughter nuclei at the therapy site. When 225Ac is attached to targeting agents via standard chelate conjugation methods, all of the daughter radionuclides are released after the initial -decay occurs. In this work, 225Ac was incorporated into lanthanum phosphate NPs to determine whether the radioisotope and its daughters would be retained within the dense mineral lattice. Further, the 225Ac-doped NPs were conjugated to the monoclonal antibody mAb 201B, which targets mouse lung endothelium through the vasculature, to ascertain the targeting efficacy and in vivo retention of radioisotopes. Standard biodistribution techniques and microSPECT/CT imaging of 225Ac as well as the daughter radioisotopes showed that the NPs accumulated rapidly in mouse lung after intravenous injection. By showing that excess, competing, uncoupled antibodies or NPs coupled to control mAbs are deposited primarily in the liver and spleen, specific targeting of NP-mAb 201B conjugates was demonstrated. Biodistribution analysis showed that ~30% of the total injected dose of La(225Ac)PO4 NPs accumulated in mouse lungs 1 h post-injection yielding a value of % ID/g >200. Furthermore, after 24 h, 80% of the 213Bi daughter produced from 225Ac decay was retained within the target organ and 213Bi retention increased to ~87% at 120 h. In

  6. A model to explain suicide by self-immolation among Iranian women: A grounded theory study.

    Science.gov (United States)

    Khankeh, Hamid Reza; Hosseini, Seyed Ali; Rezaie, Leeba; Shakeri, Jalal; Schwebel, David C

    2015-11-01

    Self-immolation is a common method of suicide among Iranian women. There are several contributing motives for attempting self-immolation, and exploration of the process of self-immolation incidents will help interventionists and clinicians develop prevention programs. A grounded theory study using face-to-face, recorded interviews was conducted with surviving self-immolated patients (n=14), their close relatives (n=5), and medical staff (n=8) in Kermanshah, Iran. Data were analyzed using constant comparison in open, axial, and selective coding stages. A conceptual model was developed to explain the relationships among the main categories extracted through the grounded theory study. Family conflicts emerged as the core category. Cultural context of self-immolated patients offered a contextual condition. Other important categories linked to the core category were mental health problems, distinct characteristics of the suicidal method, and self-immolation as a threat. The role of mental health problems as a causal condition was detected in different levels of the self-immolation process. Finally, adverse consequences of self-immolation emerged as having important impact. The conceptual model, derived through grounded theory study, can guide design of prevention programs. The pivotal role of family conflicts should be emphasized in mental health interventions. The impact of adverse consequences of self-immolation on further suicidal processes necessitates post-suicide prevention programs. Further research to design specific interventions is recommended. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

  7. A Survey of Characteristics of Self-Immolation in the East of Iran

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    Saeed Dastgiri

    2012-05-01

    Full Text Available The aim of this study was investigating the characteristic and outcome of self-immolation cases admitted to the Burn Centre of Birjand, Iran over an eight year period. This study is a retrospective review of case notes for patients with self-Immolation and admitted to our referral burn centre in the last 8 years (January 2003-January 2011. A performa was designed to collect the data such as: demographic information, length of hospital stay, extent of the burn injuries as %TBSA (Total Body Surface Area and final outcome. Data was analyzed by SPSS software. Between 2003 and 2011, 188 self-immolation cases admitted. The mean age was 26.97 ±12.6 years. Female to male ratio was 1.7:1. Housewives represented the largest group (43.1% and kerosene was the most frequent agent used (74.6%. There was significant different between mortality and TBSA and low educational level (P=0.0001. There was a significant fluctuation time trend in the incidence (per 100,000 population of self-immolation from 2003 (4.64, CI 95%: 4.62-4.65 to 2008 (5.2, CI 95%: 5.19-5.21. Mortality rate was 64%. The survival rates at three weeks survival for patients who self-immolated was 24 percent (CI 95%: 17-31. The mean and median survival times were 6 days (CI 95%: 4.8-7.2 and 17.5 days (CI 95%: 13.3-21.6, respectively. Our study has shown a lower incidence of self-immolation (5.3% in the South Khorasan region, when compared with other parts of Iran, as well as a relatively low mortality rate. We have also reported self-immolation in pregnant women which has rarely been reported in medical literature.

  8. What is missed in self-immolated patients' care? A grounded theory study.

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    Norouzi, Kian; Taghinejad, Hamid; Mohammadi, Farahnaz; Mohammadi, Eesa; Suhrabi, Zainab

    2012-12-01

    To explore rehabilitation care process in patients who commit self-immolation. Self-immolation is not only a type of burn injury, but it is also a suicidal method. It is placed in burn injury category that requires long-term rehabilitation and treatment measures. As a suicidal method, among all forms of suicidal attempts, it is the most dramatic, violent and often difficult one to understand. Unfortunately, there are few reported studies investigating experiences and perceptions of nurses about burn care and with qualitative study about the patients' experiences and perceptions. On the basis of the research question, the grounded theory method was used. Considering ethical codes of Belmont and Helsinki statements, purposive sampling was used to select the participants. The patients were deliberately selected, based on the research needs. They were self-immolated patients being referred to Talaghani hospital of Ilam (western Iran) or discharged previously (time of interview and observation ranged from immediately later the burn till 5 years after), in Ilam, where self-immolation rate is very high. The main methods for data collection were deep, open ended, semi-structured interviews, dairies and observations. The interviews were audio taped in Persian, and verbatim transcriptions were made. By doing so, semantic meaning is preserved, and misinterpretation of data due to translation into English is minimised. Data analysis was conducted using the Strauss and Corbin method. Five main categories were emerged: situation of crisis unprofessional care, prolongation and formidability of the journey, self-immolation as paralyse, and attempt for self-management. Finally, by constant, comparison of collected data and emerged categories, central variable entitled unintegrated care emerged as the main problem of self-immolated patients' care. The study comes to the conclusion that we need to focus on specific considerations to provide integrated care for the burned patients as

  9. The trend of indexed papers in PubMed covering different aspects of self-immolation.

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    Mohsen Rezaeian

    2014-02-01

    Full Text Available Self-immolation is a fatal and devastating method of committing suicide used around the world. The chief aim of the present article is to look at the trend of indexed papers in PubMed covering different aspects of self-immolation. PubMed search engine (http://www.ncbi.nlm.nih.gov was searched by using six keywords i.e. "self-immolation", "self-inflicted burn", "self-burning", "self-incineration", "suicidal burns" and "suicide by burning". These keywords should appear either in the title or the abstract of the articles. The time frame was set as to retrieve papers expanding from early indexing time up to end of the year 2011. Based on the search strategy 132 papers were retrieved from these total numbers; 12 (9% were categorized as review papers; 24 (18% as case reports and the rest 96 (73% were original studies. It seems that the number of papers increased during the years of investigations and the highest indexed papers i.e. 14 (10.6% belonged to the year 2011. While most journals, published only one article the highest indexed papers i.e. 35 (26.5% belonged to Burns. There was an increasing trend in the number of self-immolation articles indexed in PubMed since 1965. Three journals i.e. Burns, Journal of Burn Care and Rehabilitation and Journal of Forensic Sciences hosted for more than 37% of all those indexed articles. However, given the increasing trend of self-immolation still more studies are needed to shed light on the diverse aspects of this appalling human behavior.

  10. Activity-linked labeling of enzymes by self-immolative polymers.

    Science.gov (United States)

    Weinstain, Roy; Baran, Phil S; Shabat, Doron

    2009-09-01

    The development and application of tools that allow labeling of proteins in vitro and in vivo is a highly active and interdisciplinary area of research. Self-immolative polymers (SIPs) are a unique type of molecules that respond to external stimuli by undergoing head-to-tail disassembly through a self-immolative fragmentation. We have demonstrated how these polymers can be applied as activity-linked labeling probes for proteins with catalytic activity. A real-time detection of the protein labeling can be monitored due to a change in the fluorescence emission wavelength of the probe during the polymer disassembly process. The SIP-based labeling approach showed considerable conservation of catalytic activity of the labeled protein and significant preference toward labeling of the activating protein.

  11. Hyperbranched Self-Immolative Polymers (hSIPs) for Programmed Payload Delivery and Ultrasensitive Detection.

    Science.gov (United States)

    Liu, Guhuan; Zhang, Guofeng; Hu, Jinming; Wang, Xiaorui; Zhu, Mingqiang; Liu, Shiyong

    2015-09-16

    Upon stimuli-triggered single cleavage of capping moieties at the focal point and chain terminal, self-immolative dendrimers (SIDs) and linear self-immolative polymers (l-SIPs) undergo spontaneous domino-like radial fragmentation and cascade head-to-tail depolymerization, respectively. The nature of response selectivity and signal amplification has rendered them a unique type of stimuli-responsive materials. Moreover, novel design principles are required for further advancement in the field of self-immolative polymers (SIPs). Herein, we report the facile fabrication of water-dispersible SIPs with a new chain topology, hyperbranched self-immolative polymers (hSIPs), by utilizing one-pot AB2 polycondensation methodology and sequential postfunctionalization. The modular engineering of three categories of branching scaffolds, three types of stimuli-cleavable capping moieties at the focal point, and seven different types of peripheral functional groups and polymeric building blocks affords both structurally and functionally diverse hSIPs with chemically tunable amplified-release features. On the basis of the hSIP platform, we explored myriad functions including visible light-triggered intracellular release of peripheral conjugated drugs in a targeted and spatiotemporally controlled fashion, intracellular delivery and cytoplasmic reductive milieu-triggered plasmid DNA release via on/off multivalency switching, mitochondria-targeted fluorescent sensing of H2O2 with a detection limit down to ∼20 nM, and colorimetric H2O2 assay via triggered dispersion of gold nanoparticle aggregates. To further demonstrate the potency and generality of the hSIP platform, we further configure it into biosensor design for the ultrasensitive detection of pathologically relevant antigens (e.g., human carcinoembryonic antigen) by integrating with enzyme-mediated cycle amplification with positive feedback and enzyme-linked immunosorbent assay (ELISA).

  12. From Querulous to Suicidal: Self-immolation in Public Places as a Symbolic Response to the Feeling of Injustice

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    Benjamin T. Lévy

    2017-10-01

    Full Text Available Aim: This paper sheds light on the context that leads some querulous patients to self-immolate in front of, or into, public buildings (e.g., tribunals, city halls, and employment agencies.Method: The author defines paranoid querulousness. A psychoanalytic perspective, but also a judicial and a psychiatric point of view, over querulous claimants is presented. The links between political or social claims and self-immolation are studied. The expression of suicidal thoughts voiced by four querulous subjects is analyzed. Eight examples of self-immolation are presented.Results: The querulous subjects' self-aggressive behaviors seem to be caused by a loss of hope to obtain compensation for a prejudice they allegedly suffered. Querulous individuals tend to self-immolate in front of, or into, public buildings when no answer is given to their claims. These gestures may be both a consequence of some personal distress and triggered by a difficult social or professional context.Discussion: Five sets of assumptions derived from Freudian and Lacanian psychoanalytic theories are advanced. The status of the object over which the querulous claimants wish to assert their rights is clarified. The meaning of self-aggressive gestures is outlined by making reference to the concepts of instinct for mastery, symbolic other, chain of signifiers, masochism, pleasure principle, and reality principle.Conclusion: Prevention of self-immolation could involve that members of the legal professions, social workers, civil servants, and mental health professionals in contact with querulous subjects openly show their will to listen to these claimants' voice: self-aggressive gestures might be avoided by supporting the querulous person's hope to obtain compensation for the prejudice allegedly suffered.

  13. From Querulous to Suicidal: Self-immolation in Public Places as a Symbolic Response to the Feeling of Injustice.

    Science.gov (United States)

    Lévy, Benjamin T; Prudent, Cécile; Liétard, Florian; Evrard, Renaud

    2017-01-01

    Aim: This paper sheds light on the context that leads some querulous patients to self-immolate in front of, or into, public buildings (e.g., tribunals, city halls, and employment agencies). Method: The author defines paranoid querulousness. A psychoanalytic perspective, but also a judicial and a psychiatric point of view, over querulous claimants is presented. The links between political or social claims and self-immolation are studied. The expression of suicidal thoughts voiced by four querulous subjects is analyzed. Eight examples of self-immolation are presented. Results: The querulous subjects' self-aggressive behaviors seem to be caused by a loss of hope to obtain compensation for a prejudice they allegedly suffered. Querulous individuals tend to self-immolate in front of, or into, public buildings when no answer is given to their claims. These gestures may be both a consequence of some personal distress and triggered by a difficult social or professional context. Discussion: Five sets of assumptions derived from Freudian and Lacanian psychoanalytic theories are advanced. The status of the object over which the querulous claimants wish to assert their rights is clarified. The meaning of self-aggressive gestures is outlined by making reference to the concepts of instinct for mastery, symbolic other, chain of signifiers, masochism, pleasure principle, and reality principle. Conclusion: Prevention of self-immolation could involve that members of the legal professions, social workers, civil servants, and mental health professionals in contact with querulous subjects openly show their will to listen to these claimants' voice: self-aggressive gestures might be avoided by supporting the querulous person's hope to obtain compensation for the prejudice allegedly suffered.

  14. Stimuli-Responsive Self-Immolative Polymer Nanofiber Membranes Formed by Coaxial Electrospinning.

    Science.gov (United States)

    Han, Daewoo; Yu, Xinjun; Chai, Qinyuan; Ayres, Neil; Steckl, Andrew J

    2017-04-05

    The first self-immolative polymer (SIP) nanofiber membrane is demonstrated in this report, in which the immolation can be triggered by external stimulus. Electrospun SIP/polyacrylonitrile (PAN) fibers provide depolymerization that is ∼25 times quicker and more responsive (i.e., immolation) than that of a cast film in the triggering condition. Depolymerization of SIP in the SIP/PAN blended fiber membrane results in the transition of the surface properties from hydrophobic (∼110°) to hygroscopic (∼0°). Triggered release of encapsulated functional molecules was demonstrated using coaxially electrospun fiber membrane made of a SIP/PAN blend sheath and polyvinylpyrrolidone/dye core. Coaxial fibers with the SIP/PAN sheath provide minimal release of the encapsulated material in nontriggering solution, while it releases the encapsulated material instantly when the triggering condition is met. Its versatility has been strengthened compared to that of non-SIP coaxial fibers that provide no triggering reaction by external stimulus.

  15. Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers.

    Science.gov (United States)

    Pillow, Thomas H; Schutten, Melissa; Yu, Shang-Fan; Ohri, Rachana; Sadowsky, Jack; Poon, Kirsten Achilles; Solis, Willy; Zhong, Fiona; Del Rosario, Geoffrey; Go, Mary Ann T; Lau, Jeffrey; Yee, Sharon; He, Jintang; Liu, Luna; Ng, Carl; Xu, Keyang; Leipold, Douglas D; Kamath, Amrita V; Zhang, Donglu; Masterson, Luke; Gregson, Stephen J; Howard, Philip W; Fang, Fan; Chen, Jinhua; Gunzner-Toste, Janet; Kozak, Katherine K; Spencer, Susan; Polakis, Paul; Polson, Andrew G; Flygare, John A; Junutula, Jagath R

    2017-05-01

    A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety. Mol Cancer Ther; 16(5); 871-8. ©2017 AACR . ©2017 American Association for Cancer Research.

  16. An enzyme-activatable probe with a self-immolative linker for rapid and sensitive alkaline phosphatase detection and cell imaging through a cascade reaction.

    Science.gov (United States)

    Zhang, Hongmei; Xu, Chenglong; Liu, Jie; Li, Xiaohong; Guo, Lin; Li, Xinming

    2015-04-25

    We report the design and synthesis of a novel probe (1) for ALP assay by incorporating a self-immolative linker between a phosphate moiety and resorufin. Because of its good biocompatibility and rapid cell internalization, this probe also exhibited great potential for real-time monitoring of endogenous phosphatase activity in living cells.

  17. A self-immolative prodrug nanosystem capable of releasing a drug and a NIR reporter for in vivo imaging and therapy.

    Science.gov (United States)

    Wang, Ziqian; Wu, Hao; Liu, Peilian; Zeng, Fang; Wu, Shuizhu

    2017-09-01

    In vivo monitoring of the biodistribution and activation of prodrugs is highly attractive, and the self-immolative dendritic architecture is deemed as a promising approach for constructing theranostic prodrug in which the release/activation of different payloads is needed. Herein, A GSH-triggered and self-immolative dendritic platform comprising an anticancer drug camptothecin (CPT), a cleavable linker and a two-photon NIR fluorophore (dicyanomethylene-4H-pyran, DCM) has been developed for in situ tracking of drug release and antitumour therapy. In vitro experiments demonstrate that, the presence of glutathione (GSH) induces the cleavage of the self-immolative linker, resulting in comitant release of the drug and the dye. Upon cell internalization and under one- or two-photon excitation, prominent intracellular fluorescence can be observed, indicating the release of the payloads in live cells. Upon loaded in phospholipid vesicles, the prodrug has also been successfully utilized for in vivo and in situ tracking of drug release and cancer therapy in a mouse model. Several hours post injection, the prodrug generates strong fluorescence on tumour sites, demonstrating the prodrug's capability of monitoring the on-site drug release. Moreover, the prodrug shows considerable high activity and exerts obvious inhibition towards tumour growth. This work suggests that the prodrug with self-immolative dendritic structure can work well in vivo and this strategy may provide an alternative approach for designing theranostic drug delivery systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. A study of suicide and attempted suicide by self-immolation in an Irish psychiatric population: an increasing problem.

    LENUS (Irish Health Repository)

    O'Donoghue, J M

    2012-02-03

    In the Western World self-immolation is an uncommon but dramatic method of attempting suicide. In-patients who attempt suicide by fire-setting tend to be female with severe psychopathology. In a previous study from the South of Ireland, seven cases from a psychiatric and prison population were identified in a five year period from 1984 to 1989. This would represent an annual rate of 1.07 per cent of burns treated in the burns unit at Cork University Hospital. In this study 12 cases were identified for the years 1994 and 1995. This represents an increase of 3.5 per cent from 1.07 to 4.6 per cent of all burns treated at the same institution. Ten of these patients had a previous psychiatric history and eight of them were resident on a psychiatric ward when they committed the act. Seven of the patients were found to have a high degree of suicide intent of whom four died of their injuries, which gives a mortality rate for this group of 33 per cent. Effective prevention policies are necessary if this increasing problem is to be curtailed.

  19. Design, Synthesis and Application of Fluorine-Labeled Taxoids as19F NMR Probes for the Metabolic Stability Assessment of Tumor-Targeted Drug Delivery Systems.

    Science.gov (United States)

    Seitz, Joshua D; Vineberg, Jacob G; Wei, Longfei; Khan, Jonathan F; Lichtenthal, Brendan; Lin, Chi-Feng; Ojima, Iwao

    2015-03-01

    Novel tumor-targeting drug conjugates, BLT-F 2 ( 1 ) and BLT-S-F 6 ( 2 ), bearing a fluorotaxoid as the warhead, a mechanism-based self-immolative disulfide linker, and biotin as the tumor-targeting module, were designed and synthesized as 19 F NMR probes. Fluorine atoms and CF 3 groups were strategically incorporated into the conjugates to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time monitoring with 19 F NMR. Time-resolved 19 F NMR study on probe 1 disclosed a stepwise mechanism for release of a fluorotaxoid, which might not have been detected by other analytical methods. Probe 2 was designed to bear two CF 3 groups in the taxoid moiety as "3-FAB" reporters for enhanced sensitivity and a polyethylene glycol oligomer insert to improve solubility. The clean analysis of the linker stability and reactivity of drug conjugates in blood plasma or cell culture media by HPLC and 1 H NMR is troublesome, due to the overlap of key signals/peaks with background arising from highly complex ingredients in biological systems. Accordingly, the use of 19 F NMR would provide a practical solution to this problem. In fact, our "3-FAB" probe 2 was proven to be highly useful to investigate the stability and reactivity of the self-immolative disulfide linker system in human blood plasma by 19 F NMR. It has also been revealed that the use of polysorbate 80 as excipient for the formulation of probe 2 dramatically increases the stability of the disulfide linker system. This finding further indicates that the tumor-targeting drug conjugates with polysorbate 80/EtOH/saline formulation for in vivo studies would have high stability in blood plasma, while the drug release in cancer cells proceeds smoothly.

  20. Glyceride-Mimetic Prodrugs Incorporating Self-Immolative Spacers Promote Lymphatic Transport, Avoid First-Pass Metabolism, and Enhance Oral Bioavailability.

    Science.gov (United States)

    Hu, Luojuan; Quach, Tim; Han, Sifei; Lim, Shea F; Yadav, Preeti; Senyschyn, Danielle; Trevaskis, Natalie L; Simpson, Jamie S; Porter, Christopher J H

    2016-10-24

    First-pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first-pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first-pass drug, glyceride-mimetic prodrugs incorporating self-immolative (SI) spacers, resulted in remarkable increases (up to 90-fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first-pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Carbohydrate plasma expanders for passive tumor targeting

    DEFF Research Database (Denmark)

    Hoffmann, Stefan; Caysa, Henrike; Kuntsche, Judith

    2013-01-01

    The objective of this study was to investigate the suitability of carbohydrate plasma volume expanders as a novel polymer platform for tumor targeting. Many synthetic polymers have already been synthesized for targeted tumor therapy, but potential advantages of these carbohydrates include...... inexpensive synthesis, constant availability, a good safety profile, biodegradability and the long clinical use as plasma expanders. Three polymers have been tested for cytotoxicity and cytokine activation in cell cultures and conjugated with a near-infrared fluorescent dye: hydroxyethyl starches (HES 200 k...

  2. High efficiency diffusion molecular retention tumor targeting.

    Directory of Open Access Journals (Sweden)

    Yanyan Guo

    Full Text Available Here we introduce diffusion molecular retention (DMR tumor targeting, a technique that employs PEG-fluorochrome shielded probes that, after a peritumoral (PT injection, undergo slow vascular uptake and extensive interstitial diffusion, with tumor retention only through integrin molecular recognition. To demonstrate DMR, RGD (integrin binding and RAD (control probes were synthesized bearing DOTA (for (111 In(3+, a NIR fluorochrome, and 5 kDa PEG that endows probes with a protein-like volume of 25 kDa and decreases non-specific interactions. With a GFP-BT-20 breast carcinoma model, tumor targeting by the DMR or i.v. methods was assessed by surface fluorescence, biodistribution of [(111In] RGD and [(111In] RAD probes, and whole animal SPECT. After a PT injection, both probes rapidly diffused through the normal and tumor interstitium, with retention of the RGD probe due to integrin interactions. With PT injection and the [(111In] RGD probe, SPECT indicated a highly tumor specific uptake at 24 h post injection, with 352%ID/g tumor obtained by DMR (vs 4.14%ID/g by i.v.. The high efficiency molecular targeting of DMR employed low probe doses (e.g. 25 ng as RGD peptide, which minimizes toxicity risks and facilitates clinical translation. DMR applications include the delivery of fluorochromes for intraoperative tumor margin delineation, the delivery of radioisotopes (e.g. toxic, short range alpha emitters for radiotherapy, or the delivery of photosensitizers to tumors accessible to light.

  3. Self-immolation after forehead flap

    Directory of Open Access Journals (Sweden)

    Melyssa Hancock

    2016-12-01

    Conclusions: Despite the widespread use of petrolatum-based products and their role as potential fuel sources, the flammability potential of these products is poorly described in the literature. Nonetheless, petroleum-based products are associated with potential risks, especially for patients who smoke or for those who engage in activities or occupations that pose a greater risk for fire exposure. Surgeons must be explicit in communicating this risk to patients to prevent acutely devastating complications.

  4. An eighteen-membered macrocyclic ligand for actinium-225 targeted alpha therapy

    Energy Technology Data Exchange (ETDEWEB)

    Thiele, Nikki A.; MacMillan, Samantha N.; Wilson, Justin J. [Cornell Univ., Ithaca, NY (United States). Chemistry and Chemical Biology; Brown, Victoria; Jermilova, Una; Ramogida, Caterina F.; Robertson, Andrew K.H.; Schaffer, Paul; Radchenko, Valery [TRIUMF, Vancouver, BC (Canada). Life Science Div.; Kelly, James M.; Amor-Coarasa, Alejandro; Nikolopoulou, Anastasia; Ponnala, Shashikanth; Williams, Clarence Jr.; Babich, John W. [Radiology, Weill Cornell Medicine, New York, NY (United States); Rodriguez-Rodriguez, Cristina [British Columbia Univ., Vancouver, BC (Canada). Dept. of Physics and Astronomy and Centre for Comparative Medicine

    2017-11-13

    The 18-membered macrocycle H{sub 2}macropa was investigated for {sup 225}Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all {sup 225}Ac (26 kBq) in 5 min at RT. [{sup 225}Ac(macropa)]{sup +} remained intact over 7 to 8 days when challenged with either excess La{sup 3+} ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled {sup 225}Ac in just minutes at RT, and macropa-Tmab retained >99 % of its {sup 225}Ac in human serum after 7 days. In LNCaP xenograft mice, {sup 225}Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free {sup 225}Ac over 96 h. These findings establish macropa to be a highly promising ligand for {sup 225}Ac chelation that will facilitate the clinical development of {sup 225}Ac TAT for the treatment of soft-tissue metastases. (copyright 2017 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim)

  5. Tumor-colonizing bacteria: a potential tumor targeting therapy.

    Science.gov (United States)

    Zu, Chao; Wang, Jiansheng

    2014-08-01

    In 1813, Vautier published his observation of tumor regression in patients who had suffered from gas gangrene. Since then, many publications have described the use of bacteria as antitumor therapy. For example, Bifidobacterium and Clostridium have been shown to selectively colonize tumors and to reduce tumor size. In addition, recent studies have focused on the use of genetic engineering to induce the expression of pro-drug converting enzymes, cytokines, specific antibodies, or suicide genes in tumor-colonizing bacteria. Moreover, some animal experiments have reported the treatment of tumors with engineered bacteria, and few side effects were observed. Therefore, based on these advances in tumor targeting therapy, bacteria may represent the next generation of cancer therapy.

  6. Advancing theranostics with tumor-targeting peptides for precision otolaryngology

    Directory of Open Access Journals (Sweden)

    Chadwick L. Wright

    2016-06-01

    Full Text Available Worldwide, about 600,000 head and neck squamous cell carcinoma (HNSCC are detected annually, many of which involve high risk human papilloma virus (HPV. Surgery is the primary and desired first treatment option. Following surgery, the existence of cancer cells at the surgical margin is strongly associated with eventual recurrence of cancer and a poor outcome. Despite improved surgical methods (robotics, microsurgery, endoscopic/laparoscopic, and external imaging, surgeons rely only on their vision and touch to locate tumors during surgery. Diagnostic imaging systems like computed tomography (CT, magnetic resonance imaging (MRI, single-photon emission computed tomography (SPECT and positron-emission tomography (PET are too large, slow and costly to use efficiently during most surgeries and, ultrasound imaging, while fast and portable, is not cancer specific. This purpose of this article is to review the fundamental technologies that will radically advance Precision Otolaryngology practices to the benefit of patients with HNSCC. In particular, this article will address the potential for tumor-targeting peptides to enable more precise diagnostic imaging while simultaneously advancing new therapeutic paradigms for next generation image-guided surgery, tumor-specific chemotherapeutic delivery and tumor-selective targeted radiotherapy (i.e., theranostic. Keywords: Squamous cell carcinoma, Peptide, Optical surgical navigation, Diagnostic imaging, Theranostic

  7. Purification of radium-226 for the manufacturing of actinium-225 in a cyclotron for alpha-immunotherapy; Radium-Aufreinigung zur Herstellung von Actinium-225 am Zyklotron fuer die Alpha-Immuntherapie

    Energy Technology Data Exchange (ETDEWEB)

    Marx, Sebastian Markus

    2014-09-23

    The thesis describes the development of methods for the purification of Ra-226. The objective was to obtain the radionuclide in the quality that is needed to be used as starting material in the manufacturing process for Ac-225 via proton-irradiated Ra-226. The radionuclide has been gained efficiently out of huge excesses of impurities. The high purity of the obtained radium affords its use as staring material in a pharmaceutical manufacturing process.

  8. Tumor Targeting using Radiolabeled Antibodies for Image-Guided Drug Delivery

    NARCIS (Netherlands)

    Rijpkema, M.J.P.; Boerman, O.C.; Oyen, W.J.G.

    2015-01-01

    Due to their high target affinity and specificity, antibodies are very suitable tumor-targeting vehicles for imaging and therapeutic application. This enables a theranostic approach of imaging targeted drug delivery in oncology and opens the way for personalized medicine, predicting drug delivery,

  9. Passive versus active tumor targeting using RGD- and NGR-modified polymeric nanomedicines

    NARCIS (Netherlands)

    Kunjachan, S.; Pola, R.; Gremse, F.; Theek, B.; Ehling, J.; Moeckel, D.; Hermanns-Sachweh, B.; Pechar, M.; Ulbrich, K.; Hennink, W.E.; Storm, Gerrit; Lederle, W.; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria

    2014-01-01

    Enhanced permeability and retention (EPR) and the (over-) expression of angiogenesis-related surface receptors are key features of tumor blood vessels. As a consequence, EPR-mediated passive and Arg-Gly-Asp (RGD) and Asn-Gly-Arg (NGR) based active tumor targeting have received considerable attention

  10. Chemosensitizing indomethacin-conjugated chitosan oligosaccharide nanoparticles for tumor-targeted drug delivery.

    Science.gov (United States)

    Lee, Jae-Young; Termsarasab, Ubonvan; Lee, Mee Yeon; Kim, Dong-Hwan; Lee, Song Yi; Kim, Jung Sun; Cho, Hyun-Jong; Kim, Dae-Duk

    2017-07-15

    A chitosan oligosaccharide (CSO)-indomethacin (IDM) conjugate (CI) was synthesized to fabricate chemosensitizing nanoparticles (NPs) for tumor-targeted drug delivery. IDM was conjugated to a CSO backbone via amide bond formation, of which successful synthesis was confirmed by proton-nuclear magnetic resonance analyses. Doxorubicin (DOX)-loaded CI (CI10/DOX; CI:DOX=10:1 [w/w]) NPs with IDM increased in the presence of A549 cell lysates. In A549 cells (human lung carcinoma cells), more efficient cellular uptake of CI10/DOX NPs than that of free DOX was observed by using confocal laser scanning microscopy and flow cytometry. The in vitro cytotoxicity of CI10/DOX NPs in A549 cells was higher than those of free DOX and CI NPs with free DOX groups. In vivo pharmacokinetic studies after intravenous administration in rats showed significantly lower clearance of DOX from NPs compared with the free DOX group. Tumor targetability of the developed CI NPs was also verified by a real-time optical imaging study. In summary, the chemosensitizing CI/DOX NP with enhanced anticancer activity, prolonged blood circulation, and passive tumor targeting can be a promising anticancer drug delivery system for tumor-targeted therapy. Chemosensitizing nanoparticles (NPs) based on amphiphilic chitosan oligosaccharide-indomethacin (CSO-IDM; CI) conjugate were developed for tumor-targeted delivery of doxorubicin (DOX). IDM was introduced to the CSO backbone as a hydrophobic residue to synthesize an amphiphilic conjugate and a chemosenstizer of DOX for improving antitumor efficacies. IDM, conjugated to CSO, may inhibit the efflux of cellular uptaken DOX via multidrug resistance-associated protein (MRP) and subsequently augment the anti-proliferation potentials of DOX in A549 cells (MRP-expressed human lung cancer cells). Chemosensitizing properties of developed CI NPs were assessed in cell culture models and the tumor targetability of CI/DOX NPs was demonstrated in A549 tumor-xenografted mouse

  11. Design and synthesis of tumor-targeting theranostic drug conjugates for SPECT and PET imaging studies.

    Science.gov (United States)

    Wang, Tao; Vineberg, Jacob G; Honda, Tadashi; Ojima, Iwao

    2017-12-11

    Theranostics will play a significant role in the next-generation chemotherapy. Two novel tumor-targeting theranostic drug conjugates, bearing imaging arms, were designed and synthesized. These theranostic conjugates consist of biotin as the tumor-targeting moiety, a second generation taxoid, SB-T-1214, as a potent anticancer drug, and two different imaging arms for capturing 99mTc for SPECT (single photon emission computed tomography) and 64Cu for PET (positron emission tomography). To explore the best reaction conditions for capturing radionuclides and work out the chemistry directly applicable to "hot" nuclides, cold chemistry was investigated to capture 185Re(I) and 63Cu(II) species as surrogates for 99mTc and 64Cu, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Synthesis and Evaluation of Paclitaxel-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery.

    Science.gov (United States)

    Paciotti, Giulio F; Zhao, Jielu; Cao, Shugeng; Brodie, Peggy J; Tamarkin, Lawrence; Huhta, Marja; Myer, Lonnie D; Friedman, Jay; Kingston, David G I

    2016-11-16

    The synthesis of a series of thiolated paclitaxel analogs is described as part of a novel nanomedicine program aimed at developing formulations of paclitaxel that will bind to gold nanoparticles for tumor targeted drug delivery. Preliminary evaluation of the new nanomedicine composed of 27 nm gold nanoparticles, tumor necrosis factor alpha (TNFα), thiolated polyethylene glycol (PEG-thiol), and one of several thiolated paclitaxel analogs is presented.

  13. Recent advances in brain tumor-targeted nano-drug delivery systems.

    Science.gov (United States)

    Liu, Yu; Lu, Weiyue

    2012-06-01

    Brain tumors represent one of the most challenging and difficult areas in unmet medical needs. Fortunately, the past decade has seen momentous developments in brain tumor research in terms of brain tumor-targeted novel nano-drug delivery systems with significant important superiority over conventional formulations with respect to decreased toxicity and improved pharmacokinetics/pharmacodynamics. This review first introduces the characteristics of the two major obstacles in brain-tumor targeted delivery, blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), and then reviews recent advances in brain tumor-targeted novel nano-drug delivery systems according to their targeting strategies aimed at different stages of brain tumor development and growth. Based on continuously changing vascular characteristics of brain tumors at different development and growth stages, we propose the concept of 'whole-process targeting' for brain tumor for nano-drug delivery systems, referring to a series of overall targeted drug delivery strategies aimed at key points during the whole development of brain tumors.

  14. Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release.

    Science.gov (United States)

    Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P; Cristini, Vittorio; Brinker, Lina M; Staquicini, Fernanda I; Cardó-Vila, Marina; D'Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R; Dogra, Prashant; Melancon, Marites P; Stafford, R Jason; Miyazono, Kohei; Gelovani, Juri G; Kataoka, Kazunori; Brinker, C Jeffrey; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

    2016-02-16

    A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.

  15. Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery.

    Science.gov (United States)

    Liu, Jianfeng; Liu, Jinjian; Xu, Hongyan; Zhang, Yumin; Chu, Liping; Liu, Qingfen; Song, Naling; Yang, Cuihong

    2014-01-01

    The poor aqueous solubility and low bioavailability of curcumin restrict its clinical application for cancer treatment. In this study, a novel tumor-targeting nanofiber carrier was developed to improve the solubility and tumor-targeting ability of curcumin using a self-assembled Nap-GFFYG-RGD peptide. The morphologies of the peptide nanofiber and the curcumin-encapsulated nanofiber were visualized by transmission electron microscopy. The tumor-targeting activity of the curcumin-encapsulated Nap-GFFYG-RGD peptide nanofiber (f-RGD-Cur) was studied in vitro and in vivo, using Nap-GFFYG-RGE peptide nanofiber (f-RGE-Cur) as the control. Curcumin was encapsulated into the peptide nanofiber, which had a diameter of approximately 10-20 nm. Curcumin showed sustained-release behavior from the nanofibers in vitro. f-RGD-Cur showed much higher cellular uptake in αvβ3 integrin-positive HepG2 liver carcinoma cells than did non-targeted f-RGE-Cur, thereby leading to significantly higher cytotoxicity. Ex vivo studies further demonstrated that curcumin could accumulate markedly in mouse tumors after administration of f-RGD-Cur via the tail vein. These results indicate that Nap-GFFYG-RGD peptide self-assembled nanofibers are a promising hydrophobic drug delivery system for targeted treatment of cancer.

  16. Identification of functional peptides from natural and synthetic products on their anticancer activities by tumor targeting.

    Science.gov (United States)

    Ko, Joshua K; Auyeung, Kathy K

    2014-01-01

    Cancer cells can express specific membrane proteins, which act as biomarkers for chemotherapeutic targeting. Functional peptides possess unique properties that will ensure efficacy, selectivity, specificity and low toxicity when used as therapeutic agents. Therapeutic peptides have been derived in treatment of cancers through improvement of cellular uptake, drug targeting and vaccine development. Peptides from natural source have been used for chemoprevention and therapy of various cancers. These include peptides derived from food, marine products, venom components and other animal constituents. Besides, chemically- and recombinantly-synthesized peptides have also been produced and extensively studied in contemporary applications. Improvement of tumor targeting is essential for chemotherapeutic development. This can be achieved through enhancement of intracellular delivery and/or increased specific binding affinity to cancer cells by pore-forming and cytotoxic peptides. Cytotoxic peptides such as the Bcl-2 family members can induce receptor-specific binding to tumor cells and promote apoptosis by targeting lipid membranes. This approach has some limitations in targeting, penetration and localization within tumors. Cell-penetrating peptides (CPPs) belong to a new class of tumor-targeting peptides that can facilitate internalization of tumor markers and/or chemotherapeutic drugs. In order to overcome the problem of serum instability in classical CPPs (e.g. Tat), newer classes of CPPs has been recently introduced. Nevertheless, some cyclized CPPs can further enhance cellular uptake and binding selectivity when compared to activities of their linear counterpart, especially when treating chemoresistant tumors. This review compiles the use of effective tumor-targeting peptides including novel CPPs that represents new therapeutic strategies for the treatment of cancers.

  17. Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies.

    Science.gov (United States)

    Mangraviti, Antonella; Gullotti, David; Tyler, Betty; Brem, Henry

    2016-10-28

    Despite recent technological advancements and promising preclinical experiments, brain tumor patients are still met with limited treatment options. Some of the barriers to clinical improvements include the systemic toxicity of cytotoxic compounds, the impedance of the blood brain barrier (BBB), and the lack of therapeutic agents that can selectively target the intracranial tumor environment. To overcome such barriers, a number of chemotherapeutic agents and nucleic acid-based therapies are rapidly being synthesized and tested as new brain tumor-targeted delivery strategies. Novel carriers include liposomal and polymeric nanoparticles, wafers, microchips, microparticle-based nanoplatforms and cells-based vectors. Strong preclinical results suggest that these nanotechnologies are set to transform the therapeutic paradigm for brain tumor treatment. In addition to new tumoricidal agents, parallel work is also being conducted on the BBB front. Preclinical testing of chemical and physical modulation strategies is yielding improved intracranial concentrations. New diagnostic and therapeutic imaging techniques, such as high-intensity focused ultrasound and MRI-guided focused ultrasound, are being used to modulate the BBB in a more precise and non-invasive manner. This review details some of the tremendous advances that are being explored in current brain tumor targeted therapies, including local implant development, nanobiotechnology-based delivery strategies, and techniques of BBB manipulation. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Linker structure-activity relationships in fluorodeoxyglucose chlorambucil conjugates for tumor-targeted chemotherapy.

    Science.gov (United States)

    El Hilali, Mostafa; Reux, Bastien; Debiton, Eric; Leal, Fernand; Galmier, Marie-Josephe; Vivier, Magali; Chezal, Jean-Michel; Miot-Noirault, Elisabeth; Coudert, Pascal; Weber, Valérie

    2017-10-15

    Nitrogen mustards, such as chlorambucil (CLB), can cause adverse side-effects due to ubiquitous distribution in non-target organs. To minimize this toxicity, strategies of tumor-targeting drug delivery have been developed, where a cytotoxic warhead is linked to a tumor-cell-specific small ligand. Malignant cells exhibit marked glucose avidity and an accelerated metabolism by aerobic glycolysis, known as the Warburg effect, and recognized as a hallmark of cancer. A targeting approach exploiting the Warburg effect by conjugation of CLB to 2-fluoro-2-deoxyglucose (FDG) was previously reported and identified two peracetylated glucoconjugates 2 and 3 with promising antitumor activities in vivo. These results prompted us to investigate the importance of the spacer in this tumor-targeting glucose-based conjugates. Here we report the chemical synthesis and an in vitro cytotoxicity evaluation, using a 5-member panel of human tumor cell lines and human fibroblasts, of 16 new CLB glucoconjugates in which the alkylating drug is attached to the C-1 position of FDG via different linkages. We studied the structure-activity relationships in the linker, and evidenced the positive impact of an aromatic linker on in vitro cytotoxicity: compound 51 proved to be the most active FDG-CLB glucoside, characterized by a bis-aromatic spacer tethered to CLB through an amide function. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Multi-Functional Self-Fluorescent Unimolecular Micelles for Tumor-Targeted Drug Delivery and Bioimaging

    Science.gov (United States)

    Chen, Guojun; Wang, Liwei; Cordie, Travis; Vokoun, Corinne; Eliceiri, Kevin W.

    2015-01-01

    A novel type of self-fluorescent unimolecular micelle nanoparticle (NP) formed by multi-arm star amphiphilic block copolymer, Boltron® H40 (H40, a 4th generation hyperbranched polymer)-biodegradable photo-luminescent polymer (BPLP)-poly(ethylene glycol) (PEG) conjugated with cRGD peptide (i.e., H40-BPLP-PEG-cRGD) was designed, synthesized, and characterized. The hydrophobic BPLP segment was self-fluorescent, thereby making the unimolecular micelle NP self-fluorescent. cRGD peptides, which can effectively target αvβ3 integrin-expressing tumor neovasculature and tumor cells, were selectively conjugated onto the surface of the micelles to offer active tumor-targeting ability. This unique self-fluorescent unimolecular micelle exhibited excellent photostability and low cytotoxicity, making it an attractive bioimaging probe for NP tracking for a variety of microscopy techniques including fluorescent microscopy, confocal laser scanning microscopy (CLSM), and two-photon microscopy. Moreover, this self-fluorescent unimolecular micelle NP also demonstrated excellent stability in aqueous solutions due to its covalent nature, high drug loading level, pH-controlled drug release, and passive and active tumor-targeting abilities, thereby making it a promising nanoplatform for targeted cancer theranostics. PMID:25682159

  20. Liposomal Tumor Targeting in Drug Delivery Utilizing MMP-2- and MMP-9-Binding Ligands

    Directory of Open Access Journals (Sweden)

    Oula Penate Medina

    2011-01-01

    Full Text Available Nanotechnology offers an alternative to conventional treatment options by enabling different drug delivery and controlled-release delivery strategies. Liposomes being especially biodegradable and in most cases essentially nontoxic offer a versatile platform for several different delivery approaches that can potentially enhance the delivery and targeting of therapies to tumors. Liposomes penetrate tumors spontaneously as a result of fenestrated blood vessels within tumors, leading to known enhanced permeability and subsequent drug retention effects. In addition, liposomes can be used to carry radioactive moieties, such as radiotracers, which can be bound at multiple locations within liposomes, making them attractive carriers for molecular imaging applications. Phage display is a technique that can deliver various high-affinity and selectivity peptides to different targets. In this study, gelatinase-binding peptides, found by phage display, were attached to liposomes by covalent peptide-PEG-PE anchor creating a targeted drug delivery vehicle. Gelatinases as extracellular targets for tumor targeting offer a viable alternative for tumor targeting. Our findings show that targeted drug delivery is more efficient than non-targeted drug delivery.

  1. Aptamer-Modified Tetrahedral DNA Nanostructure for Tumor-Targeted Drug Delivery.

    Science.gov (United States)

    Li, Qianshun; Zhao, Dan; Shao, Xiaoru; Lin, Shiyu; Xie, Xueping; Liu, Mengting; Ma, Wenjuan; Shi, Sirong; Lin, Yunfeng

    2017-10-25

    Tetrahedral DNA nanostructures (TDNs) are considered promising drug delivery carriers because they are able to permeate cellular membrane and are biocompatible and biodegradable. Furthermore, they can be modified by functional groups. To improve the drug-delivering ability of TDNs, we chose anticancer aptamer AS1411 to modify TDNs for tumor-targeted drug delivery. AS1411 can specifically bind to nucleolin, which is overexpressed on the cell membrane of tumor cells. Furthermore, AS1411 can inhibit NF-κB signaling and reduce the expression of bcl-2. In this study, we compared the intracellular localization of AS1411-modified TDNs (Apt-TDNs) with that of TDNs in different cells under hypoxic condition. Furthermore, we compared the effects of Apt-TDNs and TDNs on cell growth and cell cycle under hypoxic condition. A substantial amount of Apt-TDNs entered and accumulated in the nucleus of MCF-7 cells; however, the amount of Apt-TDNs that entered L929 cells was comparatively less. TDNs entered in much lower quantity in MCF-7 cells than Apt-TDNs. Moreover, there was little difference in the amount of TDNs that entered L929 cells and MCF-7 cells. Apt-TDNs can inhibit MCF-7 cell growth and promote L929 cell growth, while TDNs can promote both MCF-7 and L929 cell growth. Thus, the results indicate that Apt-TDNs are more effective tumor-targeted drug delivery vehicles than TDNs, with the ability to specifically inhibit tumor cell growth.

  2. PEG-transferrin conjugated TRAIL (TNF-related apoptosis-inducing ligand) for therapeutic tumor targeting.

    Science.gov (United States)

    Kim, Tae Hyung; Jo, Young Gi; Jiang, Hai Hua; Lim, Sung Mook; Youn, Yu Seok; Lee, Seulki; Chen, Xiaoyuan; Byun, Youngro; Lee, Kang Choon

    2012-09-10

    Transferrin (Tf) is considered an effective tumor-targeting agent, and PEGylation effectively prolongs in vivo pharmacokinetics by delaying excretion via the renal route. The authors describe the active tumor targeting of long-acting Tf-PEG-TNF-related apoptosis-inducing ligand conjugate (Tf-PEG-TRAIL) for effective cancer therapy. Tf-PEG-TRAIL was prepared using a two-step N-terminal specific PEGylation procedure using different PEGs (Mw: 3.4, 5, 10 kDa). Eventually, only 10 kDa PEG was linked to Tf and TRAIL because TRAIL (66 kDa) and Tf (81 kDa) were too large to link to 3.4 and 5 kDa PEG. The final conjugate Tf-PEG(10K)-TRAIL was successfully purified and characterized by SDS-PAGE, western blotting. To determine the specific binding of Tf-PEG(10K)-TRAIL to Tf receptor, competitive receptor binding assays were performed on K 562 cells. The results obtained demonstrate that the affinity of Tf-PEG(10K)-TRAIL for Tf receptor is similar to that of native Tf. In contrast, PEG(10K)-TRAIL demonstrated no specificity. Biodistribution patterns and antitumor effects were investigated in C57BL6 mice bearing B16F10 murine melanomas and BALB/c athymic mice bearing HCT116. Tumor accumulation of Tf-PEG(10K)-TRAIL was 5.2 fold higher (at 2 h) than TRAIL, because Tf-PEG(10K)-TRAIL has both passive and active tumor targeting ability. Furthermore, the suppression of tumors by Tf-PEG(10K)-TRAIL was 3.6 and 1.5 fold those of TRAIL and PEG(10K)-TRAIL, respectively. These results suggest that Tf-PEG(10K)-TRAIL is a superior pharmacokinetic conjugate that potently targets tumors and that it should be viewed as a potential cancer therapy. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. A Functional Iron Oxide Nanoparticles Modified with PLA-PEG-DG as Tumor-Targeted MRI Contrast Agent.

    Science.gov (United States)

    Xiong, Fei; Hu, Ke; Yu, Haoli; Zhou, Lijun; Song, Lina; Zhang, Yu; Shan, Xiuhong; Liu, Jianping; Gu, Ning

    2017-08-01

    Tumor targeting could greatly promote the performance of magnetic nanomaterials as MRI (Magnetic Resonance Imaging) agent for tumor diagnosis. Herein, we reported a novel magnetic nanoparticle modified with PLA (poly lactic acid)-PEG (polyethylene glycol)-DG (D-glucosamine) as Tumor-targeted MRI Contrast Agent. In this work, we took use of the D-glucose passive targeting on tumor cells, combining it on PLA-PEG through amide reaction, and then wrapped the PLA-PEG-DG up to the Fe 3 O 4 @OA NPs. The stability and anti phagocytosis of Fe 3 O 4 @OA@PLA-PEG-DG was tested in vitro; the MRI efficiency and toxicity was also detected in vivo. These functional magnetic nanoparticles demonstrated good biocompatibility and stability both in vitro and in vivo. Cell experiments showed that Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles exist good anti phagocytosis and high targetability. In vivo MRI images showed that the contrast effect of Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles prevailed over the commercial non tumor-targeting magnetic nanomaterials MRI agent at a relatively low dose. The DG can validly enhance the tumor-targetting effect of Fe 3 O 4 @OA@PLA-PEG nanoparticle. Maybe MRI agents with DG can hold promise as tumor-targetting development in the future.

  4. Advances in Functionalized Mesoporous Silica Nanoparticles for Tumor Targeted Drug Delivery and Theranostics.

    Science.gov (United States)

    Zhang, Wenjia; Liu, Mengrui; Liu, Anchang; Zhai, Guangxi

    2017-01-01

    In recent years, nanocarriers have played increasingly significant roles in cancer therapy. Among various nanoplatforms, mesoporous silica nanoparticles (MSNs) have been given serious attention due to their good colloidal stablity, tunable pore sizes, extensive drug loading capacity and easily modified surface. In this review, functionalized MSNs are introduced as an efficient nanocarrier for cancer treatment. First, MSN preparation strategies are generally introduced. Next, passive and active tumor targeting methods for the functionalization of MSNs are reviewed. Then, several types of stimuli-responsive strategies for on-demand drug release, a wide variety of designs integrating with magnetic resonance imaging agents, optical imaging agents, and positron emission tomography imaging agents, etc. for theranostic purpose are summarized. A discussion relating to the future perspectives of MSNs for clinical translocation is also included in this review. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Solid Tumor-Targeting Theranostic Polymer Nanoparticle in Nuclear Medicinal Fields

    Directory of Open Access Journals (Sweden)

    Akira Makino

    2014-01-01

    Full Text Available Polymer nanoparticles can be prepared by self-assembling of amphiphilic polymers, and various types of molecular assemblies have been reported. In particular, in medicinal fields, utilization of these polymer nanoparticles as carriers for drug delivery system (DDS has been actively tried, and some nanoparticulate drugs are currently under preclinical evaluations. A radionuclide is an unstable nucleus and decays with emission of radioactive rays, which can be utilized as a tracer in the diagnostic imaging systems of PET and SPECT and also in therapeutic purposes. Since polymer nanoparticles can encapsulate most of diagnostic and therapeutic agents with a proper design of amphiphilic polymers, they should be effective DDS carriers of radionuclides in the nuclear medicinal field. Indeed, nanoparticles have been recently attracting much attention as common platform carriers for diagnostic and therapeutic drugs and contribute to the development of nanotheranostics. In this paper, recent developments of solid tumor-targeting polymer nanoparticles in nuclear medicinal fields are reviewed.

  6. Solid tumor-targeting theranostic polymer nanoparticle in nuclear medicinal fields.

    Science.gov (United States)

    Makino, Akira; Kimura, Shunsaku

    2014-01-01

    Polymer nanoparticles can be prepared by self-assembling of amphiphilic polymers, and various types of molecular assemblies have been reported. In particular, in medicinal fields, utilization of these polymer nanoparticles as carriers for drug delivery system (DDS) has been actively tried, and some nanoparticulate drugs are currently under preclinical evaluations. A radionuclide is an unstable nucleus and decays with emission of radioactive rays, which can be utilized as a tracer in the diagnostic imaging systems of PET and SPECT and also in therapeutic purposes. Since polymer nanoparticles can encapsulate most of diagnostic and therapeutic agents with a proper design of amphiphilic polymers, they should be effective DDS carriers of radionuclides in the nuclear medicinal field. Indeed, nanoparticles have been recently attracting much attention as common platform carriers for diagnostic and therapeutic drugs and contribute to the development of nanotheranostics. In this paper, recent developments of solid tumor-targeting polymer nanoparticles in nuclear medicinal fields are reviewed.

  7. Conjugate of biotin with silicon(IV) phthalocyanine for tumor-targeting photodynamic therapy.

    Science.gov (United States)

    Li, Ke; Qiu, Ling; Liu, Qingzhu; Lv, Gaochao; Zhao, Xueyu; Wang, Shanshan; Lin, Jianguo

    2017-09-01

    In order to improve the efficacy of photodynamic therapy (PDT), biotin was axially conjugated with silicon(IV) phthalocyanine (SiPc) skeleton to develop a new tumor-targeting photosensitizer SiPc-biotin. The target compound SiPc-biotin showed much higher binding affinity toward BR-positive (biotin receptor overexpressed) HeLa human cervical carcinoma cells than its precursor SiPc-pip. However, when the biotin receptors of HeLa cells were blocked by free biotin, >50% uptake of SiPc-biotin was suppressed, demonstrating that SiPc-biotin could selectively accumulate in BR-positive cancer cells via the BR-mediated internalization. The confocal fluorescence images further confirmed the target binding ability of SiPc-biotin. As a consequence of specificity of SiPc-biotin toward BR-positive HeLa cells, the photodynamic effect was also largely dependent on the BR expression level of HeLa cells. The photodynamic activities of SiPc-biotin against HeLa cells were dramatically reduced when the biotin receptors were blocked by the free biotin (IC50: 0.18μM vs. 0.46μM). It is concluded that SiPc-biotin can selectively damage BR-positive cancer cells under irradiation. Furthermore, the dark toxicity of SiPc-biotin toward human normal liver cell lines LO2 was much lower than that of its precursor SiPc-pip. The targeting photodynamic activity and low dark toxicity suggest that SiPc-biotin is a promising photosensitizer for tumor-targeting photodynamic therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Characteristics of oncolytic vesicular stomatitis virus displaying tumor-targeting ligands.

    Science.gov (United States)

    Ammayappan, Arun; Peng, Kah-Whye; Russell, Stephen J

    2013-12-01

    We sought proof of principle that tumor-targeting ligands can be displayed on the surface of vesicular stomatitis virus (VSV) by engineering its glycoprotein. Here, we successfully rescued VSVs displaying tumor vasculature-targeting ligands. By using a rational approach, we investigated various feasible insertion sites on the G protein of VSV (VSV-G) for display of tumor vasculature-targeting ligands, cyclic RGD (cRGD) and echistatin. We found seven sites on VSV-G that tolerated insertion of the 9-residue cRGD peptide, two of which could tolerate insertion of the 49-amino acid echistatin domain. All of the ligand-displaying viruses replicated as well as the parental virus. In vitro studies demonstrated that the VSV-echistatin viruses specifically bound to targeted integrins. Since the low-density lipoprotein receptor (LDLR) was recently identified as a major receptor for VSV, we investigated the entry of ligand-displaying viruses after masking LDLR. The experiment showed that the modified viruses can enter the cell independently of LDLR, whereas entry of unmodified virus is significantly blocked by a specific monoclonal antibody against LDLR. Both parental and ligand-displaying viruses displayed equal oncolytic efficacies in a syngeneic mouse myeloma model. We further demonstrated that single-chain antibody fragments against tumor-specific antigens can be inserted at the N terminus of the G protein and that corresponding replication-competent VSVs can be rescued efficiently. Overall, we demonstrated that functional tumor-targeting ligands can be displayed on replication-competent VSVs without perturbing viral growth and oncolytic efficacy. This study provides a rational foundation for the future development of fully retargeted oncolytic VSVs.

  9. Canine parvovirus-like particles, a novel nanomaterial for tumor targeting

    Directory of Open Access Journals (Sweden)

    Destito Giuseppe

    2006-02-01

    Full Text Available Abstract Specific targeting of tumor cells is an important goal for the design of nanotherapeutics for the treatment of cancer. Recently, viruses have been explored as nano-containers for specific targeting applications, however these systems typically require modification of the virus surface using chemical or genetic means to achieve tumor-specific delivery. Interestingly, there exists a subset of viruses with natural affinity for receptors on tumor cells that could be exploited for nanotechnology applications. For example, the canine parvovirus (CPV utilizes transferrin receptors (TfRs for binding and cell entry into canine as well as human cells. TfRs are over-expressed by a variety of tumor cells and are widely being investigated for tumor-targeted drug delivery. We explored whether the natural tropism of CPV to TfRs could be harnessed for targeting tumor cells. Towards this goal, CPV virus-like particles (VLPs produced by expression of the CPV-VP2 capsid protein in a baculovirus expression system were examined for attachment of small molecules and delivery to tumor cells. Structural modeling suggested that six lysines per VP2 subunit are presumably addressable for bioconjugation on the CPV capsid exterior. Between 45 and 100 of the possible 360 lysines/particle could be routinely derivatized with dye molecules depending on the conjugation conditions. Dye conjugation also demonstrated that the CPV-VLPs could withstand conditions for chemical modification on lysines. Attachment of fluorescent dyes neither impaired binding to the TfRs nor affected internalization of the 26 nm-sized VLPs into several human tumor cell lines. CPV-VLPs therefore exhibit highly favorable characteristics for development as a novel nanomaterial for tumor targeting.

  10. Multifunctional nanosheets based on folic acid modified manganese oxide for tumor-targeting theranostic application

    Science.gov (United States)

    Hao, Yongwei; Wang, Lei; Zhang, Bingxiang; Zhao, Hongjuan; Niu, Mengya; Hu, Yujie; Zheng, Cuixia; Zhang, Hongling; Chang, Junbiao; Zhang, Zhenzhong; Zhang, Yun

    2016-01-01

    It is highly desirable to develop smart nanocarriers with stimuli-responsive drug-releasing and diagnostic-imaging functions for cancer theranostics. Herein, we develop a reduction and pH dual-responsive tumor theranostic platform based on degradable manganese dioxide (MnO2) nanosheets. The MnO2 nanosheets with a size of 20-60 nm were first synthesized and modified with (3-Aminopropyl) trimethoxysilane (APTMS) to get amine-functionalized MnO2, and then functionalized by NH2-PEG2000-COOH (PEG). The tumor-targeting group, folic acid (FA), was finally conjugated with the PEGylated MnO2 nanosheets. Then, doxorubicin (DOX), a chemotherapeutic agent, was loaded onto the modified nanosheets through a physical adsorption, which was designated as MnO2-PEG-FA/DOX. The prepared MnO2-PEG-FA/DOX nanosheets with good biocompatibility can not only efficiently deliver DOX to tumor cells in vitro and in vivo, leading to enhanced anti-tumor efficiency, but can also respond to a slightly acidic environment and high concentration of reduced glutathione (GSH), which caused degradation of MnO2 into manganese ions enabling magnetic resonance imaging (MRI). The longitudinal relaxation rate r 1 was 2.26 mM-1 s-1 at pH 5.0 containing 2 mM GSH. These reduction and pH dual-responsive biodegradable nanosheets combining efficient MRI and chemotherapy provide a novel and promising platform for tumor-targeting theranostic application.

  11. Modulation of hydrogel nanoparticle intracellular trafficking by multivalent surface engineering with tumor targeting peptide

    Science.gov (United States)

    Karamchand, Leshern; Kim, Gwangseong; Wang, Shouyan; Hah, Hoe Jin; Ray, Aniruddha; Jiddou, Ruba; Koo Lee, Yong-Eun; Philbert, Martin A.; Kopelman, Raoul

    2013-10-01

    Surface engineering of a hydrogel nanoparticle (NP) with the tumor-targeting ligand, F3 peptide, enhances both the NP's binding affinity for, and internalization by, nucleolin overexpressing tumor cells. Remarkably, the F3-functionalized NPs consistently exhibited significantly lower trafficking to the degradative lysosomes than the non-functionalized NPs, in the tumor cells, after internalization. This is attributed to the non-functionalized NPs, but not the F3-functionalized NPs, being co-internalized with Lysosome-associated Membrane Protein-1 (LAMP1) from the surface of the tumor cells. Furthermore, it is shown that the intracellular trafficking of the F3-functionalized NPs differs significantly from that of the molecular F3 peptides (untethered to NPs). This has important implications for designing effective, chemically-responsive, controlled-release and multifunctional nanodrugs for multi-drug-resistant cancers.Surface engineering of a hydrogel nanoparticle (NP) with the tumor-targeting ligand, F3 peptide, enhances both the NP's binding affinity for, and internalization by, nucleolin overexpressing tumor cells. Remarkably, the F3-functionalized NPs consistently exhibited significantly lower trafficking to the degradative lysosomes than the non-functionalized NPs, in the tumor cells, after internalization. This is attributed to the non-functionalized NPs, but not the F3-functionalized NPs, being co-internalized with Lysosome-associated Membrane Protein-1 (LAMP1) from the surface of the tumor cells. Furthermore, it is shown that the intracellular trafficking of the F3-functionalized NPs differs significantly from that of the molecular F3 peptides (untethered to NPs). This has important implications for designing effective, chemically-responsive, controlled-release and multifunctional nanodrugs for multi-drug-resistant cancers. Electronic supplementary information (ESI) available: Effect of Potassium depletion on F3 peptide subcellular localization, MTT

  12. Tumor targeting profiling of hyaluronan-coated lipid based-nanoparticles

    Science.gov (United States)

    Mizrahy, Shoshy; Goldsmith, Meir; Leviatan-Ben-Arye, Shani; Kisin-Finfer, Einat; Redy, Orit; Srinivasan, Srimeenakshi; Shabat, Doron; Godin, Biana; Peer, Dan

    2014-03-01

    Hyaluronan (HA), a naturally occurring high Mw (HMw) glycosaminoglycan, has been shown to play crucial roles in cell growth, embryonic development, healing processes, inflammation, and tumor development and progression. Low Mw (LMw, melanoma cells. LMw HA-tsNPs exhibited weak binding, while binding of tsNPs coated with HMw HA was characterized by high binding. Both types of tsNPs had no measured effect on cytokine induction in vivo following intravenous administration to healthy C57BL/6 mice suggesting no immune activation. HMw HA-tsNPs showed enhanced circulation time and tumor targeting specificity, mainly by accumulating in the tumor and its vicinity compared with LMw HA-tsNPs. Finally, we show that methotrexate (MTX), a drug commonly used in cancer chemotherapy, entrapped in HMw HA-tsNPs slowly diffused from the particles with a half-life of 13.75 days, and improved the therapeutic outcome in a murine B16F10 melanoma model compared with NPs suggesting an active cellular targeting beyond the Enhanced Permeability and Retention (EPR) effect. Taken together, these findings have major implications for the use of high molecular weight HA in nanomedicine as a selective and safe active cellular targeting moiety.Hyaluronan (HA), a naturally occurring high Mw (HMw) glycosaminoglycan, has been shown to play crucial roles in cell growth, embryonic development, healing processes, inflammation, and tumor development and progression. Low Mw (LMw, melanoma cells. LMw HA-tsNPs exhibited weak binding, while binding of tsNPs coated with HMw HA was characterized by high binding. Both types of tsNPs had no measured effect on cytokine induction in vivo following intravenous administration to healthy C57BL/6 mice suggesting no immune activation. HMw HA-tsNPs showed enhanced circulation time and tumor targeting specificity, mainly by accumulating in the tumor and its vicinity compared with LMw HA-tsNPs. Finally, we show that methotrexate (MTX), a drug commonly used in cancer

  13. RGD peptide functionalized and reconstituted high-density lipoprotein nanoparticles as a versatile and multimodal tumor targeting molecular imaging probe

    NARCIS (Netherlands)

    Chen, Wei; Jarzyna, Peter A.; van Tilborg, Geralda A. F.; Nguyen, Van Anh; Cormode, David P.; Klink, Ahmed; Griffioen, Arjan W.; Randolph, Gwendalyn J.; Fisher, Edward A.; Mulder, Willem J. M.; Fayad, Zahi A.

    2010-01-01

    High density lipoprotein (HDL), an endogenous nanoparticle, transports fat throughout the body and is capable of transferring cholesterol from atheroma in the vessel wall to the liver. In the present study, we utilized HDL as a multimodal nanoparticle platform for tumor targeting and imaging via

  14. Physico-Chemical Strategies to Enhance Stability and Drug Retention of Polymeric Micelles for Tumor-Targeted Drug Delivery

    NARCIS (Netherlands)

    Shi, Yang; Lammers, Twan|info:eu-repo/dai/nl/304824577; Storm, G|info:eu-repo/dai/nl/073356328; Hennink, Wim E.|info:eu-repo/dai/nl/070880409

    2017-01-01

    Polymeric micelles (PM) have been extensively used for tumor-targeted delivery of hydrophobic anti-cancer drugs. The lipophilic core of PM is naturally suitable for loading hydrophobic drugs and the hydrophilic shell endows them with colloidal stability and stealth properties. Decades of research on

  15. A tumor-targeted activatable phthalocyanine-tetrapeptide-doxorubicin conjugate for synergistic chemo-photodynamic therapy.

    Science.gov (United States)

    Ke, Mei-Rong; Chen, Shao-Fang; Peng, Xiao-Hui; Zheng, Qiao-Feng; Zheng, Bi-Yuan; Yeh, Chih-Kuang; Huang, Jian-Dong

    2017-02-15

    Chemo-photodynamic therapy is a promising strategy for cancer treatments. However, it remains a challenge to develop a chemo-photodynamic therapeutic agent with little side effect, high tumor-targeting, and efficient synergistic effect simultaneously. Herein, we report a zinc(II) phthalocyanine (ZnPc)-doxorubicin (DOX) prodrug linked with a fibroblast activation protein (FAP)-responsive short peptide with the sequence of Thr-Ser-Gly-Pro for chemo-photodynamic therapy. In the conjugate, both photosensitizing activity of ZnPc and cytotoxicity of DOX are inhibited obviously. However, FAP-triggered separation of the photosensitizer and DOX can enhance fluorescence emission, singlet oxygen generation, dark- and photo-cytotoxicity significantly, and lead to a synergistic anticancer efficacy against HepG2 cells. The prodrug can also be specifically and efficiently activated in tumor tissue of mice. Thus, this prodrug shows great potential for clinical application in chemo-photodynamic therapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Hybrid protein-inorganic nanoparticles: From tumor-targeted drug delivery to cancer imaging.

    Science.gov (United States)

    Elzoghby, Ahmed O; Hemasa, Ayman L; Freag, May S

    2016-12-10

    Recently, a great interest has been paid to the development of hybrid protein-inorganic nanoparticles (NPs) for drug delivery and cancer diagnostics in order to combine the merits of both inorganic and protein nanocarriers. This review primarily discusses the most outstanding advances in the applications of the hybrids of naturally-occurring proteins with iron oxide, gadolinium, gold, silica, calcium phosphate NPs, carbon nanotubes, and quantum dots in drug delivery and cancer imaging. Various strategies that have been utilized for the preparation of protein-functionalized inorganic NPs and the mechanisms involved in the drug loading process are discussed. How can the protein functionalization overcome the limitations of colloidal stability, poor dispersibility and toxicity associated with inorganic NPs is also investigated. Moreover, issues relating to the influence of protein hybridization on the cellular uptake, tumor targeting efficiency, systemic circulation, mucosal penetration and skin permeation of inorganic NPs are highlighted. A special emphasis is devoted to the novel approaches utilizing the protein-inorganic nanohybrids in combined cancer therapy, tumor imaging, and theranostic applications as well as stimuli-responsive drug release from the nanohybrids. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Solid tumor-targeted infiltrating cytotoxic T lymphocytes retained by a superantigen fusion protein.

    Directory of Open Access Journals (Sweden)

    Jialin Sun

    Full Text Available Successful immune-mediated regression of solid tumors is difficult because of the small number of cytotoxic T lymphocytes (CTLs that were traffic to the tumor site. Here, the targeting of tumor-specific infiltrating CTLs was dependent on a fusion protein consisting of human epidermal growth factor (EGF and staphylococcal enterotoxin A (SEA with the D227A mutation. EGF-SEA strongly restrained the growth of murine solid sarcoma 180 (S180 tumors (control versus EGF-SEA, mean tumor weight: 1.013 versus 0.197 g, difference  = 0.816 g. In mice treated with EGF-SEA, CD4+, CD8+ and SEA-reactive T lymphocytes were enriched around the EGFR expressing tumor cells. The EGF receptors were potentially phosphorylated by EGF-SEA stimulation and the fusion protein promoted T cells to release the tumoricidal cytokines interferon-γ (IFN-γ and tumor necrosis factor-α (TNF-α. Intratumoral CTLs secreted cytolytic pore-forming perforins and granzyme B proteins near the surface of carcinomas, causing the death of many tumor cells. We additionally show that labeled EGF-SEA was directly targeted to the tumor tissue after intravenous (i.v. injection. The findings demonstrate that antibody-like EGF-SEA plays an important role in arresting CTLs in the solid tumor site and has therapeutic potential as a tumor-targeting agent.

  18. Tumor Targeting Using Radiolabeled Antibodies for Image-Guided Drug Delivery.

    Science.gov (United States)

    Rijpkema, Mark; Boerman, Otto C; Oyen, Wim J G

    2015-01-01

    Due to their high target affinity and specificity, antibodies are very suitable tumor-targeting vehicles for imaging and therapeutic application. This enables a theranostic approach of imaging targeted drug delivery in oncology and opens the way for personalized medicine, predicting drug delivery, response, and treatment outcome in the individual patient. Of the currently available molecular imaging techniques, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are the best suited imaging techniques to visualize and determine drug delivery to the target tissue quantitatively. Using the same antibody for imaging and targeted therapy may eliminate some limitations of antibody-based molecular imaging and therapy, like heterogeneous antigen expression and poor accessibility. However, challenges of this approach remain, for example in the pharmacokinetic behavior of radiolabeled antibodies and antibody-drug-conjugates. Despite these challenges, also exciting opportunities are at the horizon, by using antibodies as multimodal vehicles carrying both a diagnostic agent and a therapeutic agent. In this review, both the challenges and the opportunities of using radiolabeled antibodies for image-guided drug delivery are discussed.

  19. Identification of a New Peptide for Fibrosarcoma Tumor Targeting and Imaging In Vivo

    Directory of Open Access Journals (Sweden)

    Chia-Che Wu

    2010-01-01

    Full Text Available A 12-mer amino acid peptide SATTHYRLQAAN, denominated TK4, was isolated from a phage-display library with fibrosarcoma tumor-binding activity. In vivo biodistribution analysis of TK4-displaying phage showed a significant increased phage titer in implanted tumor up to 10-fold in comparison with normal tissues after systemic administration in mouse. Competition assay confirmed that the binding of TK4-phage to tumor cells depends on the TK4 peptide. Intravenous injection of 131I-labeled synthetic TK4 peptide in mice showed a tumor retention of 3.3% and 2.7% ID/g at 1- and 4-hour postinjection, respectively. Tumor-to-muscle ratio was 1.1, 5.7, and 3.2 at 1-, 4-, and 24-hour, respectively, and tumors were imaged on a digital γ-camera at 4-hour postinjection. The present data suggest that TK4 holds promise as a lead structure for tumor targeting, and it could be further applied in the development of diagnostic or therapeutic agent.

  20. Tumor targeting using polyamidoamine dendrimer-cisplatin nanoparticles functionalized with diglycolamic acid and herceptin.

    Science.gov (United States)

    Kesavan, Akila; Ilaiyaraja, P; Sofi Beaula, W; Veena Kumari, Vuttaradhi; Sugin Lal, J; Arunkumar, C; Anjana, G; Srinivas, Satish; Ramesh, Anita; Rayala, Suresh Kumar; Ponraju, D; Venkatraman, Ganesh

    2015-10-01

    Polymer mediated drug delivery system represents a novel promising platform for tumor-targeting with reduced systemic side effects and improved chemotherapeutical efficacy. In this study, we report the preparation and characterization of herceptin targeted, diglycolamic acid (DGA) functionalized polyamidoamine (PAMAM) dendrimer as a potent drug carrier for cisplatin. DGA dendrimers carrying cisplatin demonstrated enhanced anticancer activity when targeted with herceptin. In vitro cell line studies with herceptin-DGA-G4-cisplatin in HER-2 +ve and HER-2 -ve human ovarian cancer cell lines showed that these nanoparticles possessed remarkable features such as lower IC50 value, improved S-phase arrest, and enhanced apoptosis due to increased cellular uptake and accumulation than the untargeted DGA-G4-cisplatin and free cisplatin. Furthermore, in vivo results in SCID mice bearing SKOV-3 tumor xenografts, herceptin-DGA-G4-cisplatin, appeared to be more effective in inducing tumor regression as compared to free cisplatin. Collectively, these results indicate that herceptin targeted DGA functionalized PAMAM-cisplatin conjugates serve as better anti-tumor agents than individual therapeutic agents. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Identification of a New Peptide for Fibrosarcoma Tumor Targeting and Imaging In Vivo

    Science.gov (United States)

    Wu, Chia-Che; Lin, Erh-Hsuan; Lee, Yu-Ching; Tai, Cheng-Jeng; Kuo, Tsu-Hsiang; Wang, Hsin-Ell; Luo, Tsai-Yueh; Fu, Ying-Kai; Chen, Haw-Jan; Sun, Ming-Ding; Wu, Chih-Hsiung; WU, Cheng-Wen; Leu, Sy-Jye; Deng, Win-Ping

    2010-01-01

    A 12-mer amino acid peptide SATTHYRLQAAN, denominated TK4, was isolated from a phage-display library with fibrosarcoma tumor-binding activity. In vivo biodistribution analysis of TK4-displaying phage showed a significant increased phage titer in implanted tumor up to 10-fold in comparison with normal tissues after systemic administration in mouse. Competition assay confirmed that the binding of TK4-phage to tumor cells depends on the TK4 peptide. Intravenous injection of 131I-labeled synthetic TK4 peptide in mice showed a tumor retention of 3.3% and 2.7% ID/g at 1- and 4-hour postinjection, respectively. Tumor-to-muscle ratio was 1.1, 5.7, and 3.2 at 1-, 4-, and 24-hour, respectively, and tumors were imaged on a digital γ-camera at 4-hour postinjection. The present data suggest that TK4 holds promise as a lead structure for tumor targeting, and it could be further applied in the development of diagnostic or therapeutic agent. PMID:21151669

  2. Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides.

    Science.gov (United States)

    Dissanayake, Shama; Denny, William A; Gamage, Swarna; Sarojini, Vijayalekshmi

    2017-03-28

    Efficient intracellular trafficking and targeted delivery to the site of action are essential to overcome the current drawbacks of cancer therapeutics. Cell Penetrating Peptides (CPPs) offer the possibility of efficient intracellular trafficking, and, therefore the development of drug delivery systems using CPPs as cargo carriers is an attractive strategy to address the current drawbacks of cancer therapeutics. Additionally, the possibility of incorporating Tumor Targeting Peptides (TTPs) into the delivery system provides the necessary drug targeting effect. Therefore the conjugation of CPPs and/or TTPs with therapeutics provides a potentially efficient method of improving intracellular drug delivery mechanisms. Peptides used as cargo carriers in DDS have been shown to enhance the cellular uptake of drugs and thereby provide an efficient therapeutic benefit over the drug on its own. After providing a brief overview of various drug targeting approaches, this review focusses on peptides as carriers and targeting moieties in drug-peptide covalent conjugates and summarizes the most recent literature examples where CPPs on their own or CPPs together with TTPs have been conjugated to anticancer drugs such as Doxorubicin, Methotrexate, Paclitaxel, Chlorambucil etc. A short section on CPPs used in multicomponent drug delivery systems is also included. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Matrix Metalloprotease 2-Responsive Multifunctional Liposomal Nanocarrier for Enhanced Tumor Targeting

    Science.gov (United States)

    Zhu, Lin; Kate, Pooja; Torchilin, Vladimir P.

    2012-01-01

    A novel “smart” multifunctional drug delivery system was successfully developed to respond to the up-regulated matrix metalloprotease 2 (MMP2) in the tumor microenvironment and improve cancer cell-specific delivery of loaded drugs. The system represents a surface-functionalized liposomal nanocarrier, for which two functional polyethylene glycol (PEG)-lipid conjugates were synthesized and characterized. The functionalized liposome was further modified with the tumor cell-specific anti-nucleosome monoclonal antibody (mAb 2C5). In the resulting system, several drug delivery strategies were combined in the same nanocarrier in a simple way and coordinated in an optimal fashion. The functions of the nanocarrier include: i) the hydrophilic and flexible long PEG chains to prevent nanocarrier non-specific interactions and prolong its circulation time; ii) a nanoscale size of the system that allows for its passive tumor targeting via the enhanced permeability and retention (EPR) effect; iii) a mAb 2C5 to allow for the specific targeting of tumor cells; iv) a matrix metalloprotease 2-sensitive bond between PEG and lipid that undergoes cleavage in the tumor by the highly expressed extracellular MMP2 for the removal of PEG chains; v) The cell-penetrating peptide (TATp) triggering of the enhanced intracellular delivery of the system after long-chain PEG removal and exposure of the previously hidden surface-attached TATp. It is shown that such a design can enhance the targetability and internalization of nanocarriers in cancer cells. PMID:22409425

  4. Tumor targeting with a (99m)Tc-labeled AS1411 aptamer in prostate tumor cells.

    Science.gov (United States)

    Noaparast, Zohreh; Hosseinimehr, Seyed Jalal; Piramoon, Majid; Abedi, Seyed Mohammad

    2015-01-01

    AS1411, a 26-base guanine-rich oligonucleotide aptamer, has high affinity to nucleolin, mainly on tumor cell surfaces. In this study, a modified AS1411 was labeled with (99m)Tc and evaluated as a potential tumor-targeting agent for imaging. The AS1411 aptamer was conjugated with HYNIC and labeled with (99m)Tc in the presence a co-ligand. Radiochemical purity and stability testing of the (99m)Tc-HYNIC-AS1411 aptamer were carried out with thin layer chromatography and a size-exclusion column in normal saline and human serum. Cellular nucleolin-specific binding, cellular internalization in DU-145 cells, as high levels of nucleolin expression, were performed. Additionally, biodistribution in normal mice and DU-145 tumour-bearing mice was assessed. Radiolabeling of the aptamer resulted in a reasonable yield and radiochemical purity after purification. The aptamer was stable in normal saline and human serum, and cellular experiments demonstrated specific binding of the AS1411 aptamer to the nucleolin protein. Based on biodistribution assessment of (99m)Tc-HYNIC-AS1411, rapid blood clearance was seen after injection and it appears that the excretion route was via the urinary system at 1 h post-injection. Tumours also showed a higher accumulation of radioactivity with this labeled aptamer. (99m)Tc-AS1411 can be a potential tool for the molecular imaging of nucleolin-overexpressing cancers.

  5. Recombinant expression and purification of a tumor-targeted toxin in Bacillus anthracis

    Energy Technology Data Exchange (ETDEWEB)

    Bachran, Christopher; Abdelazim, Suzanne; Fattah, Rasem J.; Liu, Shihui [National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 (United States); Leppla, Stephen H., E-mail: sleppla@niaid.nih.gov [National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 (United States)

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Non-infectious and protease-deficient Bacillus anthracis protein expression system. Black-Right-Pointing-Pointer Successful expression and purification of a tumor-targeted fusion protein drug. Black-Right-Pointing-Pointer Very low endotoxin contamination of purified protein. Black-Right-Pointing-Pointer Efficient protein secretion simplifies purification. Black-Right-Pointing-Pointer Functional anti-tumor fusion protein purified. -- Abstract: Many recombinant therapeutic proteins are purified from Escherichia coli. While expression in E. coli is easily achieved, some disadvantages such as protein aggregation, formation of inclusion bodies, and contamination of purified proteins with the lipopolysaccharides arise. Lipopolysaccharides have to be removed to prevent inflammatory responses in patients. Use of the Gram-positive Bacillus anthracis as an expression host offers a solution to circumvent these problems. Using the multiple protease-deficient strain BH460, we expressed a fusion of the N-terminal 254 amino acids of anthrax lethal factor (LFn), the N-terminal 389 amino acids of diphtheria toxin (DT389) and human transforming growth factor alpha (TGF{alpha}). The resulting fusion protein was constitutively expressed and successfully secreted by B. anthracis into the culture supernatant. Purification was achieved by anion exchange chromatography and proteolytic cleavage removed LFn from the desired fusion protein (DT389 fused to TGF{alpha}). The fusion protein showed the intended specific cytotoxicity to epidermal growth factor receptor-expressing human head and neck cancer cells. Final analyses showed low levels of lipopolysaccharides, originating most likely from contamination during the purification process. Thus, the fusion to LFn for protein secretion and expression in B. anthracis BH460 provides an elegant tool to obtain high levels of lipopolysaccharide-free recombinant protein.

  6. Tumor targeting HPMA-porphyrin-99mTc copolymer molecular imaging agent.

    Science.gov (United States)

    Yuan, Long; Ma, Yabing; Yuan, Jianchao

    2014-01-01

    Porphyrins typically show preferential uptake and retention by tumor tissues via receptor-mediated endocytosis of low-density lipoproteins. To investigate the relative importance of active and passive targeting strategies, the synthesis, characterization, in vitro uptake, and in vivo biodistribution of specific targeting porphyrin HPMA [HPMA: N-(2-hydroxypropyl)methacrylamide] copolymer tracer poly(HPMA)-porphyrin-DTPA-(99m)Tc (DTPA: diethylenetriaminepentaacetic acid), nonspecific targeting HPMA copolymer tracer poly(HPMA)-DTPA-(99m)Tc, and nontargeting tracer DTPA-(99m)Tc are described in this study. The results showed that the cellular accumulation of poly(HPMA)-porphyrin-DTPA-(99m)Tc complex was found to be time-dependent. The uptake of poly(HPMA)-porphyrin-DTPA-(99m)Tc was significantly higher than that of poly(HPMA)-DTPA-(99m)Tc, indicating that uptake of the poly(HPMA)-porphyrin-DTPA-(99m)Tc was active binding. The uptake of poly(HPMA)-DTPA-(99m)Tc was significantly higher than that of DTPA-(99m)Tc, suggesting that uptake of the poly(HPMA)-DTPA-(99m)Tc was passive binding. Twenty-four hour necropsy data in the hepatocellular carcinoma tumor model showed significantly higher (p HPMA)-porphyrin-DTPA-(99m)Tc (5.18 ± 0.50% ID/g [percentage injected dose per gram tissue]) compared with poly(HPMA)-DTPA-(99m)Tc (2.69 ± 0.15% ID/g) and DTPA-(99m)Tc (0.83 ± 0.03% ID/g). Moreover, higher T/B for poly(HPMA)-porphyrin-DTPA-(99m)Tc indicated reduced extravasation of the targeted polymeric conjugates in normal tissues. Thus, the poly(HPMA)-porphyrin-DTPA-(99m)Tc is a potential macromolecular tumor targeting molecular agent.

  7. Oncolytic Adenovirus and Tumor-Targeting Immune Modulatory Therapy Improve Autologous Cancer Vaccination.

    Science.gov (United States)

    Jiang, Hong; Rivera-Molina, Yisel; Gomez-Manzano, Candelaria; Clise-Dwyer, Karen; Bover, Laura; Vence, Luis M; Yuan, Ying; Lang, Frederick F; Toniatti, Carlo; Hossain, Mohammad B; Fueyo, Juan

    2017-07-15

    Oncolytic viruses selectively lyse tumor cells, disrupt immunosuppression within the tumor, and reactivate antitumor immunity, but they have yet to live up to their therapeutic potential. Immune checkpoint modulation has been efficacious in a variety of cancer with an immunogenic microenvironment, but is associated with toxicity due to nonspecific T-cell activation. Therefore, combining these two strategies would likely result in both effective and specific cancer therapy. To test the hypothesis, we first constructed oncolytic adenovirus Delta-24-RGDOX expressing the immune costimulator OX40 ligand (OX40L). Like its predecessor Delta-24-RGD, Delta-24-RGDOX induced immunogenic cell death and recruit lymphocytes to the tumor site. Compared with Delta-24-RGD, Delta-24-RGDOX exhibited superior tumor-specific activation of lymphocytes and proliferation of CD8+ T cells specific to tumor-associated antigens, resulting in cancer-specific immunity. Delta-24-RGDOX mediated more potent antiglioma activity in immunocompetent C57BL/6 but not immunodeficient athymic mice, leading to specific immune memory against the tumor. To further overcome the immune suppression mediated by programmed death-ligand 1 (PD-L1) expression on cancer cells accompanied with virotherapy, intratumoral injection of Delta-24-RGDOX and an anti-PD-L1 antibody showed synergistic inhibition of gliomas and significantly increased survival in mice. Our data demonstrate that combining an oncolytic virus with tumor-targeting immune checkpoint modulators elicits potent in situ autologous cancer vaccination, resulting in an efficacious, tumor-specific, and long-lasting therapeutic effect. Cancer Res; 77(14); 3894-907. ©2017 AACR. ©2017 American Association for Cancer Research.

  8. Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide

    Energy Technology Data Exchange (ETDEWEB)

    Park, Ji-Ae, E-mail: jpark@kirams.re.kr [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Yong Jin; Ko, In Ok [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Tae-Jeong; Chang, Yongmin [Institute of Biomedical Engineering, Kyungpook National University, Daegu (Korea, Republic of); Lim, Sang Moo [Department of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Kyeong Min [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Jung Young, E-mail: jykim@kirams.re.kr [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2014-12-12

    Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.

  9. Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice

    OpenAIRE

    Miwa, Shinji; Yano, Shuya; Zhang, Yong; Matsumoto,Yasunori; Uehara, Fuminari; Yamamoto, Mako; Hiroshima, Yukihiko; Kimura, Hiroaki; Hayashi, Katsuhiro; Yamamoto, Norio; Bouvet, Michael; Tsuchiya, Hiroyuki; Hoffman, Robert M.; Zhao, Ming

    2014-01-01

    Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely...

  10. Macromolecular pHPMA-based nanoparticles with cholesterol for solid tumor targeting: behavior in HSA protein environment

    Czech Academy of Sciences Publication Activity Database

    Zhang, X.; Niebuur, B.-J.; Chytil, Petr; Etrych, Tomáš; Filippov, Sergey K.; Kikhney, A.; Wieland, D. C. F.; Svergun, D. I.; Papadakis, C. M.

    2018-01-01

    Roč. 19, č. 2 (2018), s. 470-480 ISSN 1525-7797 R&D Projects: GA ČR(CZ) GC15-10527J; GA MZd(CZ) NV16-28594A; GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : polymer carriers * N-(2-hydroxypropyl)methacrylamide * tumor targeting Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 5.246, year: 2016

  11. A survey of characteristics of self-immolation in the northern Iran ...

    African Journals Online (AJOL)

    Background: Suicide is an action deliberately initiated and performed by a person with complete awareness of its fatal outcome, prevalence of which is very rare in developed countries, but it is reported with more frequency in Middle East including Iran. Aim: This study was carried out to analyze the characteristics, mortality, ...

  12. Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle

    Science.gov (United States)

    Dreaden, Erik C.; Kong, Yi Wen; Morton, Stephen W.; Correa, Santiago; Choi, Ki Young; Shopsowitz, Kevin E.; Renggli, Kasper; Drapkin, Ronny; Yaffe, Michael B.; Hammond, Paula T.

    2015-01-01

    Purpose Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways—horizontal blockade—is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. Experimental Design AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation—layer-by-layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, Western blotting, serum cytokine analysis, and immunohistochemistry. Results Combined MAPK and PI3K axis blockade from the nanoscale formulations (160 ± 20 nm, −40 ± 1 mV) was synergistically toxic toward triple-negative breast (MDA-MB-231) and RAS-mutant lung tumor cells (KP7B) in vitro, effects that were further enhanced upon encapsulation. In vivo, systemically administered LbL nanoparticles preferentially targeted subcutaneous MDA-MB-231 tumor xenografts, simultaneously blocked tumor-specific phosphorylation of the terminal kinases Erk and Akt, and elicited significant disease stabilization in the absence of dose-limiting hepatotoxic effects observed from the free drug combination. Mice receiving untargeted, but dual drug-loaded nanoparticles exhibited progressive disease. Conclusions Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic. PMID:26034127

  13. Bilayered near-infrared fluorescent nanoparticles based on low molecular weight PEI for tumor-targeted in vivo imaging

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Hao; Li, Ke [Xi’an Jiaotong University, Key Laboratory of Biomedical Information Engineering of Education Ministry, School of Life Science and Technology (China); Xu, Liang [The University of Kansas, Department of Molecular Biosciences (United States); Wu, Daocheng, E-mail: wudaocheng@mail.xjtu.edu.cn [Xi’an Jiaotong University, Key Laboratory of Biomedical Information Engineering of Education Ministry, School of Life Science and Technology (China)

    2014-12-15

    To improve the tumor fluorescent imaging results in vivo, bilayered nanoparticles encapsulating a lipophilic near-infrared (NIR) fluorescent dye 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotri-carbocyanine iodide (DiR) were prepared using low molecular weight stearic acid-grafted polyethyleneimine and hyaluronic acid (DiR-PgSHA nanoparticles), which were investigated as a novel NIR fluorescent nano-probe for in vivo tumor-targeted optical imaging. These nanoparticles were characterized by transmission electron microscopy (TEM), infrared (IR) spectra, UV-visual absorption, and fluorescent emission spectra. Their cytotoxicity in vitro and hepatotoxicity in vivo were tested by MTT assay and histological study, respectively. In vivo NIR fluorescence imaging of the DiR-PgSHA nanoparticles was performed using a Carestream imaging system. The DiR-PgSHA nanoparticles were sphere shaped with a diameter of approximately 50 nm according to the TEM images. The DiR-PgSHA nanoparticles had a low cytotoxicity in vitro according to the MTT assay and low hepatotoxicity in vivo as determined in histological studies. The fluorescent emission of DiR-PgSHA nanoparticles was stable in pH values of 5–9 in solution, with only slight blue-shifts of the emission maxima at the basic pH range. The DiR-PgSHA nanoparticles exhibited a substantial tumor-targeting ability in the optical imaging with the use of tumor-bearing mice. These results demonstrated that the DiR-PgSHA nanoparticle is an excellent biocompatible nano-probe for in vivo tumor-targeted NIR fluorescence imaging with a potential for clinical applications.

  14. Zinc phthalocyanine conjugated with the amino-terminal fragment of urokinase for tumor-targeting photodynamic therapy.

    Science.gov (United States)

    Chen, Zhuo; Xu, Peng; Chen, Jincan; Chen, Hongwei; Hu, Ping; Chen, Xueyuan; Lin, Lin; Huang, Yunmei; Zheng, Ke; Zhou, Shanyong; Li, Rui; Chen, Song; Liu, Jianyong; Xue, Jinping; Huang, Mingdong

    2014-10-01

    Photodynamic therapy (PDT) has attracted much interest for the treatment of cancer due to the increased incidence of multidrug resistance and systemic toxicity in conventional chemotherapy. Phthalocyanine (Pc) is one of main classes of photosensitizers for PDT and possesses optimal photophysical and photochemical properties. A higher specificity can ideally be achieved when Pcs are targeted towards tumor-specific receptors, which may also facilitate specific drug delivery. Herein, we develop a simple and unique strategy to prepare a hydrophilic tumor-targeting photosensitizer ATF-ZnPc by covalently coupling zinc phthalocyanine (ZnPc) to the amino-terminal fragment (ATF) of urokinase-type plasminogen activator (uPA), a fragment responsible for uPA receptor (uPAR, a biomarker overexpressed in cancer cells), through the carboxyl groups of ATF. We demonstrate the high efficacy of this tumor-targeting PDT agent for the inhibition of tumor growth both in vitro and in vivo. Our in vivo optical imaging results using H22 tumor-bearing mice show clearly the selective accumulation of ATF-ZnPc in tumor region, thereby revealing the great potential of ATF-ZnPc for clinical applications such as cancer detection and guidance of tumor resection in addition to photodynamic treatment. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  15. Nano-sized metabolic precursors for heterogeneous tumor-targeting strategy using bioorthogonal click chemistry in vivo.

    Science.gov (United States)

    Lee, Sangmin; Jung, Seulhee; Koo, Heebeom; Na, Jin Hee; Yoon, Hong Yeol; Shim, Man Kyu; Park, Jooho; Kim, Jong-Ho; Lee, Seulki; Pomper, Martin G; Kwon, Ick Chan; Ahn, Cheol-Hee; Kim, Kwangmeyung

    2017-12-01

    Herein, we developed nano-sized metabolic precursors (Nano-MPs) for new tumor-targeting strategy to overcome the intrinsic limitations of biological ligands such as the limited number of biological receptors and the heterogeneity in tumor tissues. We conjugated the azide group-containing metabolic precursors, triacetylated N-azidoacetyl-d-mannosamine to generation 4 poly(amidoamine) dendrimer backbone. The nano-sized dendrimer of Nano-MPs could generate azide groups on the surface of tumor cells homogeneously regardless of cell types via metabolic glycoengineering. Importantly, these exogenously generated 'artificial chemical receptors' containing azide groups could be used for bioorthogonal click chemistry, regardless of phenotypes of different tumor cells. Furthermore, in tumor-bearing mice models, Nano-MPs could be mainly localized at the target tumor tissues by the enhanced permeation and retention (EPR) effect, and they successfully generated azide groups on tumor cells in vivo after an intravenous injection. Finally, we showed that these azide groups on tumor tissues could be used as 'artificial chemical receptors' that were conjugated to bioorthogonal chemical group-containing liposomes via in vivo click chemistry in heterogeneous tumor-bearing mice. Therefore, overall results demonstrated that our nano-sized metabolic precursors could be extensively applied to new alternative tumor-targeting technique for molecular imaging and drug delivery system, regardless of the phenotype of heterogeneous tumor cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Drug-Induced Self-Assembly of Modified Albumins as Nano-theranostics for Tumor-Targeted Combination Therapy.

    Science.gov (United States)

    Chen, Qian; Wang, Xin; Wang, Chao; Feng, Liangzhu; Li, Yonggang; Liu, Zhuang

    2015-05-26

    Paclitaxel (PTX) can bind to human serum albumin (HSA) via hydrophobic interaction, forming Abraxane, which is a U.S. Food and Drug Administration (FDA) approved effective antitumor nanomedicine drug. Herein, the effective antitumor drug PTX is used to induce the self-assembly of HSA modified with either a photosensitizer chlorin e6 (Ce6), which at the same time serves as a chelating agent for Mn(2+) to enable magnetic resonance imaging, or acyclic Arg-Gly-Asp (cRGDyK) peptide that targets αvβ3-integrin overexpressed on tumor angiogenic endothelium. Two types of tumor-targeting theranostic nanoparticles are constructed, either by coassembly of both HSA-Ce6 and HSA-RGD simultaneously or by forming an HSA-Ce6@HSA-RGD core-shell structure, with the assistance of PTX-induced albumin aggregation. Such albumin-based nanoparticles on one hand could targetαvβ3-integrin, as evidenced by both in vitro and in vivo experiments, and on the other hand enable combined photodynamic/chemotherapy, which offers remarkably improved therapeutic efficacy to kill cancer in comparison to the respective monotherapies. Our work presents a new type of tumor-targeted multifunctional albumin-based nanoparticles by drug-induced self-assembly, which is a rather simple method without any sophisticated chemistry or materials engineering and is promising for multimodel imaging-guided combination therapy of cancer.

  17. On the hypoxic tumor targeting ability of two chitosan micelles loaded with oil-soluble CdSe quantum dots.

    Science.gov (United States)

    Zhang, Shengyu; Zhao, Liuwan; Qiu, Nanqin; Liu, Yanjun; Xu, Bohui; Zhu, Hongyan

    2018-01-01

    Hypoxia, an outstanding characteristic of various solid tumors, has been considered a critical factor of aggressive tumor phenotypes, poor clinical prognosis, and increased expression of the multidrug-resistant gene. Therefore, it is critical to develop a drug delivery system to enhance the delivery effect of the antitumor drug in the hypoxic tumor. We constructed two types of tumor targeting micelles based on chitosan and evaluated their properties in targeting hypoxic tumors. Chitosan-based micelles consisted of a hydrophobic group octyl group, a hydrophilic polyethylene glycol, tumor targeting ligands glucosamine or folic acid, and a transmembrane peptide 9-d-arginine. The molecular structure, morphology, size distribution, zeta potential, and biosafety of two micelles were characterized. Oil-soluble CdSe quantum dots were used as a fluorescent probe to evaluate the hypoxic tumor cell targeting properties of the micelles. Moreover, HepG2 human hepatocellular carcinoma cells and HeLa human cervical carcinoma cells were used as in vitro models. We demonstrated that, under hypoxic conditions, two chitosan micelles showed better targeting ability to HepG2 and HeLa cells, which enhanced the effect of antitumor drugs by specifically targeting transport in hypoxic tumors. Therefore, chitosan micelles may be a potential drug delivery system that can be used to deliver antitumor drugs to hypoxic tumors.

  18. Tumor-targeting templated silica nanoparticles as a dual-drug delivery system for anti-angiogenic ovarian cancer therapy

    Science.gov (United States)

    Zheng, Tianying; Wang, Aijun; Hu, Dongyan; Wang, Yonggang

    2017-01-01

    The present study indicated the successful construction of a silica nanoparticle (SLN)-based drug delivery system (DDS) for the tumor-targeted co-delivery of two anti-angiogenic drugs, candesartan (CD) and trastuzumab (Tra), for ovarian cancer therapy via different anti-angiogenic mechanisms using hyaluronic acid (HA)/Tra/CD/SLNs. In vitro and in vivo anti-angiogenic assays indicated that CD and Tra exert beneficial functions on suppressing cancer angiogenesis, and exhibited significantly enhanced effects compared with the angiotensin stimulated group (PTra co-delivery also significantly increased the anti-angiogenic effect compared with applying either drug alone (PTra/CD/SLNs may be a preferable formulation for anti-angiogenic ovarian cancer therapy. PMID:28962137

  19. Preparation and bioevaluation of a {sup 99m}Tc-labeled chlorambucil analog as a tumor targeting agent

    Energy Technology Data Exchange (ETDEWEB)

    Satpati, Drishty; Korde, Aruna; Venkatesh, Meera [Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400085 (India); Banerjee, Sharmila [Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400085 (India)], E-mail: sharmila@barc.gov.in

    2009-09-15

    Chlorambucil belongs to a group of nitrogen mustards which are used for the treatment of variety of cancers. Hence, a chlorambucil derivative has been radiolabeled with [{sup 99m}Tc(CO){sub 3}(H{sub 2}O){sub 3}]{sup +} core and its efficacy as a tumor targeting agent has been evaluated. Radiochemical yield of the complex was >98% as observed by HPLC. The in vitro studies in MCF-7 breast cancer cells showed about 30% inhibition of the radiolabeled complex in presence of the cold chlorambucil derivative. Biodistribution studies in Swiss mice bearing fibrosarcoma tumor showed an uptake of 3.2{+-}0.3% ID/g at 3 h.p.i.

  20. Rapid and accurate tumor-target bio-imaging through specific in vivo biosynthesis of a fluorescent europium complex.

    Science.gov (United States)

    Ye, Jing; Wang, Jianling; Li, Qiwei; Dong, Xiawei; Ge, Wei; Chen, Yun; Jiang, Xuerui; Liu, Hongde; Jiang, Hui; Wang, Xuemei

    2016-04-01

    A new and facile method for rapidly and accurately achieving tumor targeting fluorescent images has been explored using a specifically biosynthesized europium (Eu) complex in vivo and in vitro. It demonstrated that a fluorescent Eu complex could be bio-synthesized through a spontaneous molecular process in cancerous cells and tumors, but not prepared in normal cells and tissues. In addition, the proteomics analyses show that some biological pathways of metabolism, especially for NADPH production and glutamine metabolism, are remarkably affected during the relevant biosynthesis process, where molecular precursors of europium ions are reduced to fluorescent europium complexes inside cancerous cells or tumor tissues. These results proved that the specific self-biosynthesis of a fluorescent Eu complex by cancer cells or tumor tissues can provide a new strategy for accurate diagnosis and treatment strategies in the early stages of cancers and thus is beneficial for realizing precise surgical intervention based on the relevant cheap and readily available agents.

  1. Fullerene (C60)-based tumor-targeting nanoparticles with "off-on" state for enhanced treatment of cancer.

    Science.gov (United States)

    Shi, Jinjin; Wang, Binghua; Wang, Lei; Lu, Tingting; Fu, Yu; Zhang, Hongling; Zhang, Zhenzhong

    2016-08-10

    The traditional drug delivery systems always suffer from the unexpected drug release during circulation and the sluggish release of drug in target site. To address the problem, an "off-on" type drug delivery system with precise control was developed in this study. Doxorubicin (DOX) was covalently conjugated to fullerene (C60) nanoaggregates via a reactive oxygen species (ROS)-sensitive thioketal linker (C60-DOX NPs), and then the hydrophilic shell (Distearoyl-sn-glycero-3-phosphoethanolamine-PEG-CNGRCK2HK3HK11, DSPE-PEG-NGR) was attached to the outer surface of C60-DOX, giving it (C60-DOX-NGR NP) excellent stability in physiological solutions and active tumor-targeting capacity. C60-DOX-NGR NPs were able to entrap DOX efficiently even at acidic environment (pH5.5) when they were "off" state. In sharp contrast, when the NPs were "on" state, a large number of ROS were generated by C60, leading to the breaking of ROS-sensitive linker, thereby enabling the burst release of DOX. The "off" or "on" state of C60-DOX-NGR NPs could be precisely remote-controlled by a 532nm laser (at a low power density) with a high spatial/temporal resolution. In the in vivo and in vitro studies, the C60-based drug delivery system with "off-on" state exhibited a high antitumor efficacy and a low toxicity to normal tissues due to its tumor-targeting ability, remote-controlled drug release property and combined therapeutic effect (photodynamic therapy combined with chemotherapy). Copyright © 2016 Elsevier B.V. All rights reserved.

  2. The effect of polyethylene glycol spacer chain length on the tumor-targeting potential of folate-modified PPI dendrimers

    Energy Technology Data Exchange (ETDEWEB)

    Thakur, Shrikant [Dr. Hari Singh Gour University, Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences (India); Tekade, Rakesh K., E-mail: rakeshtekade@yahoo.com [University of Hawai' i at Hilo, College of Pharmacy (United States); Kesharwani, Prashant, E-mail: prashant_pharmacy04@rediffmail.com; Jain, Narendra K., E-mail: jnarendr@yahoo.co.in [Dr. Hari Singh Gour University, Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences (India)

    2013-05-15

    The objective of the present investigation was to assess the tumor-targeting potential of ligand-spacer-engineered poly (propylene imine) (PPI) dendrimers as nanoscale drug delivery units for site-specific delivery of a model anticancer agent, docetaxel (DTX). PPI dendrimers were engineered by direct and indirect conjugation of folic acid (FA) via different types of polyethylene glycols (PEGs) [Mw (molecular weight): 1,000, 4,000, 6,000, 7,500] as spacers. The synthesized nanoconjugates (PPIFA, PPIP1FA, PPIP4FA, PPIP6FA, and PPIP7.5FA) were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance ({sup 1}H-NMR) and transmission electron microscopic (TEM) studies. Nanoconjugates were evaluated for entrapment, in vitro drug release (under various pH conditions) and hemolytic studies. Cell uptake and cytotoxicity studies were performed on human malignant cell lines (MCF-7) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [MTT] assay. This debut study explored the effect of PEG spacer length on the targeting potential of folate-conjugated 5.0 G PPI dendrimer. DTX entrapment and in vitro drug release from nanoconjugates augmented, and hemolytic toxicity of nanoconjugates slashed with the molecular weight of PEGs. Further, nanoconjugates with PEG 4000 displayed highest tumor-targeting potential as compared to other spacer conjugated nanoconjugates due to optimized steric hindrance and receptor mediated endocytosis among other PEGs. This work is expected to shed new light on the role of spacer chain length in targeting potential of folate-anchored dendrimer.Graphical Abstract.

  3. Enhanced anticancer efficacy of paclitaxel through multistage tumor-targeting liposomes modified with RGD and KLA peptides.

    Science.gov (United States)

    Sun, Jiawei; Jiang, Lei; Lin, Yi; Gerhard, Ethan Michael; Jiang, Xuehua; Li, Li; Yang, Jian; Gu, Zhongwei

    2017-01-01

    Mitochondria serve as both "energy factories" and "suicide weapon stores" of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Here, multistage tumor-targeting liposomes containing two targeted peptide-modified lipids, cRGD-PEG2000-DSPE and KLA-PEG2000-DSPE, were developed for encapsulation of the anticancer drug paclitaxel (PTX, RGD-KLA/PTX-Lips). Compared with Taxol (free PTX), RGD/PTX-Lips and KLA/PTX-Lips, the half-maximal inhibitory concentration (IC50) value of RGD-KLA/PTX-Lips in vitro was 1.9-, 36.7- and 22.7-fold lower with 4T1 cells, respectively, because of higher levels of cellular uptake. Similar results were also observed with human umbilical vascular endothelial cells (HUVECs). An apoptosis assay showed that the total apoptotic ratio of RGD-KLA/PTX-Lips was the highest because of the mitochondria-targeted drug delivery and the activation of mitochondrial apoptosis pathways, as evidenced by visible mitochondrial localization, decreased mitochondrial membrane potential, release of cytochrome c and increased activities of caspase-9 and caspase-3. The strongest tumor growth inhibition (TGI; 80.6%) and antiangiogenesis effects without systemic toxicity were also observed in RGD-KLA/PTX-Lip-treated 4T1 tumor xenograft BALB/c mice. In conclusion, these multistage tumor-targeting liposomes represent a promising anticancer drug delivery system (DDS) capable of maximizing anticancer therapeutic efficacy and minimizing systemic toxicity.

  4. Integrin αvβ3 targeting activity study of different retro-inverso sequences of RGD and their potentiality in the designing of tumor targeting peptides.

    Science.gov (United States)

    Liu, Yayuan; Mei, Ling; Yu, Qianwen; Zhang, Qianyu; Gao, Huile; Zhang, Zhirong; He, Qin

    2015-12-01

    Retro-inverso peptide represented the isomer of a parent peptide in which the direction of the sequence was reversed and the chirality of each amino acid residue was inverted. Generally, retro-inverso peptides possessed equal or even higher activities compared to the original peptide. RGD was a commonly used ligand for tumor and vascular targeting due to its affinity to integrin αvβ3 receptors. The biological activity study of the isomers of RGD would indeed provide useful suggestions for the design of tumor targeting peptides. Therefore, the tumor targeting activities of octa-arginine which was modified with different retro-inverso sequences of RGD peptide were investigated in this study. Three different tandem peptides (R8-GDGR, R8-GdGr and R8-GdGR) were designed on the basis of R8-GRGD. The tumor targeting activities of these tandem peptides were evaluated both in vitro and in vivo. Finally, R8-GdGR displayed selective binding affinity to integrin αvβ3 at the cellular level, and exhibited efficient tumor homing and penetrating capabilities in vivo. Meanwhile, R8-GdGR also showed stronger neovessel targeting ability compared to the others. In conclusion, all the results demonstrated that dGR possessed similar biological activity to RGD and was a potential ligand for further designing of tumor targeting peptides.

  5. Characterization of tumor-targeting Ag2S quantum dots for cancer imaging and therapy in vivo

    Science.gov (United States)

    Chen, Haiyan; Li, Bowen; Zhang, Min; Sun, Kang; Wang, Yiran; Peng, Kerui; Ao, Mengdi; Guo, Yiran; Gu, Yueqing

    2014-10-01

    Nanomedicine platforms that have the potential to simultaneously provide the function of molecular imaging and therapeutic treatment in one system are beneficial to address the challenges of cancer heterogeneity and adaptive resistance. In this study, Cyclic RGD peptide (cRGD), a less-expensive active tumor targeting tri-peptide, and doxorubicin (DOX), a widely used chemotherapeutic drug, were covalently attached to Ag2S quantum dots (QDs) to form the nano-conjugates Ag2S-DOX-cRGD. The optical characterization of Ag2S-DOX-cRGD manifested the maintenance of QDs fluorescence, which suggested the potential of Ag2S for monitoring intracellular and systemic drug distribution. The low biotoxicity of Ag2S QDs indicated that they are promisingly safe nanoparticles for bio-applications. Furthermore, the selective imaging and favorable tumor inhibition of the nanoconjugates were demonstrated at both cell and animal levels. These results indicated a promising future for the utilization of Ag2S QDs as a kind of multi-functional nano platform to achieve imaging-visible nano-therapeutics.

  6. Enhanced tumor targeting and antitumor efficacy via hydroxycamptothecin-encapsulated folate-modified N-succinyl-N'-octyl chitosan micelles.

    Science.gov (United States)

    Zhu, Hongyan; Cao, Jie; Cui, Sisi; Qian, Zhiyu; Gu, Yueqing

    2013-04-01

    10-Hydroxycamptothecin (HCPT) is an effective anticancer drug against various types of solid tumors. But the antitumor efficacy of HCPT is far from satisfactory because of its poor physicochemical properties, short circulating half-life, low stability, and nonspecific toxicity to normal tissues. Therefore, a targeted delivery strategy for HCPT to pathological sites is eagerly needed to overcome these limitations. The folate-modified N-succinyl-N'-octyl chitosan (folate-SOC) micelle was chosen in this study and served as the targeted delivery system for HCPT to improve the antitumor efficacy. The water-insoluble anticancer drug HCPT was encapsulated into the folate-SOC micelles by the dialysis method. The near-spherical HCPT-loaded folate-SOC (HCPT/folate-SOC) micelles were formed in aqueous media with diameter of about 100-200 nm. The HCPT/folate-SOC micelles displayed a good stability, reasonable drug-loading content (about 10%), and sustained release behavior for the water-insoluble HCPT. Compared with free HCPT, HCPT/folate-SOC micelles exhibited a significant enhancement of cellular uptake, higher cytotoxicity against folate receptor positive tumor cell (Bel-7402), excellent tumor-targeting capability and substantially better antitumor efficacy on the nude mice bearing Bel-7402 xenografts. These results demonstrate the potential of folate-SOC micelles as long-term stable and effective drug delivery systems in cancer therapy. Copyright © 2013 Wiley Periodicals, Inc.

  7. Chaperonin-GroEL as a Smart Hydrophobic Drug Delivery and Tumor Targeting Molecular Machine for Tumor Therapy.

    Science.gov (United States)

    Yuan, Yi; Du, Chong; Sun, Cuiji; Zhu, Jin; Wu, Shan; Zhang, Yinlong; Ji, Tianjiao; Lei, Jianlin; Yang, Yinmo; Gao, Ning; Nie, Guangjun

    2018-02-14

    The targeted delivery of hydrophobic therapeutic drugs to tumors is one of the major challenges in drug development. The use of natural proteins as drug delivery vehicles holds great promise due to various functionalities of proteins. In the current study, we exploited a natural protein, GroEL, which possesses a double layer cage structure, as a hydrophobic drug container, which is switchable by ATP binding to a hydrophilic status, to design a novel and intelligent hydrophobic drug delivery molecular machine with a controlled drug release profile. When loaded with the hydrophobic antitumor drug, Doxorubicin (Dox), GroEL was able to shield the drug from the aqueous phase of blood, releasing the drug once in the presence of a critical concentration of ATP at the tumor site. Unexpectedly, we found that GroEL has a specific affinity for the cell structural protein, plectin, which is expressed at abnormally elevated levels on the membranes of tumor cells but not in normal cells. This finding, in combination with the ATP sensitivity, makes GroEL a superior natural tumor targeting nanocarrier. Our data show that GroEL-Dox is able to effectively, and highly selectively, deliver the hydrophobic drug to fast growing tumors without overt adverse effects on the major organs. GroEL is therefore a promising drug delivery platform that can overcome the obstacles to hydrophobic drug targeting and delivery.

  8. Germ Cell Tumor Targeting Chemotherapy in Gastric Adenocarcinoma with an Endodermal Sinus Tumor Component: A Case Report.

    Science.gov (United States)

    Choi, Jung Eun; Choe, A Reum; Yoon, Sang Eun; Nam, Eun Mi; Park, Heejung; Lee, Kyoung Eun

    2017-01-01

    The most common sites for extragonadal germ cell tumors are the midline mediastinum, retroperitoneum and, much less frequently, the stomach. The stomach-originated primary germ cell tumor carries a poor prognosis, especially when metastasis occurs to the liver, with a mean survival time of 1 month. We describe the case of a 77-year-old male who presented with usual symptoms of gastric malignancy. Gastrectomy was performed. Histopathology of surgically resected tissue revealed a mixture of adenocarcinoma and endodermal sinus tumor components with α-fetoprotein production. After liver metastasis was identified, oxaliplatin and capecitabine were administered as palliative chemotherapy. The response was poor. For the second-line therapy, bleomycin, etoposide, and cisplatin (BEP) therapy was initiated. The overall response to these drugs was a partial response and the residual liver lesion was considered to be resectable. The patient died of pneumonia 11 months following the BEP session, representing an overall survival time of 22 months. Gastric adenocarcinoma with a germ cell tumor component is uncommon and an effective combination of chemotherapeutic agents is not yet clear. In this case, the patient received germ cell tumor-targeting chemotherapy and showed a durable response. Hence, germ cell-targeting cytotoxic agents have potential as the 'front-line regimen'. © 2016 S. Karger AG, Basel.

  9. Facile synthesis of CdTe@GdS fluorescent-magnetic nanoparticles for tumor-targeted dual-modal imaging.

    Science.gov (United States)

    Zhang, Fei; Kong, Xiu-Qi; Li, Qiong; Sun, Ting-Ting; Chai, Chao; Shen, Wen; Hong, Zhang-Yong; He, Xi-Wen; Li, Wen-You; Zhang, Yu-Kui

    2016-01-01

    Multimodal imaging has made great contribution for diagnosis and therapy of disease since it can provide more effective and complementary information in comparison to any single imaging modality. The design and fabrication of fluorescent-magnetic nanoparticles for multimodal imaging has rapidly developed over the years. Herein, we demonstrate the facile synthesis of GdS coated CdTe nanoparticles (CdTe@GdS NPs) as multimodal agents for fluorescence (FL) and T1-weighted magnetic resonance (MR) imaging. These nanoparticles obtain both prominent fluorescent and paramagnetic properties by coating the GdS shell on the surface of CdTe core via a simple room-temperature route in aqueous solution directly. It is shown that the as-prepared CdTe@GdS NPs have high quantum yield (QY) value of 12% and outstanding longitudinal relaxation rate (r1) of 11.25 mM s(-1), which allow them to be employed as FL/MR dual-modal imaging contrast agents. They also exhibit small particle size of 5 nm, excellent colloidal stability and low cellular toxicity for concentrations up to 750 μg mL(-1). In addition, with the conjugation of folic acid, the nanoparticles were successfully used for tumor-targeted FL/MR dual-modal imaging in vitro and in vivo. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Dual tumor-targeted multifunctional magnetic hyaluronic acid micelles for enhanced MR imaging and combined photothermal-chemotherapy.

    Science.gov (United States)

    Zheng, Shaohui; Han, Jiwon; Jin, Zhen; Kim, Chang-Sei; Park, Sukho; Kim, Kyu-Pyo; Park, Jong-Oh; Choi, Eunpyo

    2018-02-05

    Multifunctional polymeric micelles were developed as a promising dual tumor-targeted drug delivery platform for magnetic resonance (MR) imaging and combined photothermal-chemotherapy. HA-C 16 copolymers were synthesized via peptide formation process with subsequent co-encapsulation of therapeutic agent docetaxel (DTX) and superparamagnetic iron oxide nanoparticles (SPIONs) to form the multifunctional micelles. The micelles exhibited uniform nanosize and remarkable colloidal stability in aqueous solution. The sustained drug release behavior from HA micelles was observed over the test period. Moreover, the specific targeting capability based on CD44 recptor-mediated endocytosis and the enhanced targeting efficacy by in presence of external magnetic field were investigated. The clustered SPIONs within micelles exerted excellent contrast effect with high r 2 relaxivity in MR phantom test. Furthermore, the multifunctional micelles could readily convert light to heat to hyperthermia temperature upon near infrared light irradition and induce photothermal ablation to breast cancer cells. The combined photothermal therapy with DTX-mediated chemotherapy of the developed multifunctional polymeric micells could generate a synergistic therapeutic effect. Based on these findings, the resulting multifunctional micelles may provide high potential for multimodality theragnosis of cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Improving tumor targeting and therapeutic potential of Salmonella VNP20009 by displaying cell surface CEA-specific antibodies.

    Science.gov (United States)

    Bereta, Michal; Hayhurst, Andrew; Gajda, Mariusz; Chorobik, Paulina; Targosz, Marta; Marcinkiewicz, Janusz; Kaufman, Howard L

    2007-05-22

    Genetically modified Salmonella typhimurium VNP20009 (VNP) is a useful vehicle for cancer therapy and vaccine development but exhibits limited tumor targeting in vivo. We engineered a novel VNP derivative that expressed carcinoembryonic antigen (CEA)-specific single chain antibody fragments (scFv) on the cell surface to increase tumor-specific targeting. There was significant scFv cell surface display visualized by flow cytometry and confocal microscopy when cells were probed with fluorescently labeled CEA. Atomic force microscopy (AFM) measurements on whole bacteria confirmed binding of unlabeled CEA to the displayed scFv. The modified VNP strain exhibited increased localization in the upper gastrointestinal tract of CEA transgenic mice and accumulated in CEA-expressing tumors. Furthermore, treatment with a single dose of the VNP derivative inhibited growth of MC38CEA tumors and was associated with local accumulation of CD3(+) T cells and CD11b(+) macrophages. The display of antibody fragments on the surface of VNP represents a novel strategy for both targeting CEA-expressing tumors and increasing the immunogenicity of Salmonella-based vaccines for cancer.

  12. Tumor-targeted inhibition by a novel strategy - mimoretrovirus expressing siRNA targeting the Pokemon gene.

    Science.gov (United States)

    Tian, Zhiqiang; Wang, Huaizhi; Jia, Zhengcai; Shi, Jinglei; Tang, Jun; Mao, Liwei; Liu, Hongli; Deng, Yijing; He, Yangdong; Ruan, Zhihua; Li, Jintao; Wu, Yuzhang; Ni, Bing

    2010-12-01

    Pokemon gene has crucial but versatile functions in cell differentiation, proliferation and tumorigenesis. It is a master regulator of the ARF-HDM2-p53 and Rb-E2F pathways. The facts that the expression of Pokemon is essential for tumor formation and many kinds of tumors over-express the Pokemon gene make it an attractive target for therapeutic intervention for cancer treatment. In this study, we used an RNAi strategy to silence the Pokemon gene in a cervical cancer model. To address the issues involving tumor specific delivery and durable expression of siRNA, we applied the Arg-Gly-Asp (RGD) peptide ligand and polylysine (K(18)) fusion peptide to encapsulate a recombinant retrovirus plasmid expressing a siRNA targeting the Pokemon gene and produced the 'mimoretrovirus'. At charge ratio 2.0 of fusion peptide/plasmid, the mimoretrovirus formed stable and homogenous nanoparticles, and provided complete DNase I protection and complete gel retardation. This nanoparticle inhibited SiHa cell proliferation and invasion, while it promoted SiHa cell apoptosis. The binding of the nanoparticle to SiHa cells was mediated via the RGD-integrin α(v)β(3) interaction, as evidenced by the finding that unconjugated RGD peptide inhibited this binding significantly. This tumor-targeting mimoretrovirus exhibited excellent anti-tumor capacity in vivo in a nude mouse model. Moreover, the mimoretrovirus inhibited tumor growth with a much higher efficiency than recombinant retrovirus expressing siRNA or the K(18)/P4 nanoparticle lacking the RGD peptide. Results suggest that the RNAi/RGD-based mimoretrovirus developed in this study represents a novel anti-tumor strategy that may be applicable to most research involving cancer therapy and, thus, has promising potential as a cervical cancer treatment.

  13. Synthesis and Bioevaluation of Iodine-131 Directly Labeled Cyclic RGD-PEGylated Gold Nanorods for Tumor-Targeted Imaging

    Directory of Open Access Journals (Sweden)

    Yingying Zhang

    2017-01-01

    Full Text Available Introduction. Radiolabeled gold nanoparticles play an important role in biomedical application. The aim of this study was to prepare iodine-131 (131I-labeled gold nanorods (GNRs conjugated with cyclic RGD and evaluate its biological characteristics for targeted imaging of integrin αvβ3-expressing tumors. Methods. HS-PEG(5000-COOH molecules were applied to replace CTAB covering the surface of bare GNRs for better biocompatibility, and c(RGDfK peptides were conjugated onto the carboxyl terminal of GNR-PEG-COOH via EDC/NHS coupling reactions. The nanoconjugate was characterized, and 131I was directly tagged on the surface of GNRs via AuI bonds for SPECT/CT imaging. We preliminarily studied the characteristics of the probe and its feasibility for tumor-targeting SPECT/CT imaging. Results. The [131I]GNR-PEG-cRGD probe was prepared in a simple and rapid manner and was stable in both PBS and fetal bovine serum. It targeted selectively and could be taken up by tumor cells mainly via integrin αvβ3-receptor-mediated endocytosis. In vivo imaging, biodistribution, and autoradiography results showed evident tumor uptake in integrin αvβ3-expressing tumors. Conclusions. These promising results showed that this smart nanoprobe can be used for angiogenesis-targeted SPECT/CT imaging. Furthermore, the nanoprobe possesses a remarkable capacity for highly efficient photothermal conversion in the near-infrared region, suggesting its potential as a multifunctional theranostic agent.

  14. Enhancement of ovarian cancer chemotherapy by delivery of multidrug-resistance gene small interfering RNA using tumor targeting Salmonella.

    Science.gov (United States)

    Deng, Jiaqi; Guo, Yi; Jiang, Zhongmin; Yang, Min; Li, Huaifang; Wang, Jianjun

    2015-04-01

    The aim of this study was to observe the effect of attenuated Salmonella typhi as a tumor-targeting delivery vector for multidrug-resistance gene (MDR1) small interfering RNA (siRNA). The cisplatin (DDP)-resistant ovarian cancer cell line SKOV-3/DDP was established by treatment with gradually increasing concentrations of cisplatin. MDR1 siRNA expression plasmid containing short hairpin RNA (shRNA) of MDR1 gene was constructed and transformed into attenuated Salmonella typhi strain  SL7207. SKOV-3/DDP cells were incubated with recombinant Salmonella and then subjected to analysis of MDR1 expression by real-time polymerase chain reaction and Western blot. SKOV-3/DDP tumor-bearing mice were established by subcutaneously injecting BALB/c nude mice with SKOV-3/DDP cells, and were orally inoculated with Salmonella carrying MDR1 siRNA plasmid and simultaneously injected intraperitoneally with cisplatin. Tumor growth and mouse survival were observed. Compared with parental cell line, the DDP-resistant SKOV-3/DDP cells expressed a much higher level of MDR1. The expression of MDR1 in SKOV-3/DDP cells infected with the Salmonella strain bearing MDR1 siRNA plasmid in vitro was detected to be downregulated and DDP tolerance of these cells was reversed. Tumor-bearing nude mice that were orally receiving recombinant Salmonella experienced a slow tumor growth and became more sensitive to DDP. Attenuated Salmonella typhi may represent a promising vector for in vivo administration of RNA interference therapy against malignant tumors. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

  15. Tumor targeting and SPECT imaging properties of an {sup 111}In-labeled galectin-3 binding peptide in prostate carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Deutscher, Susan L. [Department of Biochemistry, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Research Division, Harry S. Truman Veterans Hospital, Columbia, MO 65201 (United States); Figueroa, Said D. [Research Division, Harry S. Truman Veterans Hospital, Columbia, MO 65201 (United States); Kumar, Senthil R. [Department of Biochemistry, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States)], E-mail: kumars@missouri.edu

    2009-02-15

    Introduction: Galectin-3 (gal-3) is a carbohydrate binding protein that has been implicated in cell adhesion, tumor invasion and metastasis. The objective of this study was to evaluate the tumor targeting and imaging properties of a gal-3 binding peptide selected by phage display in a mouse model of metastatic human prostate carcinoma expressing gal-3. Methods: A gal-3 binding peptide, ANTPCGPYTHDCPVKR, was synthesized with a Gly-Ser-Gly (GSG) spacer and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and then radiolabeled with {sup 111}In. The in vitro cell binding properties of {sup 111}In-DOTA-(GSG)-ANTPCGPYTHDCPVKR were determined in metastatic human PC3-M prostate carcinoma cells. The pharmacokinetics and single-photon emission computed tomographic (SPECT/CT) imaging with the radiolabeled peptide were evaluated in SCID mice bearing human PC3-M prostate carcinoma tumor xenografts. Results: The radiolabeled peptide bound with a 50% inhibitory concentration of 191{+-}10.2 nM to cultured PC3-M prostate carcinoma cells. In vivo tumor uptake and retention coupled with fast whole-body clearance of the peptide were demonstrated in PC3-M tumor-bearing SCID mice. The tumor uptake rates of the radiolabeled peptide were 1.27{+-}0.10%ID/g at 30 min, 0.82{+-}0.15%ID/g at 1 h and 0.57{+-}0.09%ID/g at 2 h. MicroSPECT/CT studies revealed good tumor uptake of {sup 111}In-DOTA-(GSG)-ANTPCGPYTHDCPVKR 2 h postinjection, while uptake in normal organs was low, with the exception of the kidneys. Conclusions: In vitro cell binding along with tumor uptake of {sup 111}In-DOTA-(GSG)-ANTPCGPYTHDCPVKR in PC3-M human prostate carcinoma tumor-bearing SCID mice suggests the potential of this peptide as a radiopharmaceutical for imaging of gal-3-expressing prostate tumors.

  16. RGD peptide conjugation results in enhanced antitumor activity of PD0325901 against glioblastoma by both tumor-targeting delivery and combination therapy.

    Science.gov (United States)

    Hou, Jianjun; Diao, Yiping; Li, Wei; Yang, Zhenjun; Zhang, Lihe; Chen, Zili; Wu, Yun

    2016-05-30

    Glioblastoma (GBM) is the most aggressive tumor type in the central nervous system. Both tumor-targeting drug delivery and combination therapy of multiple therapeutic agents with distinct mechanisms are important for GBM treatment. We combined these two strategies and developed a new platform of peptide-drug conjugate (RGD-PEG-Suc-PD0325901, W22) for tumor-targeting delivery using a combination of PD0325901 (a MEK1/2 inhibitor) and RGD peptide. In the present study, the combination of PD0325901 and RGD peptide strongly inhibited U87MG model in vitro and in vivo. This inhibition contributed to synergistic suppression of cell proliferation by blocking ERK pathway activity and cell migration. Modified by conjugation strategy, their conjugate W22 enhanced PD0325901 delivery to GBM cells by receptor mediated cellular internalization. W22 showed great superiority in targeting to U87MG xenografted tumors and strong anti-tumor efficacy based on ERK pathway inhibition and tumor-targeted delivery in vitro and in vivo. Moreover, W22 was stable in serum and able to release PD0325901 in the enzymatic environment. These data indicated that the RGD-PEG-Suc-PD0325901 conjugate provided a strategy for effective delivery of PD0325901 and RGD peptide into the GBM cells and inhibition of tumor growth in a synergistic manner. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Melanin-manganese nanoparticles with ultrahigh efficient clearance in vivo for tumor-targeting T1magnetic resonance imaging contrast agent.

    Science.gov (United States)

    Xu, Wen; Sun, Jinghua; Li, Liping; Peng, Xiaoyang; Zhang, Ruiping; Wang, Binquan

    2017-12-19

    Endogenous biomaterials in organisms, with native biocompatibility and biodegradability, appear more advantageous in the development of nanoscale diagnostic and therapeutic systems for future clinical translation. Herein, a novel tumor-targeting Magnetic Resonance Imaging (MRI) contrast agent was developed based on Mn 2+ -chelating ultrasmall water-soluble melanin nanoparticles (MNP-PEG-Mn). The nanoparticles, with a size of about 5.6 nm, presented high chelation stability and showed negligible cytotoxicity as estimated by MTT assay. Moreover, the r 1 longitudinal relaxivity (20.56 mM -1 s -1 ) of MNP-PEG-Mn was much higher than that of Gadodiamide (6.00 mM -1 s -1 ), which is a clinically approved MRI contrast agent. In vivo MRI experiments revealed excellent tumor-targeting specificity after tumor-bearing mice were intravenously injected with MNP-PEG-Mn. Additionally, MNP-PEG-Mn could be excreted via renal and hepatobiliary pathways with negligible toxicity to body tissues. These preliminary results indicated the clinically translatable potential of MNP-PEG-Mn as a T 1 MRI contrast agent for tumor-targeted imaging.

  18. Self-immolative bioluminogenic quinone luciferins for NAD(P)H assays and reducing capacity-based cell viability assays.

    Science.gov (United States)

    Zhou, Wenhui; Leippe, Donna; Duellman, Sarah; Sobol, Mary; Vidugiriene, Jolanta; O'Brien, Martha; Shultz, John W; Kimball, Joshua J; DiBernardo, Céline; Moothart, Leonard; Bernad, Laurent; Cali, James; Klaubert, Dieter H; Meisenheimer, Poncho

    2014-03-21

    Highly sensitive self-cleavable trimethyl lock quinone-luciferin substrates for diaphorase were designed and synthesized to measure NAD(P)H in biological samples and monitor viable cells via NAD(P)H-dependent cellular oxidoreductase enzymes and their NAD(P)H cofactors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. pH-Responsive Tumor-Targetable Theranostic Nanovectors Based on Core Crosslinked (CCL Micelles with Fluorescence and Magnetic Resonance (MR Dual Imaging Modalities and Drug Delivery Performance

    Directory of Open Access Journals (Sweden)

    Sidan Tian

    2016-06-01

    Full Text Available The development of novel theranostic nanovectors is of particular interest in treating formidable diseases (e.g., cancers. Herein, we report a new tumor-targetable theranostic agent based on core crosslinked (CCL micelles, possessing tumor targetable moieties and fluorescence and magnetic resonance (MR dual imaging modalities. An azide-terminated diblock copolymer, N3-POEGMA-b-P(DPA-co-GMA, was synthesized via consecutive atom transfer radical polymerization (ATRP, where OEGMA, DPA, and GMA are oligo(ethylene glycolmethyl ether methacrylate, 2-(diisopropylaminoethyl methacrylate, and glycidyl methacrylate, respectively. The resulting diblock copolymer was further functionalized with DOTA(Gd (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid or benzaldehyde moieties via copper(I-catalyzed alkyne-azide cycloaddition (CuAAC chemistry, resulting in the formation of DOTA(Gd-POEGMA-b-P(DPA-co-GMA and benzaldehyde-POEGMA-b-P(DPA-co-GMA copolymers. The resultant block copolymers co-assembled into mixed micelles at neutral pH in the presence of tetrakis[4-(2-mercaptoethoxyphenyl]ethylene (TPE-4SH, which underwent spontaneous crosslinking reactions with GMA residues embedded within the micellar cores, simultaneously switching on TPE fluorescence due to the restriction of intramolecular rotation. Moreover, camptothecin (CPT was encapsulated into the crosslinked cores at neutral pH, and tumor-targeting pH low insertion peptide (pHLIP, sequence: AEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTCG moieties were attached to the coronas through the Schiff base chemistry, yielding a theranostic nanovector with fluorescence and MR dual imaging modalities and tumor-targeting capability. The nanovectors can be efficiently taken up by A549 cells, as monitored by TPE fluorescence. After internalization, intracellular acidic pH triggered the release of loaded CPT, killing cancer cells in a selective manner. On the other hand, the nanovectors labeled with DOTA

  20. Tumor-targeted and multi-stimuli responsive drug delivery system for near-infrared light induced chemo-phototherapy and photoacoustic tomography.

    Science.gov (United States)

    Feng, Qianhua; Zhang, Yuanyuan; Zhang, Wanxia; Shan, Xiaoning; Yuan, Yujie; Zhang, Hongling; Hou, Lin; Zhang, Zhenzhong

    2016-07-01

    In this work, a tumor-targeted and multi-stimuli responsive drug delivery system has been developed for combining photoacoustic tomography imaging with chemo-phototherapy. We utilized a kind of near infrared (NIR) resonant material-hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) to encapsulate doxorubicin (DOX). After that, the outer surface of HMCuS NPs was capped with multifunctional hyaluronic acid (HA) simultaneously as smart gatekeeper as well as tumor targeting moiety. Herein, HMCuS-HA could serve as a powerful contrast agent for photoacoustic tomography (PAT) to guide chemo-phototherapy by providing the identification of cancerous lesions. In vitro and in vivo studies, the nanoplatform (DOX/HMCuS-HA) pinpointed MCF-7 cells via CD44 receptor-mediated endocytosis pathway. Subsequently, intracellular enzyme-responsive controlled drug release would take place in lysosome after the HA degradation by hyaluronidase. Under near infrared (NIR) light irradiation, HMCuS NPs could not only effectively convert NIR light into heat for photothermal therapy, but also generate high levels of reactive oxygen species (ROS) for photodynamic therapy. In addition, NIR light and low pH environment could facilitate intracellular tunable drug release with spatial/temporal resolution, and thus synergistic combination of chemo-phototherapy should be simultaneously driven by an 808nm laser irradiation, which brought out an outstanding therapeutic effect. In vivo optical imaging demonstrated that HMCuS-HA significantly enhanced targeting and accumulation capacity in tumor site. Furthermore, tumor-bearing mice treated with DOX/HMCuS-HA under NIR irradiation (808nm, 2W/cm(2), 0.5min) in vivo displayed the highest inhibition ratio of about 88.9%. Taken together, our present study of the tumor-targeted and multi-stimuli responsive drug delivery system provides new insights into multimodality theranostic applications in cancer treatment. Until now, chemotherapy is still the major

  1. Therapeutic efficacy of tumor-targeting Salmonella typhimurium A1-R on human colorectal cancer liver metastasis in orthotopic nude-mouse models.

    Science.gov (United States)

    Murakami, Takashi; Hiroshima, Yukihiko; Zhao, Ming; Zhang, Yong; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2015-10-13

    Liver metastasis is the most frequent cause of death from colon and other cancers. Generally, liver metastasis is recalcitrant to treatment. The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R on liver metastasis in orthotopic mouse models. HT-29 human colon cancer cells expressing red fluorescent protein (RFP) were used in the present study. S. typhimurium A1-R infected HT-29 cells in a time-dependent manner, inhibiting cancer-cell proliferation in vitro. S. typhimurium A1-R promoted tumor necrosis and inhibited tumor growth in a subcutaneous tumor mouse model of HT-29-RFP. In orthotopic mouse models, S. typhimurium A1-R targeted liver metastases and significantly reduced their growth. The results of this study demonstrate the future clinical potential of S. typhimurium A1-R targeting of liver metastasis.

  2. Facile Synthesis of Gd-Cu-In-S/ZnS Bimodal Quantum Dots with Optimized Properties for Tumor Targeted Fluorescence/MR In Vivo Imaging.

    Science.gov (United States)

    Yang, Weitao; Guo, Weisheng; Gong, Xiaoqun; Zhang, Bingbo; Wang, Sheng; Chen, Na; Yang, Wentao; Tu, Yu; Fang, Xiangming; Chang, Jin

    2015-08-26

    Dual-modal imaging techniques have gained intense attention for their potential role in the dawning era of tumor early accurate diagnosis. Chelate-free robust dual-modal imaging nanoprobes with high efficiency and low toxicity are of essential importance for tumor targeted dual-modal in vivo imaging. It is still a crucial issue to endow Cd-free dual-modal nanoprobes with bright fluorescence as well as high relaxivity. Herein, a facile synthetic strategy was developed to prepare Gd-doped CuInS/ZnS bimodal quantum dots (GCIS/ZnS, BQDs) with optimized properties. The fluorescent properties of the GCIS/ZnS BQDs can be thoroughly optimized by varying reaction temperature, aging time, and ZnS coating. The amount of Gd precursor can be well-controlled to realize the optimized balance between the MR relaxivity and optical properties. The obtained hydrophobic GCIS/ZnS BQDs were surface engineered into aqueous phase with PEGylated dextran-stearyl acid polymeric lipid vesicles (PEG-DS PLVs). Upon the phase transfer, the hydrophilic GCIS/ZnS@PLVs exhibited pronounced near-infrared fluorescence as well as high longitudinal relaxivity (r1 = 9.45 mM(-1) S(-1)) in water with good colloidal stability. In vivo tumor-bearing animal experiments further verified GCIS/ZnS@PLVs could achieve tumor-targeted MR/fluorescence dual-modal imaging. No toxicity was observed in the in vivo and ex vivo experiments. The GCIS/ZnS@PLVs present great potential as bimodal imaging contrast agents for tumor diagnosis.

  3. Tumor-targeted SN38 inhibits growth of early stage non-small cell lung cancer (NSCLC in a KRas/p53 transgenic mouse model.

    Directory of Open Access Journals (Sweden)

    Alexander Y Deneka

    Full Text Available Non-small cell lung cancer (NSCLC is the leading cause of cancer death worldwide, with a 5-year survival of only ~16%. Potential strategies to address NSCLC mortality include improvements in early detection and prevention, and development of new therapies suitable for use in patients with early and late stage diagnoses. Controlling the growth of early stage tumors could yield significant clinical benefits for patients with comorbidities that make them poor candidates for surgery: however, many drugs that limit cancer growth are not useful in the setting of long-term use or in comorbid patients, because of associated toxicities. In this study, we explored the use of a recently described small molecule agent, STA-8666, as a potential agent for controlling early stage tumor growth. STA-8666 uses a cleavable linker to merge a tumor-targeting moiety that binds heat shock protein 90 (HSP90 with the cytotoxic chemical SN38, and has been shown to have high efficacy and low toxicity, associated with efficient tumor targeting, in preclinical studies using patient-derived and other xenograft models for pancreatic, bladder, and small cell lung cancer. Using a genetically engineered model of NSCLC arising from induced mutation of KRas and knockout of Trp53, we continuously dosed mice with STA-8666 from immediately after tumor induction for 15 weeks. STA-8666 significantly slowed the rate of tumor growth, and was well tolerated over this extended dosing period. STA-8666 induced DNA damage and apoptosis, and reduced proliferation and phosphorylation of the proliferation-associated protein ERK1/2, selectively in tumor tissue. In contrast, STA-8666 did not affect tumor features, such as degree of vimentin staining, associated with epithelial-mesenchymal transition (EMT, or downregulate tumor expression of HSP90. These data suggest STA-8666 and other similar targeted compounds may be useful additions to control the growth of early stage NSCLC in patient

  4. Efficacy of tumor-targeting Salmonella typhimurium A1-R on nude mouse models of metastatic and disseminated human ovarian cancer.

    Science.gov (United States)

    Matsumoto, Yasunori; Miwa, Shinji; Zhang, Yong; Hiroshima, Yukihiko; Yano, Shuya; Uehara, Fuminari; Yamamoto, Mako; Toneri, Makoto; Bouvet, Michael; Matsubara, Hisahiro; Hoffman, Robert M; Zhao, Ming

    2014-11-01

    We report here the efficacy of tumor-targeting Salmonella typhimurium A1-R (A1-R) on mouse models of disseminated and metastatic ovarian cancer. The proliferation-inhibitory efficacy of A1-R on human ovarian cancer cell lines (SKOV-3-GFP, OVCAR-3-RFP) was initially demonstrated in vitro. Orthotopic and dissemination mouse models of ovarian cancer were made with the human ovarian cancer cell line SKOV-3-GFP. After tumor implantation, the mice were treated with A1-R (5 × 10(7)  colony-forming units [CFU], i.v.), and there were no severe adverse events observed. In the orthotopic model, tumor volume after treatment was 276 ± 60.8 mm(3), compared to 930 ± 342 mm(3) in the untreated control group (P = 0.022). There was also a significant difference in survival between treated mice and untreated mice in a peritoneal dissemination model (P = 0.005). The results of this report demonstrate that A1-R is effective for highly aggressive human ovarian cancer in metastatic and dissemination mouse models and suggest its clinical potential for this highly treatment-resistant disease. © 2014 Wiley Periodicals, Inc.

  5. Gene recombinant bone marrow mesenchymal stem cells as a tumor-targeted suicide gene delivery vehicle in pulmonary metastasis therapy using non-viral transfection.

    Science.gov (United States)

    Zhang, Tian-Yuan; Huang, Bing; Yuan, Zhong-Yue; Hu, Yu-Lan; Tabata, Yasuhiko; Gao, Jian-Qing

    2014-01-01

    One of the main limitations of anti-tumor gene therapy is the lack of an effective way to deliver therapeutic genes to tumor sites. Bone marrow mesenchymal stem cells (BMSCs) have been proposed as cellular delivery vehicles to tumor sites in tumor-targeted cancer gene therapy. Here, we investigated the therapeutic effects of cytomegalovirus-thymidine kinase expressing BMSCs (TK-BMSCs) on pulmonary melanoma metastasis combined with prodrug ganciclovir. BMSCs were successfully engineered through a non-viral gene vector. The gene recombinant BMSCs migrated to the pulmonary area and were found to have the tendency to target tumor nodules after systemic delivery. In vitro results demonstrate that the engineered BMSCs have significant suicide effects in the presence of ganciclovir in a dose-dependent manner and can exert a sufficient bystander effect on B16F10 tumor cells in co-culture experiments. In vivo studies confirmed the therapeutic effects of TK-BMSCs/ganciclovir on the metastasis tumor model. This study investigates the possibility of gene transfer via bone marrow mesenchymal stem cells in anti-cancer gene therapy using a metastatic melanoma model and cytomegalovirus-thymidine kinase expressing stem cells, demonstrating clear therapeutic effects. © 2013.

  6. In vitro study of novel gadolinium-loaded liposomes guided by GBI-10 aptamer for promising tumor targeting and tumor diagnosis by magnetic resonance imaging

    Science.gov (United States)

    Gu, Meng-Jie; Li, Kun-Feng; Zhang, Lan-Xin; Wang, Huan; Liu, Li-Si; Zheng, Zhuo-Zhao; Han, Nan-Yin; Yang, Zhen-Jun; Fan, Tian-Yuan

    2015-01-01

    Novel gadolinium-loaded liposomes guided by GBI-10 aptamer were developed and evaluated in vitro to enhance magnetic resonance imaging (MRI) diagnosis of tumor. Nontargeted gadolinium-loaded liposomes were achieved by incorporating amphipathic material, Gd (III) [N,N-bis-stearylamidomethyl-N′-amidomethyl] diethylenetriamine tetraacetic acid, into the liposome membrane using lipid film hydration method. GBI-10, as the targeting ligand, was then conjugated onto the liposome surface to get GBI-10-targeted gadolinium-loaded liposomes (GTLs). Both nontargeted gadolinium-loaded liposomes and GTLs displayed good dispersion stability, optimal size, and zeta potential for tumor targeting, as well as favorable imaging properties with enhanced relaxivity compared with a commercial MRI contrast agent (CA), gadopentetate dimeglumine. The use of GBI-10 aptamer in this liposomal system was intended to result in increased accumulation of gadolinium at the periphery of C6 glioma cells, where the targeting extracellular matrix protein tenascin-C is overexpressed. Increased cellular binding of GTLs to C6 cells was confirmed by confocal microscopy, flow cytometry, and MRI, demonstrating the promise of this novel delivery system as a carrier of MRI contrast agent for the diagnosis of tumor. These studies provide a new strategy furthering the development of nanomedicine for both diagnosis and therapy of tumor. PMID:26316749

  7. Tetrameric far-red fluorescent protein as a scaffold to assemble an octavalent peptide nanoprobe for enhanced tumor targeting and intracellular uptake in vivo.

    Science.gov (United States)

    Luo, Haiming; Yang, Jie; Jin, Honglin; Huang, Chuan; Fu, Jianwei; Yang, Fei; Gong, Hui; Zeng, Shaoqun; Luo, Qingming; Zhang, Zhihong

    2011-06-01

    Relatively weak tumor affinities and short retention time in vivo hinder the application of targeting peptides in tumor molecular imaging. Multivalent strategies based on various scaffolds have been utilized to improve the ability of peptide-receptor binding or extend the clearance time of peptide-based probes. Here, we use a tetrameric far-red fluorescent protein (tfRFP) as a scaffold to create a self-assembled octavalent peptide fluorescent nanoprobe (Octa-FNP) using a genetic engineering approach. The multiligand connecting, fluorophore labeling and nanostructure formation of Octa-FNP were performed in one step. In vitro studies showed Octa-FNP is a 10-nm fluorescent probe with excellent serum stability. Cellular uptake of Octa-FNP by human nasopharyngeal cancer 5-8F cells is 15-fold of tetravalent probe, ∼80-fold of monovalent probe and ∼600-fold of nulvalent tfRFP. In vivo enhanced tumor targeting and intracellular uptake of Octa-FNP were confirmed using optical imaging and Western blot analysis. It achieved extremely high contrast of Octa-FNP signal between tumor tissue and normal organs, especially seldom Octa-FNP detected in liver and spleen. Owing to easy preparation, precise structural and functional control, and multivalent effect, Octa-FNP provides a powerful tool for tumor optical molecular imaging and evaluating the targeting ability of numerous peptides in vivo.

  8. Theranostic unimolecular micelles based on brush-shaped amphiphilic block copolymers for tumor-targeted drug delivery and positron emission tomography imaging.

    Science.gov (United States)

    Guo, Jintang; Hong, Hao; Chen, Guojun; Shi, Sixiang; Nayak, Tapas R; Theuer, Charles P; Barnhart, Todd E; Cai, Weibo; Gong, Shaoqin

    2014-12-24

    Brush-shaped amphiphilic block copolymers were conjugated with a monoclonal antibody against CD105 (i.e., TRC105) and a macrocyclic chelator for (64)Cu-labeling to generate multifunctional theranostic unimolecular micelles. The backbone of the brush-shaped amphiphilic block copolymer was poly(2-hydroxyethyl methacrylate) (PHEMA) and the side chains were poly(L-lactide)-poly(ethylene glycol) (PLLA-PEG). The doxorubicin (DOX)-loaded unimolecular micelles showed a pH-dependent drug release profile and a uniform size distribution. A significantly higher cellular uptake of TRC105-conjugated micelles was observed in CD105-positive human umbilical vein endothelial cells (HUVEC) than nontargeted micelles due to CD105-mediated endocytosis. In contrast, similar and extremely low cellular uptake of both targeted and nontargeted micelles was observed in MCF-7 human breast cancer cells (CD105-negative). The difference between the in vivo tumor accumulation of (64)Cu-labeled TRC105-conjugated micelles and that of nontargeted micelles was studied in 4T1 murine breast tumor-bearing mice, by serial positron emission tomography (PET) imaging and validated by biodistribution studies. These multifunctional unimolecular micelles offer pH-responsive drug release, noninvasive PET imaging capability, together with both passive and active tumor-targeting abilities, thus making them a desirable nanoplatform for cancer theranostics.

  9. Antitumor Activity of a Mesenchymal Stem Cell Line Stably Secreting a Tumor-Targeted TNF-Related Apoptosis-Inducing Ligand Fusion Protein.

    Science.gov (United States)

    Marini, Irene; Siegemund, Martin; Hutt, Meike; Kontermann, Roland E; Pfizenmaier, Klaus

    2017-01-01

    Mesenchymal stem cells (MSCs) are currently exploited as gene delivery systems for transient in situ expression of cancer therapeutics. As an alternative to the prevailing viral expression, we here describe a murine MSC line stably expressing a therapeutic protein for up to 42 passages, yet fully maintaining MSC features. Because of superior antitumoral activity of hexavalent TNF-related apoptosis-inducing ligand (TRAIL) formats and the advantage of a tumor-targeted action, we choose expression of a dimeric EGFR-specific diabody single-chain TRAIL (Db-scTRAIL) as a model. The bioactivity of Db-scTRAIL produced from an isolated clone (MSC.TRAIL) was revealed from cell death induction in Colo205 cells treated with either culture supernatants from or cocultured with MSC.TRAIL. In vivo, therapeutic activity of MSC.TRAIL was shown upon peritumoral injection in a Colo205 xenograft tumor model. Best antitumor activity in vitro and in vivo was observed upon combined treatment of MSC.TRAIL with bortezomib. Importantly, in vivo combination treatment did not cause apparent hepatotoxicity, weight loss, or behavioral changes. The development of well characterized stocks of stable drug-producing human MSC lines has the potential to establish standardized protocols of cell-based therapy broadly applicable in cancer treatment.

  10. Methyl 6-Amino-6-deoxy-d-pyranoside-Conjugated Platinum(II) Complexes for Glucose Transporter (GLUT)-Mediated Tumor Targeting: Synthesis, Cytotoxicity, and Cellular Uptake Mechanism.

    Science.gov (United States)

    Li, Taoli; Gao, Xiangqian; Yang, Liu; Shi, Yunli; Gao, Qingzhi

    2016-05-19

    Methyl 6-aminodeoxy-d-pyranoside-derived platinum(II) glycoconjugates were designed and synthesized based on the clinical drug oxaliplatin for glucose transporter (GLUT)-mediated tumor targeting. In addition to a substantial improvement in water solubility, the conjugates exhibited cytotoxicity similar to or higher than that of oxaliplatin in six different human cancer cell lines. GLUT-mediated transport of the complexes was investigated with a cell-based fluorescence competition assay and GLUT-inhibitor-mediated cytotoxicity analysis in a GLUT-overexpressing human colorectal adenocarcinoma (HT29) cell line. The antitumor effect of the aminodeoxypyranoside-conjugated platinum(II) complexes was found to depend significantly on the GLUT inhibitor, and the cellular uptake of the molecules was regulated by GLUT-mediated transport. The results from this study demonstrate the potential advantages of aminodeoxypyranosides as sugar motifs for glycoconjugation for Warburg-effect-targeted drug design. These fundamental results also support the potential of aminodeoxypyranoside-conjugated platinum(II) complexes as lead compounds for further preclinical evaluation. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. CuS as a gatekeeper of mesoporous upconversion nanoparticles-based drug controlled release system for tumor-targeted multimodal imaging and synergetic chemo-thermotherapy.

    Science.gov (United States)

    Su, Xiangjie; Zhao, Feifei; Wang, Yuhui; Yan, Xiaosa; Jia, Shaona; Du, Bin

    2017-07-01

    In this work, a tumor-targeted multifunctional mesoporous upconversion nanoparticle-based drug controlled release system was developed for UCL/MRI/PAT guided synergetic chemo-thermotherapy. Herein, the core-shell mesoporous upconversion nanoparticles served as drug carrier exhibiting higher upconversion luminescence emission intensity, with CuS as a gatekeeper through a cleavable disulfide bond under the influence of glutathione. CuS could not only prevent drug from early release during the delivery but also improve the delivery system function with the ability of photothermal therapy and photoacoustic tomography. Hyaluronic acid grafted on the surface of mesoporous upconversion nanoparticles could interact with CD44 receptors over-expressed in tumor cells, facilitating the drug delivery system to accumulate in tumor tissues. The synergy between chemotherapy and photothermal therapy was studied in vitro and in vivo, showing powerful anti-tumor effect. In cooperation with the multi-mode imaging, the size, site and morphology of tumor were clearly observed throughout the disease's progression. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Tumor targeting via integrin ligands

    Directory of Open Access Journals (Sweden)

    Udaya Kiran eMarelli

    2013-08-01

    Full Text Available Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug delivery systems, and discuss the prospects of such therapies to specifically target tumor cells.

  13. Rapid synthesis of highly luminescent and stable Au20 nanoclusters for active tumor-targeted imaging in vitro and in vivo

    Science.gov (United States)

    Zhang, Pu; Yang, Xiao Xi; Wang, Yi; Zhao, Ning Wei; Xiong, Zu Hong; Huang, Cheng Zhi

    2014-01-01

    Rapid synthesis of protein-stabilized Au20 nanoclusters (Au20NCs) with high fluorescence quantum yield (QY) up to ~15% is successfully achieved by manipulating the reaction kinetics. The as-obtained Au20NCs, identified by mass spectrometry, have an average size of 2.6 nm, with strong fluorescence emission at 620 nm (2.00 eV) upon excitation at either 370 nm (3.35 eV) or 470 nm (2.64 eV). The advantages of the as-obtained Au20NCs, including small sizes, high fluorescence QY, excellent photostability, non-toxicity, and good stability in biological media, make them ideal candidates as good luminescent probes for optical imaging in vitro and in vivo. Our results demonstrate that the uptake of Au20NCs by both cancer cells and tumor-bearing nude mice can be improved by receptor-mediated internalization, compared with that by passive targeting. Because of their selective accumulation at the tumor sites, the Au20NC probes can be used as potential indicators for cancer diagnosis. This work not only provides a new understanding of the rapid synthesis of highly luminescent Au20NCs but also demonstrates that the functionalized-Au20NCs are excellent probes for active tumor-targeted imaging in vitro and in vivo.Rapid synthesis of protein-stabilized Au20 nanoclusters (Au20NCs) with high fluorescence quantum yield (QY) up to ~15% is successfully achieved by manipulating the reaction kinetics. The as-obtained Au20NCs, identified by mass spectrometry, have an average size of 2.6 nm, with strong fluorescence emission at 620 nm (2.00 eV) upon excitation at either 370 nm (3.35 eV) or 470 nm (2.64 eV). The advantages of the as-obtained Au20NCs, including small sizes, high fluorescence QY, excellent photostability, non-toxicity, and good stability in biological media, make them ideal candidates as good luminescent probes for optical imaging in vitro and in vivo. Our results demonstrate that the uptake of Au20NCs by both cancer cells and tumor-bearing nude mice can be improved by receptor

  14. Efficient and Tumor Targeted siRNA Delivery by Polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol)-folate (PEI-PCL-PEG-Fol).

    Science.gov (United States)

    Liu, Li; Zheng, Mengyao; Librizzi, Damiano; Renette, Thomas; Merkel, Olivia M; Kissel, Thomas

    2016-01-04

    Efficient delivery of functional nucleic acids into specific cells or tissues is still a challenge for gene therapy and largely depends on targeted delivery strategies. The folate receptor (FR) is known to be overexpressed extracellularly on a variety of human cancers and is therefore an outstanding gate for tumor-targeted Trojan horse-like delivery of therapeutics. In this study, an amphiphilic and biodegradable ternary copolymer conjugated with folate as ligand, polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol)-folate (PEI-PCL-PEG-Fol) was synthesized and evaluated for targeted siRNA delivery via folate-FR recognition. The amphiphilic character of similar polymers was shown previously to support endosomal release of endocytosed nanocarriers and to promote formation of long circulating micelles. The obtained PEI-PCL-PEG-Fol exhibited less cytotoxicity in comparison with the corresponding ternary copolymer without folate (PEI-PCL-PEG) and with unmodified PEI25kDa. Stable micelle-like polyplexes with hydrodynamic diameters about 100 nm were found to have a zeta potential of +8.6 mV, which was lower than that of micelleplexes without folate-conjugation (+13-16 mV). Nonetheless, increased cellular uptake and in vitro gene knockdown of PEI-PCL-PEG-Fol/siRNA micelleplexes were observed in SKOV-3 cells, an FR overexpressing cell line, in comparison with the nonfolate-conjugated ones. Moreover, PEI-PCL-PEG-Fol/siRNA micelleplexes exhibited excellent stability in vivo during the analysis of 120 min and a longer circulation half life than hyPEI25kDa/siRNA polyplexes. Most interestingly, the targeted delivery system yielded 17% deposition of the i.v. injected siRNA per gram in the tumor after 24 h due to the effective folate targeting and the prolonged circulation.

  15. Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models.

    Science.gov (United States)

    Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Zhang, Nan; Murakami, Takashi; Maawy, Ali; Mii, Sumiyuki; Uehara, Fuminari; Yamamoto, Mako; Miwa, Shinji; Yano, Shuya; Momiyama, Masashi; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2015-01-01

    We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1) no treatment; (2) carboplatinum (30 mg/kg, ip, weekly, 5 weeks); (3) trastuzumab (20 mg/kg, ip, weekly, 5 weeks); (4) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks); (5) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks) + trastuzumab (20 mg/kg, ip, weekly, 5 weeks). All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007) and S. typhimurium A1-R alone (p = 0.039). No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021). Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.

  16. Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models.

    Directory of Open Access Journals (Sweden)

    Yukihiko Hiroshima

    Full Text Available We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1 no treatment; (2 carboplatinum (30 mg/kg, ip, weekly, 5 weeks; (3 trastuzumab (20 mg/kg, ip, weekly, 5 weeks; (4 S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks; (5 S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks + trastuzumab (20 mg/kg, ip, weekly, 5 weeks. All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007 and S. typhimurium A1-R alone (p = 0.039. No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021. Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.

  17. Octanoyl galactose ester-modified microemulsion system self-assembled by coix seed components to enhance tumor targeting and hepatoma therapy.

    Science.gov (United States)

    Qu, Ding; Liu, Mingjian; Huang, Mengmeng; Wang, Lixiang; Chen, Yan; Liu, Congyan; Liu, Yuping

    2017-01-01

    A nanosized drug delivery platform with a combination of rational components and tumor targeting is significant for enhancement of anticancer therapy and reduction of side effects. In this study, we developed a octanoyl galactose ester-modified microemulsion system self-assembled by coix seed components (Gal(oct)-C-MEs), which improved the tumor accumulation through asialoglycoprotein receptor-mediated endocytosis and promoted the antitumor efficacy through multicomponent-mediated synergistic effect. Octanoyl galactose ester (Gal(oct)) with a yield of 82.3% was synthesized through a green enzymatic reaction and multidimensional characterization. Gal(oct)-C-MEs with a spherical shape had a small and uniform particle size (58.49±1.03 nm), narrow polydispersity index (0.09±0.01) and neutral surface charge (-5.82±0.57 mV). In the cellular uptake studies, the internalized Gal(oct)-C-ME was 2.28-fold higher relative to that of coix seed component-based microemulsions (C-MEs). The half-maximal inhibitory concentration of Gal(oct)-C-MEs against HepG2 cells was 46.5±2.4 μg/mL, which was notably higher than that of C-MEs. Importantly, the intratumor fluorescence of HepG2 xenograft-bearing nude mice treated with Cy5/Gal(oct)-C-MEs was 1.9-fold higher relative to treatment with Cy5/C-MEs. In the study of antitumor efficacy in vivo, HepG2 xenograft-bearing nude mice intragastrically administered Gal(oct)-C-MEs for 14 days exhibited the strongest inhibition of tumor growth and the lowest toxicity against liver and kidney among all the treatments. In summary, Gal(oct)-C-ME, as a highly effective and safe anticancer drug delivery system, showed promising potential for hepatoma therapy.

  18. Tumor-targeting Salmonella typhimurium A1-R Inhibits Osteosarcoma Angiogenesis in the In Vivo Gelfoam® Assay Visualized by Color-coded Imaging.

    Science.gov (United States)

    Kiyuna, Tasuku; Tome, Yasunori; Uehara, Fuminari; Murakami, Takashi; Zhang, Yong; Zhao, Ming; Kanaya, Fuminori; Hoffman, Robert M

    2018-01-01

    We previously developed a color-coded imaging model that can quantify the length of nascent blood vessels using Gelfoam® implanted in nestin-driven green fluorescent protein (ND-GFP) nude mice. In this model, nascent blood vessels selectively express GFP. We also previously showed that osteosarcoma cells promote angiogenesis in this assay. We have also previously demonstrated the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R) can inhibit or regress all tested tumor types in mouse models. The aim of the present study was to determine if S. typhimurium A1-R could inhibit osteosarcoma angiogenesis in the in vivo Gelfoam® color-coded imaging assay. Gelfoam® was implanted subcutaneously in ND-GFP nude mice. Skin flaps were made 7 days after implantation and 143B-RFP human osteosarcoma cells expressing red fluorescent protein (RFP) were injected into the implanted Gelfoam. After establishment of tumors in the Gelfoam®, control-group mice were treated with phosphate buffered saline via tail-vein injection (iv) and the experimental group was treated with S. typhimurium A1-R iv Skin flaps were made at day 7, 14, 21, and 28 after implantation of the Gelfoam® to allow imaging of vascularization in the Gelfoam® using a variable-magnification small-animal imaging system and confocal fluorescence microscopy. Nascent blood vessels expressing ND-GFP extended into the Gelfoam® over time in both groups. However, the extent of nascent blood-vessel growth was significantly inhibited by S. typhimurium A1-R treatment by day 28. The present results indicate S. typhimurium A1-R has potential for anti-angiogenic targeted therapy of osteosarcoma. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  19. In vivo tumor targeting and imaging with anti-vascular endothelial growth factor antibody-conjugated dextran-coated iron oxide nanoparticles.

    Science.gov (United States)

    Hsieh, Wan-Ju; Liang, Chan-Jung; Chieh, Jen-Jie; Wang, Shu-Huei; Lai, I-Rue; Chen, Jyh-Horng; Chang, Fu-Hsiung; Tseng, Wei-Kung; Yang, Shieh-Yueh; Wu, Chau-Chung; Chen, Yuh-Lien

    2012-01-01

    Active targeting by specific antibodies combined with nanoparticles is a promising technology for cancer imaging and detection by magnetic resonance imaging (MRI). The aim of the present study is to investigate whether the systemic delivery of antivascular endothelial growth factor antibodies conjugating to the surface of functionalized supermagnetic iron oxide nanoparticles (anti-VEGF-NPs) led to target-specific accumulation in the tumor. The VEGF expression in human colon cancer and in Balb/c mice bearing colon cancers was examined by immunohistochemistry. The distribution of these anti-VEGF-NPs particles or NPs particles were evaluated by MRI at days 1, 2, or 9 after the injection into the jugular vein of Balb/c mice bearing colon cancers. Tumor and normal tissues (liver, spleen, lung, and kidney) were collected and were examined by Prussian blue staining to determine the presence and distribution of NPs in the tissue sections. VEGF is highly expressed in human and mouse colon cancer tissues. MRI showed significant changes in the T*(2) signal and T(2) relaxation in the anti-VEGF-NP- injected-mice, but not in mice injected with NP alone. Examination of paraffin sections of tumor tissues stained for the iron constituent of the NPs with Prussian blue revealed a strong blue reaction in the tumors of anti-VEGF-NP-treated mice, but only a weak reaction in mice injected with NPs. In both groups, at all time points, Prussian blue-stained liver and spleen sections showed only light staining, while stained cells were rarely detected in kidney and lung sections. Transmission electron microscopy showed that many more electron-dense particles were present in endothelial cells, tumor cells, and extracellular matrix in tumor tissues in mice injected with anti-VEGF-NPs than in NP-injected mice. These results demonstrated in vivo tumor targeting and efficient accumulation of anti-VEGF-NPs in tumor tissues after systemic delivery in a colon cancer model, showing that anti

  20. Improving the MR Imaging Sensitivity of Upconversion Nanoparticles by an Internal and External Incorporation of the Gd(3+) Strategy for in Vivo Tumor-Targeted Imaging.

    Science.gov (United States)

    Du, Hongli; Yu, Jiani; Guo, Dongcai; Yang, Weitao; Wang, Jun; Zhang, Bingbo

    2016-02-02

    toxicity. It could therefore be concluded, with improved MR imaging sensitivity by an internal and external incorporation of Gd(3+) strategy, that UCNPs-H@BSA·DTPA(Gd) presents great potential as an alternative in tumor-targeted MR imaging.

  1. One-pot synthesis of reactive oxygen species (ROS)-self-immolative polyoxalate prodrug nanoparticles for hormone dependent cancer therapy with minimized side effects

    Czech Academy of Sciences Publication Activity Database

    Höcherl, Anita; Jäger, Eliezer; Jäger, Alessandro; Hrubý, Martin; Konefal, Rafal; Janoušková, Olga; Spěváček, Jiří; Jiang, Y.; Schmidt, P. W.; Lodge, T. P.; Štěpánek, Petr

    2017-01-01

    Roč. 8, č. 13 (2017), s. 1999-2004 ISSN 1759-9954 R&D Projects: GA MŠk(CZ) LH14079; GA MŠk(CZ) LO1507; GA ČR(CZ) GA16-02870S; GA ČR(CZ) GA15-13853S; GA ČR(CZ) GA17-09998S Institutional support: RVO:61389013 Keywords : polyprodrug * diethylstilbestrol * cancer Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 5.375, year: 2016

  2. Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8+ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic-Cancer Orthotopic Mouse Model.

    Science.gov (United States)

    Murakami, Takashi; Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Kiyuna, Tasuku; Hwang, Ho Kyoung; Miyake, Kentaro; Homma, Yuki; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Ichikawa, Yasushi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2018-01-01

    The present study determined the effect of the tumor-targeting strain Salmonella typhimurium A1-R (S. typhimurium A1-R) on CD8+ tumor-infiltrating lymphocytes (TILs) in a syngeneic pancreatic-cancer orthotopic mouse model. The effect of tumor-targeting S. typhimurium A1-R on CD8+ TILs was determined on the Pan02 murine pancreatic-adenocarcinoma implanted orthotopically in the pancreatic tail of C57BL/6 immunocompromised mice. Three weeks after orthotopic implantation, mice were randomized as follows G1: untreated control group (n = 8); and G2: S. typhimurium A1-R-treatment group (n = 8, 1 × 107 colony forming units [CFU]/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor-volume ratio was defined as ratio of tumor volume on the 22nd day relative to the 1st day. The tumor volume ratio was significantly lower in the S. typhimurium A1-R-treated group (G2) (3.0 ± 2.8) than the untreated control (G1) (39.9 ± 30.7, P R-treated mice (G2). Six mice in G1 had peritoneal dissemination, whereas no mice showed peritoneal dissemination in G2 (P R promotes CD8+ T cell infiltration and inhibition of tumor growth and metastasis. J. Cell. Biochem. 119: 634-639, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  3. Tumor-Targeting Salmonella typhimurium A1-R Sensitizes Melanoma With a BRAF-V600E Mutation to Vemurafenib in a Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model.

    Science.gov (United States)

    Kawaguchi, Kei; Igarashi, Kentaro; Murakami, Takashi; Zhao, Ming; Zhang, Yong; Chmielowski, Bartosz; Kiyuna, Tasuku; Nelson, Scott D; Russell, Tara A; Dry, Sarah M; Li, Yunfeng; Unno, Michiaki; Eilber, Fritz C; Hoffman, Robert M

    2017-08-01

    Previously, a BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. Trametinib (TRA), an MEK inhibitor, caused tumor regression. In contrast, another MEK inhibitor, cobimetinib (COB) could slow but not arrest growth or cause regression of the melanoma PDOX. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression. In addition, vemurafenib (VEM) was not effective even though VEM is supposed to target the BRAF-V600E mutation. We also previously demonstrated that tumor-targeting with S. typhimurium A1-R combined with TEM was significantly more effective than either S. typhimurium A1-R alone or TEM alone on the melanoma PDOX with the BRAF-V600E mutation. The present study used this PDOX model of melanoma to test its sensitivity to VEM combined with S. typhimurium A1-R compared to VEM alone and VEM combined with COB. VEM combined with S. typhimurium A1-R was significantly more effective than VEM alone or VEM combined with COB (P = 0.0216) which is currently first line therapy for advanced melanoma with a BRAF-V600E mutation. J. Cell. Biochem. 118: 2314-2319, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  4. Dual tumor-targeted poly(lactic-co-glycolic acid)–polyethylene glycol–folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery

    Science.gov (United States)

    Chen, Jia; Wu, Qi; Luo, Li; Wang, Yi; Zhong, Yuan; Dai, Han-Bin; Sun, Da; Luo, Mao-Ling; Wu, Wei; Wang, Gui-Xue

    2017-01-01

    Further specific target-ability development of biodegradable nanocarriers is extremely important to promote their security and efficiency in antitumor drug-delivery applications. In this study, a facilely prepared poly(lactic-co-glycolic acid) (PLGA)–polyethylene glycol (PEG)–folic acid (FA) copolymer was able to self-assemble into nanoparticles with favorable hydrodynamic diameters of around 100 nm and negative surface charge in aqueous solution, which was expected to enhance intracellular antitumor drug delivery by advanced dual tumor-target effects, ie, enhanced permeability and retention induced the passive target, and FA mediated the positive target. Fluorescence-activated cell-sorting and confocal laser-scanning microscopy results confirmed that doxorubicin (model drug) loaded into PLGA-PEG-FA nanoparticles was able to be delivered efficiently into tumor cells and accumulated at nuclei. In addition, all hemolysis, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, and zebrafish-development experiments demonstrated that PLGA-PEG-FA nanoparticles were biocompatible and secure for biomedical applications, even at high polymer concentration (0.1 mg/mL), both in vitro and in vivo. Therefore, PLGA-PEG-FA nanoparticles provide a feasible controlled-release platform for secure and efficient antitumor drug delivery. PMID:28848351

  5. Tumor-targeted nanomedicines for cancer theranostics.

    Science.gov (United States)

    Arranja, Alexandra G; Pathak, Vertika; Lammers, Twan; Shi, Yang

    2017-01-01

    Chemotherapeutic drugs have multiple drawbacks, including severe side effects and suboptimal therapeutic efficacy. Nanomedicines assist in improving the biodistribution and target accumulation of chemotherapeutic drugs, and are therefore able to enhance the balance between efficacy and toxicity. Multiple types of nanomedicines have been evaluated over the years, including liposomes, polymer-drug conjugates and polymeric micelles, which rely on strategies such as passive targeting, active targeting and triggered release for improved tumor-directed drug delivery. Based on the notion that tumors and metastases are highly heterogeneous, it is important to integrate imaging properties in nanomedicine formulations in order to enable non-invasive and quantitative assessment of targeting efficiency. By allowing for patient pre-selection, such next generation nanotheranostics are useful for facilitating clinical translation and personalizing nanomedicine treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Versatile hyaluronic acid modified AQ4N-Cu(II)-gossypol infinite coordination polymer nanoparticles: Multiple tumor targeting, highly efficient synergistic chemotherapy, and real-time self-monitoring.

    Science.gov (United States)

    Shen, Shihong; Wu, Youshen; Li, Ke; Wang, Ya; Wu, Jimin; Zeng, Yun; Wu, Daocheng

    2018-02-01

    A novel strategy for the preparation of infinite coordination polymer nanoparticles (ICPs) based nanomedicines was developed, with which hyaluronic acid modified AQ4N-Cu(II)-gossypol nanoparticles (HA@AQ4N-Cu(II)-gossypol NPs) were obtained. This is a highly efficient nanomedicine, in which gossypol serves as a chemotherapeutic agent and a self-carrier material; Cu(II) serves as the connecting point and anti-tumor enhancer; AQ4N not only serves as a chemotherapeutic agent and self-carrier material, but also as the self-monitor based on its inherent fluorescence. HA@AQ4N-Cu(II)-gossypol NPs possessed a spherical shape with a dynamic size of 88.7 ± 7.4 nm, and the total drug-loading content and drug encapsulation efficiency are 77.41% and 100%, respectively. This nanomedicine has a multiple tumor-targeting ability caused by HA-receptor mediation and pH-responsive drug release. A significantly low combination index (0.097) of AQ4N and gossypol is ascertained. In vivo experiments indicate that it accumulates and significantly releases drugs at the tumor region. With the use of only one-fiftieth of AQ4N and half of gossypol of the generally administered dose, they can achieve significantly high anti-tumor efficiency with negligible side effects. Importantly, the switching-type changed fluorescence of AQ4N can be used for in vivo real-time self-monitoring of the drug release and distribution, which allows us to adjust the administration dose and time for different tumor types and stages for individual therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Synthesis of star-branched PLA-b-PMPC copolymer micelles as long blood circulation vectors to enhance tumor-targeted delivery of hydrophobic drugs in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Long, Li-xia [Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science & Engineering, Tianjin University, Tianjin 300072 (China); Zhao, Jin, E-mail: zhaojin@tju.edu.cn [Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science & Engineering, Tianjin University, Tianjin 300072 (China); Li, Ke; He, Li-gang; Qian, Xiao-ming; Liu, Chao-yong; Wang, Li-mei; Yang, Xin-qi [Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science & Engineering, Tianjin University, Tianjin 300072 (China); Sun, Jinjin [Department of General Surgery, The Second Hospital of Tianjin Medical University, Tianjin 300211 (China); Ren, Yu [Tianjin Research Center of Basic Medical Science, Tianjin Medical University, Tianjin 300070 (China); Kang, Chun-sheng, E-mail: kang97061@yahoo.com [Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052 (China); Yuan, Xu-bo, E-mail: xbyuan@tju.edu.cn [Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science & Engineering, Tianjin University, Tianjin 300072 (China)

    2016-09-01

    Star-branched amphiphilic copolymer nanocarriers with high-density zwitterionic shell show great promise in drug delivery due to their controllable small size and excellent anti-biofouling properties. This gives the hydrophobic cargo with high stability and long blood circulation in vivo. In the present study, star-branched polylactic acid and poly(2-methacryloyloxyethyl phosphorylcholine) copolymers with (AB{sub 3}){sub 3}–type architecture (PLA-b-PMPC{sub 3}){sub 3} were conceived as drug vectors, and the copolymers were synthesized by an “arm-first” approach via the combination of ring opening polymerization (ROP), atom transfer radical polymerization (ATRP) and the click reaction. The self-assembled star-branched copolymer micelles (sCPM) had an average diameter of about 64.5 nm and exhibited an ultra-hydrophilic surface with an ultralow water contact angle of about 12.7°, which efficiently suppressed the adhesion of serum proteins. In vivo experiments showed that the sCPM loading strongly enhanced the blood circulation time of DiI and the plasma half-life of DiI in sCPM was 19.3 h. The relative accumulation concentration in tumor of DiI delivered by sCPM was 2.37-fold higher than that of PLA-PEG, at 4 h after intravenous injection. These results demonstrated that the star-branched copolymer (PLA-b-PMPC{sub 3}){sub 3} is a promising alternative carrier material for intravenous delivery versus classic PEG-modified strategies. - Highlights: • Star-branched amphiphilic copolymer micelles (sCPM) with zwitterionic shells were prepared. • sCPM possess an ultra-hydrophilic surface and thus inhibited the protein absorption. • sCPM can effectively prolong the cargo’s plasma circulation time. • sCPM can enhance the cargo’s passive tumor-targeted delivery.

  8. WE-G-BRE-07: Proton Therapy Enhanced by Tumor-Targeting Gold Nanoparticles: A Pilot in Vivo Experiment at The Proton Therapy Center at MD Anderson Cancer Center

    Energy Technology Data Exchange (ETDEWEB)

    Wolfe, T; Grant, J; Wolfe, A; Gillin, M; Krishnan, S [MD Anderson Cancer Ctr., Houston, TX (United States)

    2014-06-15

    Purpose: Assess tumor-growth delay and survival in a mouse model of prostate cancer treated with tumor-targeting gold nanoparticles (AuNPs) and proton therapy. Methods: We first examined the accumulation of targeting nanoparticles within prostate tumors by imaging AuNPs with ultrasound-guided photoacoustics at 24h after the intravenous administration of goserelin-conjugated AuNPs (gAuNP) in three mice. Nanoparticles were also imaged at the cellular level with TEM in PC3 cells incubated with gAuNP for 24h. Pegylated AuNPs (pAuNP) were also imaged in vivo and in vitro for comparison. PC3 cells were then implanted subcutaneously in nude mice; 51mice with 8–10mm tumors were included. AuNPs were injected intravenously at 0.2%w/w final gold concentration 24h before irradiation. A special jig was designed to facilitate tumor irradiation perpendicular to the proton beam. Proton energy was set to 180MeV, the radiation field was 18×18cm{sup 2}, and 9cm or 13.5cm thick solid-water compensators were used to position the tumors at either the beam entrance (BE) or the SOBP. Physical doses of 5Gy were delivered to all tumors on a patient beam line at MD Anderson's Proton Therapy Center. Results: The photoacoustic experiment reveled that our nanoparticles leak from the tumor-feeding vasculature and accumulate within the tumor volume over time. Additionally, TEM images showed gAuNP are internalized in cancer cells, accumulating within the cytoplasm, whereas pAuNP are not. Tumor-growth was delayed by 11 or 32days in mice receiving gAuNP irradiated at the BE or the SOBP, relative to proton radiation alone. Survival curves (ongoing experiment) reveal that gAuNPs improved survival by 36% or 74% for tumors irradiated at the BE or SOBP. Conclusion: These important, albeit preliminary, in vivo findings reveal nanoparticles to be potent sensitizers to proton therapy. Further, conjugation of AuNPs to tumor-specific antigens that promote enhanced cellular internalization improved

  9. Cryptophycins: cytotoxic cyclodepsipeptides with potential for tumor targeting.

    Science.gov (United States)

    Weiss, Christine; Figueras, Eduard; Borbely, Adina N; Sewald, Norbert

    2017-07-01

    Cryptophycins are a class of 16-membered highly cytotoxic macrocyclic depsipeptides isolated from cyanobacteria. The biological activity is based on their ability to interact with tubulin. They interfere with microtubule dynamics and prevent microtubules from forming correct mitotic spindles, which causes cell-cycle arrest and apoptosis. Their strong antiproliferative activities with 100-fold to 1000-fold potency compared with those of paclitaxel and vinblastine have been observed. Cryptophycins are highly promising drug candidates, as their biological activity is not negatively affected by P-glycoprotein, a drug efflux system commonly found in multidrug-resistant cancer cell lines and solid tumors. Cryptophycin-52 had been investigated in phase II clinical trials but failed because of its high neurotoxicity. Recently, cryptophycin conjugates with peptides and antibodies have been developed for targeted delivery in tumor therapy. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

  10. Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

    Directory of Open Access Journals (Sweden)

    Grant Sugiura

    2014-02-01

    Full Text Available Owing to their large size proteinaceous drugs offer higher operative information content compared to the small molecules that correspond to the traditional understanding of druglikeness. As a consequence these drugs allow developing patient-specific therapies that provide the means to go beyond the possibilities of current drug therapy. However, the efficacy of these strategies, in particular “personalized medicine”, depends on precise information about individual target expression rates. Molecular imaging combines non-invasive imaging methods with tools of molecular and cellular biology and thus bridges current knowledge to the clinical use. Moreover, nuclear medicine techniques provide therapeutic applications with tracers that behave like the diagnostic tracer. The advantages of radioiodination, still the most versatile radiolabeling strategy, and other labeled compounds comprising covalently attached radioisotopes are compared to the use of chelator-protein conjugates that are complexed with metallic radioisotopes. With the techniques using radioactive isotopes as a reporting unit or even the therapeutic principle, care has to be taken to avoid cleavage of the radionuclide from the protein it is linked to. The tracers used in molecular imaging require labeling techniques that provide site specific conjugation and metabolic stability. Appropriate choice of the radionuclide allows tailoring the properties of the labeled protein to the application required. Until the event of positron emission tomography the spectrum of nuclides used to visualize cellular and biochemical processes was largely restricted to iodine isotopes and 99m-technetium. Today, several nuclides such as 18-fluorine, 68-gallium and 86-yttrium have fundamentally extended the possibilities of tracer design and in turn caused the need for the development of chemical methods for their conjugation.

  11. Engineering of magnetic DNA nanoparticles for tumor-targeted therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hosseinkhani, Hossein, E-mail: hosseinkhani@yahoo.com [Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology (Taiwan Tech) (China); Chen Yiru [National Yang-Ming University, Department of Biomedical Engineering (China); He Wenjie; Hong Poda [Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology (Taiwan Tech) (China); Yu, Dah-Shyong [Nanomedicine Research Center, National Defense Medical Center (China); Domb, Abraham J. [Institute of Drug Research, The Center for Nanoscience and Nanotechnology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem (Israel)

    2013-01-15

    This study aims to engineer novel targeted delivery system composed of magnetic DNA nanoparticles to be effective as an efficient targeted gene therapy vehicle for tumor therapy. A polysaccharide, dextran, was chosen as the vector of plasmid DNA-encoded NK4 that acts as an HGF-antagonist and anti-angiogenic regulator for inhibitions of tumor growth, invasion, and metastasis. Spermine (Sm) was chemically introduced to the hydroxyl groups of dextran to obtain dextran-Sm. When Fe{sup 2+} solution was added to the mixture of dextran-Sm and a plasmid DNA, homogenous DNA nanoparticles were formed via chemical metal coordination bonding with average size of 230 nm. Characterization of DNA nanoparticles was performed via dynamic light scattering measurement, electrophoretic light scattering measurement, as well as transmission electron microscope. DNA nanoparticles effectively condensed plasmid DNA into nanoparticles and enhanced the stability of DNA, while significantly improved transfection efficiency in vitro and tumor accumulation in vivo. In addition, magnetic DNA nanoparticles exhibited high efficiency in antitumor therapy with regards to tumor growth as well as survival of animals evaluated in the presence of external magnetic field. We conclude that the magnetic properties of these DNA nanoparticles would enhance the tracking of non-viral gene delivery systems when administrated in vivo in a test model. These findings suggest that DNA nanoparticles effectively deliver DNA to tumor and thereby inhibiting tumor growth.

  12. Recent Trends in Multifunctional Liposomal Nanocarriers for Enhanced Tumor Targeting

    Directory of Open Access Journals (Sweden)

    Federico Perche

    2013-01-01

    Full Text Available Liposomes are delivery systems that have been used to formulate a vast variety of therapeutic and imaging agents for the past several decades. They have significant advantages over their free forms in terms of pharmacokinetics, sensitivity for cancer diagnosis and therapeutic efficacy. The multifactorial nature of cancer and the complex physiology of the tumor microenvironment require the development of multifunctional nanocarriers. Multifunctional liposomal nanocarriers should combine long blood circulation to improve pharmacokinetics of the loaded agent and selective distribution to the tumor lesion relative to healthy tissues, remote-controlled or tumor stimuli-sensitive extravasation from blood at the tumor’s vicinity, internalization motifs to move from tumor bounds and/or tumor intercellular space to the cytoplasm of cancer cells for effective tumor cell killing. This review will focus on current strategies used for cancer detection and therapy using liposomes with special attention to combination therapies.

  13. Tumor-Targeting Peptides for Therapeutic Gene Delivery

    National Research Council Canada - National Science Library

    Pasqualini, Renata

    2000-01-01

    The identification of markers expressed on specific tumors would give valuable insights into the specialization of tumor vasculature, and would also provide a means of targeting distinct tumor sites...

  14. Amphiphilic Phospholipid-Based Riboflavin Derivatives for Tumor Targeting Nanomedicines

    NARCIS (Netherlands)

    Beztsinna, Nataliia; Tsvetkova, Yoanna; Bartneck, Matthias; Lammers, Twan; Kiessling, Fabian; Bestel, Isabelle

    2016-01-01

    Riboflavin (RF) is an essential vitamin for cellular metabolism. Recent studies have shown that RF is internalized through RF transporters, which are highly overexpressed by prostate and breast cancer cells, as well as by angiogenic endothelium. Here, we present an optimized synthesis protocol for

  15. Investigation of nanobody-decorated albumin nanoparticles for tumor targeting

    NARCIS (Netherlands)

    Altintas, I.

    2013-01-01

    Cancer is still the worldwide leading cause of death. Cancer cells are similar to and different from healthy cells and this makes the eradication of these cells difficult without harming the healthy ones. They are similar in the sense that they share the same cellular machinery with the healthy

  16. Applications of polymeric micelles with tumor targeted in chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Ding Hui; Wang Xiaojun; Zhang Song; Liu Xinli, E-mail: Vip.lxl@163.com [Shandong Polytechnic University, Shandong Provincial Key Laboratory of Microbial Engineering (China)

    2012-11-15

    Polymeric micelles (PMs) have gained more progress as a carrier system with the quick development of biological and nanoparticle techniques. In particular, PMs with smart targeting can deliver anti-cancer drugs directly into tumor cells at a sustained rate. PMs with core-shell structure (with diameters of 10 {approx} 100 nm) have been prepared by a variety of biodegradable and biocompatible polymers via a self-assembly process. The preparation of polymeric micelles with stimuli-responsive block copolymers or modification of target molecules on polymeric micelles' surface are able to significantly improve the efficiency of drug delivery. Polymeric micelles, which have been considered as a novel promising drug carrier for cancer therapeutics, are rapidly evolving and being introduced in an attempt to overcome several limitations of traditional chemotherapeutics, including water solubility, tumor-specific accumulation, anti-tumor efficacy, and non-specific toxicity. This review describes the preparation of polymeric micelles and the targeted modification which greatly enhance the effects of chemotherapeutic agents.

  17. Reduction sensitive nanosystems for tumor targeted imaging and therapy

    NARCIS (Netherlands)

    Zhu, Yaqin

    2017-01-01

    Nanomedicines based on biodegradable polymers for tumor imaging and therapy receive more and more attention due to their improved water solibility, bioavailability, and extended blood circulation times. Advanced polymer chemistry combined with a thorough understanding of the tumor microenvironment,

  18. Amphiphilic Phospholipid-Based Riboflavin Derivatives for Tumor Targeting Nanomedicines.

    Science.gov (United States)

    Beztsinna, Nataliia; Tsvetkova, Yoanna; Bartneck, Matthias; Lammers, Twan; Kiessling, Fabian; Bestel, Isabelle

    2016-09-21

    Riboflavin (RF) is an essential vitamin for cellular metabolism. Recent studies have shown that RF is internalized through RF transporters, which are highly overexpressed by prostate and breast cancer cells, as well as by angiogenic endothelium. Here, we present an optimized synthesis protocol for preparing tailor-made amphiphilic phospholipid-based RF derivatives using phosphoramidite chemistry. The prepared RF amphiphile-RfdiC14-can be inserted into liposome formulations for targeted drug delivery. The obtained liposomes had a hydrodynamic size of 115 ± 5 nm with narrow size distribution (PDI 0.06) and a zeta potential of -52 ± 3 mV. In vitro uptake studies showed that RfdiC14-containing liposomes were strongly internalized in HUVEC, PC3, and A431 cells, in a specific and transporter-mediated manner. To assess the RF targeting potential in vivo, an amphiphile containing PEG spacer between RF and a lipid was prepared-DSPE-PEG-RF. The latter was successfully incorporated into long-circulating near-infrared-labeled liposomes (141 ± 1 nm in diameter, PDI 0.07, zeta potential of -33 ± 1 mV). The longitudinal μCT/FMT biodistribution studies in PC3 xenograft bearing mice demonstrated similar pharmacokinetics profile of DSPE-PEG-RF-functionalized liposomes compared to control. The subsequent histological evaluation of resected tumors revealed higher degree of tumor retention as well as colocalization of targeted liposomes with endothelial cells emphasizing the targeting potential of RF amphiphiles and their utility for the lipid-containing drug delivery systems.

  19. Antibody-IL2 fusion proteins for tumor targeting.

    Science.gov (United States)

    Hombach, Andreas A; Abken, Hinrich

    2012-01-01

    Increasing insight into the misbalance and poor activity of tumor infiltrating immune cells raised interest to activate and improve an antitumor immune response by accumulating IL2 in the tumor tissue. IL2 can be targeted as part of an antibody-cytokine fusion protein to the tumor tissue by a single chain fragment of variable regions (scFv) antibody recognizing a tumor-associated antigen. IL2 can moreover be combined with IL12 in a dual cytokine fusion protein, which simultaneously targets both cooperating cytokines to the tumor in order to improve the activation of both T cells and innate immune cells. We here describe in detail the construction, expression, and functional testing of antibody-IL2 fusion proteins and provide a protocol to determine the biodistribution of such proteins in animal models.

  20. Synthesis and evaluation of radiolabeled peptide multimers for tumor targeting

    NARCIS (Netherlands)

    Yim, C.B.|info:eu-repo/dai/nl/30482268X

    2011-01-01

    Many cancer types express specific receptors on their cellular surface onto which regulatory peptides bind with high affinity. This mechanism can be exploited by labeling the peptide with a radionuclide and using the radiolabeled peptide as a vehicle to guide the radioactivity to receptor-rich

  1. A Survey of Characteristics of Self‑Immolation in the Northern Iran

    African Journals Online (AJOL)

    related to marriage and trousseau in India; and forced marriage in Afghanistan reported as the main factors of self-immolation in young women.[33,34] There was almost a similar finding in our study, where the incidence of self-immolation in most deprived cities was higher than affluent ones.[23]. Finding also demonstrated ...

  2. Derivation of Soil Screening Guidelines for Gross Alpha/Beta Radioactivity for United States Air Force Deployment Sites

    Science.gov (United States)

    2007-04-19

    the emission of 7 alpha particles and 4 beta particles. Three radionuclides ( francium -223, astatine-215, and polonium-211) are not listed below...no no Uranium-233 159,200 y alpha yes no Thorium-229 7,300 y alpha yes no Radium-225 14.9 d beta no no Actinium-225 10.0 d alpha no no Francium

  3. The Blazing Horror of Now

    DEFF Research Database (Denmark)

    Warner, Cameron David

    2012-01-01

    On following posts on Tibetan self-immolation on Facebook and the sense that our normal academic tools of analysis fail to give us the sense that we can derive significant meaning.......On following posts on Tibetan self-immolation on Facebook and the sense that our normal academic tools of analysis fail to give us the sense that we can derive significant meaning....

  4. Improved Tumor Targeting and Longer Retention Time of NIR Fluorescent Probes Using Bioorthogonal Chemistry.

    Science.gov (United States)

    Zhang, Xianghan; Wang, Bo; Zhao, Na; Tian, Zuhong; Dai, Yunpeng; Nie, Yongzhan; Tian, Jie; Wang, Zhongliang; Chen, Xiaoyuan

    2017-01-01

    The traditional labeling method for targeted NIR fluorescence probes requires directly covalent-bonded conjugation of targeting domains and fluorophores in vitro. Although this strategy works well, it is not sufficient for detecting or treating cancers in vivo, due to steric hindrance effects that relatively large fluorophore molecules exert on the configurations and physiological functions of specific targeting domains. The copper-free, "click-chemistry"-assisted assembly of small molecules in living systems may enhance tumor accumulation of fluorescence probes by improving the binding affinities of the targeting factors. Here, we employed a vascular homing peptide, GEBP11, as a targeting factor for gastric tumors, and we demonstrate its effectiveness for in vivo imaging via click-chemistry-mediated conjugation with fluorescence molecules in tumor xenograft mouse models. This strategy showed higher binding affinities than those of the traditional conjugation method, and our results showed that the tumor accumulation of click-chemistry-mediated probes are 11-fold higher than that of directly labeled probes. The tracking life was prolonged by 12-fold, and uptake of the probes into the kidney was reduced by 6.5-fold. For lesion tumors of different sizes, click-chemistry-mediated probes can achieve sufficient signal-to-background ratios (3.5-5) for in vivo detection, and with diagnostic sensitivity approximately 3.5 times that of traditional labeling probes. The click-chemistry-assisted detection strategy utilizes the advantages of "small molecule" probes while not perturbing their physiological functions; this enables tumor detection with high sensitivity and specific selectivity.

  5. To serve and protect: Enzyme inhibitors as radiopeptide escorts promote tumor targeting

    NARCIS (Netherlands)

    B.A. Nock (Berthold); T. Maina (Theodosia); E.P. Krenning (Eric); M. de Jong (Marcel)

    2014-01-01

    textabstractRadiolabeled octreotide analogs are most successfully being applied today in clinical cancer imaging and treatment. Propagation of this paradigm to other radiopeptide families has been greatly hampered by the inherent poor metabolic stability of systemically administered peptide analogs.

  6. Improved tumor targeting of radiolabeled RGD peptides using rapid dose fractionation.

    NARCIS (Netherlands)

    Janssen, M.; Frielink, C.; Dijkgraaf, I.; Oyen, W.J.G.; Edwards, D.S.; Liu, S.; Rajopadhye, M.; Massuger, L.F.A.G.; Corstens, F.H.M.; Boerman, O.C.

    2004-01-01

    Arginine-glycine-aspartic acid (RGD) peptides preferentially bind to alphavbeta3 integrin, an integrin expressed on newly formed endothelial cells and on various tumor cells. When labeled with beta-emitting radionuclides, these peptides can be used for peptide-receptor radionuclide therapy of

  7. Supramolecular organisation and biological properties of tumor targeted, self-assembling protein nanoparticles /

    OpenAIRE

    Pesarrodona Roches, Mireia

    2017-01-01

    Degut a la seva flexibilitat funcional i arquitectònica, l'ús de proteïnes recombinants formades per múltiples dominis representen una eina interesant pel desenvolupament de nanopartícules capaces de transportar fàrmacs de manera específica. Recentment, en el nostre grup, hem aplicat un nou sistema d'enginyeria pel desenvolupament de nanoparticles formades mitjançant l'oligomerització de proteïnes modulars. L'eficàcia selectiva i l'absència de toxicitat d'unes nanopartícules dirigides al cànc...

  8. Enhanced anticancer efficacy and tumor targeting through folate-PEG modified nanoliposome loaded with 5-fluorouracil

    Science.gov (United States)

    Le, Van Minh; Tran Nho, Trung Duc; Trieu Ly, Hai; Vo, Thanh Sang; Dung Nguyen, Hoang; Thu Huong Phung, Thi; Zou, Aihua; Liu, Jianwen

    2017-03-01

    Cancer targeted therapies have attracted considerable attention over the past year. Recently, 5-fluouracil (5-FU), which has high toxicity to normal cells and short half-life associated with rapid metabolism, is one of the most commonly used therapies in the treatment of cancer. In this study the folic acid-conjugated pegylated nanoliposomes were synthesized and then loaded into them with 5-FU to improve the anti-tumor efficacy. The average size of liposomes (LPs) was about 52.7 nm which was identified by TEM. In the liposome uptake studies, the level uptake of folate-conjugated liposomes has increased compared to non-conjugated LPs according to LPs concentration, incubation time and presence of concentration of free folic acid (FA). The MTT assay and apoptotic test were carried out in HCT116 and MCF-7 cells for 24 or 48 h. The results revealed that the folate-PEG modified 5-Fu loaded nanoliposomes had strong cytotoxicity to cancer cell compared to pure 5-FU or PEG modified 5-FU loaded liposomes in a concentration- and time-dependent manner, and mainly enhanced the cancer cell death through folate-mediated endocytosis. Hence, the folate-PEG modified nanoliposome is a potential targeted drug-delivery system for the treatment of FR-positive cancers.

  9. Synthesis and characterization of tumor-targeted copolymer nanocarrier modified by transferrin

    Directory of Open Access Journals (Sweden)

    Liu R

    2015-05-01

    Full Text Available Ran Liu,1,2 Yonglu Wang,1,3 Xueming Li,3 Wen Bao,1,2 Guohua Xia,1,2 Wei Chen,3 Jian Cheng,1,2 Yuanlong Xu,3 Liting Guo,1,2 Baoan Chen1,21Department of Hematology (Key Department of Jiangsu Medicine, Zhongda Hospital, Medical School, 2Faculty of Oncology, Medical School, Southeast University, 3College of Pharmacy, Nanjing University of Technology, Nanjing, People’s Republic of China Abstract: To increase the encapsulation of hydrophilic antitumor agent daunorubicin (DNR and multidrug resistance reversal agent tetrandrine (Tet in the drug delivery system of nanoparticles (NPs, a functional copolymer NP composed of poly(lactic-co-glycolic acid (PLGA, poly-l-lysine (PLL, and polyethylene glycol (PEG was synthesized and then loaded with DNR and Tet simultaneously to construct DNR/Tet–PLGA–PLL–PEG-NPs using a modified double-emulsion solvent evaporation/diffusion method. And to increase the targeted antitumor effect, DNR/Tet–PLGA–PLL–PEG-NPs were further modified with transferrin (Tf due to its specific binding to Tf receptors (TfR, which is highly expressed on the surface of tumor cells. In this study, the influence of the diversity of formulation parameters was investigated systematically, such as drug loading, mean particle size, molecular weight, the concentration of PLGA–PLL–PEG–Tf, volume ratio of acetone to dichloromethane, the concentration of polyvinyl alcohol (PVA in the external aqueous phase, the volume ratio of the internal aqueous phase to the external aqueous phase, and the type of surfactants in the internal aqueous phase. Meanwhile, its possible effect on cell viability was evaluated. Our results showed that the regular spherical DNR/Tet–PLGA–PLL–PEG–Tf-NPs with a smooth surface, a relatively low polydispersity index, and a diameter of 213.0±12.0 nm could be produced. The encapsulation efficiency was 70.23%±1.91% for DNR and 86.5%±0.70% for Tet, the moderate drug loading was 3.63%±0.15% for DNR and 4.27%±0.13% for Tet. Notably, the accumulated release of DNR and Tet could be sustained over 1 week, and the Tf content was 2.18%±0.04%. In cell viability tests, DNR/Tet–PLGA–PLL–PEG–Tf-NPs could inhibit the proliferation of K562/ADR cells in a dose-dependent manner, and the half maximal inhibitory concentration value (total drug of DNR/Tet–PLGA–PLL–PEG–Tf-NPs was lower than that of DNR, a mixture of DNR and Tet, and DNR/Tet–PLGA–PLL–PEG-NPs. These results clearly indicate that the PLGA–PLL–PEG formulation is a potential drug delivery system for hydrophilic and hydrophobic drugs, and that Tf modification may increase its targeting properties. Keywords: PLGA, PLL, PEG, daunorubicin, tetrandrine

  10. Tumor-Targeting Therapy Using Gene-Engineered Anaerobic-Nonpathogenic Bifidobacterium longum.

    Science.gov (United States)

    Taniguchi, Shun'ichiro; Shimatani, Yuko; Fujimori, Minoru

    2016-01-01

    Despite great progress in molecular-targeting drugs for cancer treatment, there are problems of disease recurrence due to cancer-cell resistance to those drugs, derived from the heterogeneity of tumors. On one hand, the low-oxygen microenvironment present in malignant tumor tissues has been regarded as a source of resistance of cancer cells against conventional therapie, such as radiation and chemotherapy. To overcome these problems, we have been developing a system to selectively deliver a large amount of anticancer drugs to malignant tumors by making use of the limiting factor, hypoxia, in tumors. Our strategy is to use hypoxia as a selective target. Here, we show methods and protocols using the nonpathogenic obligate anaerobic Bifidobacterium longum as a drug-delivery system (DDS) to target anaerobic tumor tissue.

  11. Development of a novel small antibody that retains specificity for tumor targeting

    Directory of Open Access Journals (Sweden)

    Zhang Si-Yuan

    2009-04-01

    Full Text Available Abstract Background For the targeted therapy of solid tumor mediated by monoclonal antibody (mAb, there have different models of rebuilding small antibodies originated from native ones. Almost all natural antibody molecules have the similar structure and conformation, but those rebuilt small antibodies cannot completely keep the original traits of parental antibodies, especially the reduced specificity, which gravely influences the efficacy of small antibodies. Methods In this study, authors developed a novel mimetic in the form of VHFR1C-10-VHCDR1-VHFR2-VLCDR3-VLFR4N-10for a parental mAb induced with human breast cancer, and the mimetic moiety was conjugated to the C-terminal of toxicin colicin Ia. The novel fusion peptide, named protomimecin (PMN, was administered to MCF-7 breast cancer cells to demonstrate its killing competency in vitro and in vivo. Results Compared with original antibody-colicin Ia (Fab-Ia and single-chain antibody-colicin Ia (Sc-Ia fusion proteins, PMN retained the targeting specificity of parental antibody and could specifically kill MCF-7 cells in vitro. By injecting intraperitoneally into BALB/c athymic mice bearing MCF-7 tumors, with reduced affinity, PMN significantly suppressed the growth of tumors compared with control mice treated by toxicin protein, Fab-Ia protein, Sc-Ia protein or by PBS (p Conclusion This novel mimetic antibody retained original specificity of parental antibody, and could effectively guide killer moiety to suppress the growth of breast cancer by targeted cell death.

  12. Fluorescent and quantitative mitochondrial redox imaging of tumor targeted by Octa-RGD probe

    Directory of Open Access Journals (Sweden)

    Shuang Sha

    2016-07-01

    Full Text Available Integrins, over-expressed in a broad range of cancer diseases, are widely utilized as a tumor biomarker. Metabolism investigation also plays important roles in tumor theranostics. Developing simple integrin-targetting probe and monitoring tumor metabolism will give opportunities to find ways for cancer treatment, however, the investigation of tumor metabolism with integrin receptor based probes has been rarely reported so far. Here, we developed an octavalent fluorescent probe Octa-RGD by convenient genetic method, based on one tetrameric far-red fluorescent protein (fRFP linked with RGD peptides. We validated its intergin targeting by confocal imaging in vitro. Then we screened a variety of tumor cells, and differentiated their binding affinity based on the fluorescence of the probe via flow cytometry. Among these cells, CNE-2 cells had the highest uptake of the probe, while B16 cells had the lowest, corresponding with their intergin expression levels. Next, the fluorescent and metabolic imaging was performed in HT1080 (intergin postive tumor, where nicotinamide adenine dinucleotide hydrogen (NADH, flavoprotein (Fp and fRFP fluorescent signals were collected. The tumor from mice intravenously injected with Octa-RGD probe displayed obviously higher NADH redox ratio NADH/(Fp+NADH and fRFP signal, than those with fRFP protein. It suggested that integrin targeting may have influence on the target cell metabolism, and further demonstrated Octa-RGD probe facilitated its uptake in the targeted tumor in vivo. This paper developed a useful probe, which can bind integrins specifically and efficiently in tumor cells, and together with tumor metabolic information, it may provide new insight for RGD targeting-based cancer therapeutics.

  13. Radiolabeled gastrin/CCK analogs in tumor diagnosis: towards higher stability and improved tumor targeting.

    Science.gov (United States)

    Kaloudi, A; Nock, B A; Krenning, E P; Maina, T; De Jong, M

    2015-09-01

    Cholecystokinin subtype 2 receptors (CCK2R) are overexpressed in several human cancers, including medullary thyroid carcinoma. Gastrin and cholecystokinin (CCK) peptides that bind with high affinity and specificity to CCK2R can be used as carriers of radioactivity to CCK2R-expressing tumor sites. Several gastrin and CCK related peptides have been proposed for diagnostic imaging and radionuclide therapy of primary and metastatic CCK2R-positive human tumors. Their clinical application has been restricted to a great extent by their fast in vivo degradation that eventually compromises tumor uptake. This problem has been addressed by structural modifications of gastrin and CCK motifs, which, however, often lead to suboptimal pharmacokinetic profiles. A major enzyme implicated in the catabolism of gastrin and CCK based peptides is neutral endopeptidase (NEP), which is widely distributed in the body. Coinjection of the NEP inhibitor phosphoramidon (PA) with radiolabeled gastrin and other peptide analogs has been recently proposed as a new promising strategy to increase bioavailability and tumor-localization of radiopeptides in tumor sites. Specifically, co-administration of PA with the truncated gastrin analog [(111)In-DOTA]MG11 ([((111)In-DOTA)DGlu(10)]gastrin(10-17)) impressively enhanced the levels of intact radiopeptide in mouse circulation and has led to an 8-fold increase of CCK2R-positive tumor uptake in SCID mice. This increased tumor uptake, visualized also by SPECT/CT imaging, is expected to eventually translate into higher diagnostic sensitivity and improved therapeutic efficacy of radiolabeled gastrin analogs in CCK2R-expressing cancer patients.

  14. Molecular tumor targeting of gelonin by fusion with F3 peptide.

    Science.gov (United States)

    Ham, Song-Hee; Min, Kyoung Ah; Shin, Meong Cheol

    2017-06-01

    Therapeutically potent macromolecular drugs have shown great promise for overcoming the limitations of small-molecule anti-cancer drugs. But tumor cell-selective intracellular delivery of the macromolecules remains a major hurdle for their successful clinical application. To overcome this challenge, we engineered a novel genetic fusion protein (F3-Gel) that composed of F3 peptide, a tumor-homing peptide, and gelonin, a plant-derived ribosome-inactivating protein (RIP), and then evaluated its anti-cancer activity in vitro and in vivo. The F3-Gel-encoding gene was synthesized by genetic recombination, and F3-Gel was successfully expressed in E coli. The anti-cancer activity of the produced F3-Gel was evaluated by various in vitro assays, which revealed that F3-Gel maintained equipotent protein synthesis inhibition activity (IC50=11 pmol/L) as unmodified gelonin (IC50=10 pmol/L). Furthermore, F3-Gel displayed enhanced cellular uptake into cancer cells (U87 MG, HeLa, LnCaP and 9L) than noncancerous cells (293 HEK and SVGp12). Compared with gelonin, F3-Gel exerted significantly higher cytotoxicity against these cancer cells. F3-Gel displayed significantly greater inhibition of protein translation in U87 MG cells: F3-Gel (0.5 μmol/L) was able to reduce the protein level to less than 50%, while gelonin (1 μmol/L) did not affect the intracellular protein level. In a U87 MG xenograft tumor-bearing mouse model, F3-Gel was accumulated in the tumor site at much higher levels and maintained for a prolonged time compared with gelonin. Administration of F3-Gel (0.5, 0.75 mol/kg, iv) caused 36% and 66%, respectively, inhibition of tumor growth in U87 MG xenograft mice, suggesting that it is a promising candidate drug for cancer treatment. Furthermore, this study demonstrates that fusion of F3 peptide to a potent macromolecule could provides an effective method for targeting tumors and eventually could improve their druggability.

  15. Molecular tumor targeting of gelonin by fusion with F3 peptide

    National Research Council Canada - National Science Library

    Song-Hee HAM Kyoung Ah MIN Meong Cheol SHIN

    2017-01-01

    .... To overcome this challenge, we engineered a novel genetic fusion protein (F3-Gel) that composed of F3 peptide, a tumor- homing peptide, and gelonin, a plant-derived ribosome-inactivating protein (RIP...

  16. Multimodality imaging in vivo for preclinical assessment of tumor-targeted doxorubicin nanoparticles.

    Directory of Open Access Journals (Sweden)

    Jae Youn Hwang

    Full Text Available This study presents a new multimodal imaging approach that includes high-frequency ultrasound, fluorescence intensity, confocal, and spectral imaging to improve the preclinical evaluation of new therapeutics in vivo. Here we use this approach to assess in vivo the therapeutic efficacy of the novel chemotherapy construct, HerDox during and after treatment. HerDox is comprised of doxorubicin non-covalently assembled in a viral-like particle targeted to HER2+ tumor cells, causing tumor cell death at over 10-fold lower dose compared to the untargeted drug, while sparing the heart. Whereas our initial proof-of-principle studies on HerDox used tumor growth/shrinkage rates as a measure of therapeutic efficacy, here we show that multimodal imaging deployed during and after treatment can supplement traditional modes of tumor monitoring to further characterize the particle in tissues of treated mice. Specifically, we show here that tumor cell apoptosis elicited by HerDox can be monitored in vivo during treatment using high frequency ultrasound imaging, while in situ confocal imaging of excised tumors shows that HerDox indeed penetrated tumor tissue and can be detected at the subcellular level, including in the nucleus, via Dox fluorescence. In addition, ratiometric spectral imaging of the same tumor tissue enables quantitative discrimination of HerDox fluorescence from autofluorescence in situ. In contrast to standard approaches of preclinical assessment, this new method provides multiple/complementary information that may shorten the time required for initial evaluation of in vivo efficacy, thus potentially reducing the time and cost for translating new drug molecules into the clinic.

  17. Multimodality imaging in vivo for preclinical assessment of tumor-targeted doxorubicin nanoparticles.

    Science.gov (United States)

    Hwang, Jae Youn; Park, Jinhyoung; Kang, Bong Jin; Lubow, David J; Chu, David; Farkas, Daniel L; Shung, K Kirk; Medina-Kauwe, Lali K

    2012-01-01

    This study presents a new multimodal imaging approach that includes high-frequency ultrasound, fluorescence intensity, confocal, and spectral imaging to improve the preclinical evaluation of new therapeutics in vivo. Here we use this approach to assess in vivo the therapeutic efficacy of the novel chemotherapy construct, HerDox during and after treatment. HerDox is comprised of doxorubicin non-covalently assembled in a viral-like particle targeted to HER2+ tumor cells, causing tumor cell death at over 10-fold lower dose compared to the untargeted drug, while sparing the heart. Whereas our initial proof-of-principle studies on HerDox used tumor growth/shrinkage rates as a measure of therapeutic efficacy, here we show that multimodal imaging deployed during and after treatment can supplement traditional modes of tumor monitoring to further characterize the particle in tissues of treated mice. Specifically, we show here that tumor cell apoptosis elicited by HerDox can be monitored in vivo during treatment using high frequency ultrasound imaging, while in situ confocal imaging of excised tumors shows that HerDox indeed penetrated tumor tissue and can be detected at the subcellular level, including in the nucleus, via Dox fluorescence. In addition, ratiometric spectral imaging of the same tumor tissue enables quantitative discrimination of HerDox fluorescence from autofluorescence in situ. In contrast to standard approaches of preclinical assessment, this new method provides multiple/complementary information that may shorten the time required for initial evaluation of in vivo efficacy, thus potentially reducing the time and cost for translating new drug molecules into the clinic.

  18. Solid Tumor-Targeting Theranostic Polymer Nanoparticle in Nuclear Medicinal Fields

    OpenAIRE

    Akira Makino; Shunsaku Kimura

    2014-01-01

    Polymer nanoparticles can be prepared by self-assembling of amphiphilic polymers, and various types of molecular assemblies have been reported. In particular, in medicinal fields, utilization of these polymer nanoparticles as carriers for drug delivery system (DDS) has been actively tried, and some nanoparticulate drugs are currently under preclinical evaluations. A radionuclide is an unstable nucleus and decays with emission of radioactive rays, which can be utilized as a tracer in the diagn...

  19. A Glycyrrhetinic Acid-Modified Curcumin Supramolecular Hydrogel for liver tumor targeting therapy

    Science.gov (United States)

    Chen, Guoqin; Li, Jinliang; Cai, Yanbin; Zhan, Jie; Gao, Jie; Song, Mingcai; Shi, Yang; Yang, Zhimou

    2017-03-01

    Curcumin (Cur), a phenolic anti-oxidant compound obtained from Curcuma longa plant, possesses a variety of therapeutic properties. However, it is suffered from its low water solubility and low bioavailability property, which seriously restricts its clinical application. In this study, we developed a glycyrrhetinic acid (GA) modified curcumin supramolecular pro-gelator (GA-Cur) and a control compound Nap-Cur by replacing GA with the naphthylacetic acid (Nap). Both compounds showed good water solubility and could form supramolecular gels by disulfide bond reduction triggered by glutathione (GSH) in vitro. Both formed gels could sustainedly release Cur in buffer solutions. We also investigated the cytotoxicity of pro-gelators to HepG2 cells by a MTT assay and determined the cellular uptake behaviours of them by fluorescence microscopy and LC-MS. Due to the over expression of GA receptor in liver cancer cells, our pro-gelator of GA-Cur showed an enhanced cellular uptake and better inhibition capacity to liver tumor cells than Nap-Cur. Therefore, the GA-Cur could significantly inhibit HepG2 cell growth. Our study provides a novel nanomaterial for liver tumor chemotherapy.

  20. Liposomes containing alkylated methotrexate analogues for phospholipase A(2) mediated tumor targeted drug delivery

    DEFF Research Database (Denmark)

    Kaasgaard, Thomas; Andresen, Thomas Lars; Jensen, Simon Skøde

    2009-01-01

    scanning calorimetry (DSC), and sPLA(2) hydrolysis was examined by fluorescence spectroscopy and high performance liquid chromatography (HPLC). The results showed that the methotrexate (MTX)-analogue could be incorporated into liposomes that were degradable by sPLA(2). However, the in vitro cytotoxicity...... of the MTX-liposomes against KATO III and HT-29 cancer cells was found to be independent of sPLA(2) hydrolysis, indicating that the alkylated MTX-analogue was available for cancer cell uptake even in the absence of liposome hydrolysis. Using a DSC based method for assessing the anchoring stability...... tightly anchored to the liposomal carrier. Also, the developed DSC-assay for Studying the anchoring stability of alkylated drugs will be a useful tool in the development of liposomal drug delivery Systems....

  1. Nano-siRNA Particles and Combination Therapies for Ovarian Tumor Targeting

    Science.gov (United States)

    2015-08-01

    Gallagher • P.T. Hammond, Elected Fellow of American Academy of Arts and Sciences, October 2013 • P.T. Hammond, recipient, AIChE Stine Award in Materials...P. A. Proceedings of the National Academy of Sciences of the United States of America 2011, 108, 745. (6) Vivas -Mejia, P. E.; Rodriguez-Aguayo

  2. Solid tumor-targeting theranostic polymer nanoparticle in nuclear medicinal fields

    National Research Council Canada - National Science Library

    Makino, Akira; Kimura, Shunsaku

    2014-01-01

    .... A radionuclide is an unstable nucleus and decays with emission of radioactive rays, which can be utilized as a tracer in the diagnostic imaging systems of PET and SPECT and also in therapeutic purposes...

  3. Bimodal tumor-targeting from microenvironment responsive hyaluronan layer-by-layer (LbL) nanoparticles.

    Science.gov (United States)

    Dreaden, Erik C; Morton, Stephen W; Shopsowitz, Kevin E; Choi, Jae-Hyeok; Deng, Zhou J; Cho, Nam-Joon; Hammond, Paula T

    2014-08-26

    Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful strategy for tumor-specific cancer diagnostics and therapy that can be accomplished using a single bilayer of polyamine and hyaluronan that, when assembled, produce a dynamic and responsive cell-particle interface.

  4. Fabrication of 14 different RNA nanoparticles for specific tumor targeting without accumulation in normal organs.

    Science.gov (United States)

    Shu, Yi; Haque, Farzin; Shu, Dan; Li, Wei; Zhu, Zhenqi; Kotb, Malak; Lyubchenko, Yuri; Guo, Peixuan

    2013-06-01

    Due to structural flexibility, RNase sensitivity, and serum instability, RNA nanoparticles with concrete shapes for in vivo application remain challenging to construct. Here we report the construction of 14 RNA nanoparticles with solid shapes for targeting cancers specifically. These RNA nanoparticles were resistant to RNase degradation, stable in serum for >36 h, and stable in vivo after systemic injection. By applying RNA nanotechnology and exemplifying with these 14 RNA nanoparticles, we have established the technology and developed "toolkits" utilizing a variety of principles to construct RNA architectures with diverse shapes and angles. The structure elements of phi29 motor pRNA were utilized for fabrication of dimers, twins, trimers, triplets, tetramers, quadruplets, pentamers, hexamers, heptamers, and other higher-order oligomers, as well as branched diverse architectures via hand-in-hand, foot-to-foot, and arm-on-arm interactions. These novel RNA nanostructures harbor resourceful functionalities for numerous applications in nanotechnology and medicine. It was found that all incorporated functional modules, such as siRNA, ribozymes, aptamers, and other functionalities, folded correctly and functioned independently within the nanoparticles. The incorporation of all functionalities was achieved prior, but not subsequent, to the assembly of the RNA nanoparticles, thus ensuring the production of homogeneous therapeutic nanoparticles. More importantly, upon systemic injection, these RNA nanoparticles targeted cancer exclusively in vivo without accumulation in normal organs and tissues. These findings open a new territory for cancer targeting and treatment. The versatility and diversity in structure and function derived from one biological RNA molecule implies immense potential concealed within the RNA nanotechnology field.

  5. A Heparan Sulfate-Binding Cell Penetrating Peptide for Tumor Targeting and Migration Inhibition

    Directory of Open Access Journals (Sweden)

    Chien-Jung Chen

    2015-01-01

    Full Text Available As heparan sulfate proteoglycans (HSPGs are known as co-receptors to interact with numerous growth factors and then modulate downstream biological activities, overexpression of HS/HSPG on cell surface acts as an increasingly reliable prognostic factor in tumor progression. Cell penetrating peptides (CPPs are short-chain peptides developed as functionalized vectors for delivery approaches of impermeable agents. On cell surface negatively charged HS provides the initial attachment of basic CPPs by electrostatic interaction, leading to multiple cellular effects. Here a functional peptide (CPPecp has been identified from critical HS binding region in hRNase3, a unique RNase family member with in vitro antitumor activity. In this study we analyze a set of HS-binding CPPs derived from natural proteins including CPPecp. In addition to cellular binding and internalization, CPPecp demonstrated multiple functions including strong binding activity to tumor cell surface with higher HS expression, significant inhibitory effects on cancer cell migration, and suppression of angiogenesis in vitro and in vivo. Moreover, different from conventional highly basic CPPs, CPPecp facilitated magnetic nanoparticle to selectively target tumor site in vivo. Therefore, CPPecp could engage its capacity to be developed as biomaterials for diagnostic imaging agent, therapeutic supplement, or functionalized vector for drug delivery.

  6. Nano-siRNA Particles and Combination Therapies for Ovarian Tumor Targeting

    Science.gov (United States)

    2014-08-01

    clearance from IV-administered BALB/c mice with various LbL-ODN-NPs formulations - fit with a 2-phase decay model (PRISM®). C) Necropsy was...pharmacokinetics (Figure Z). Necropsy and live animal imaging of mice injected with the siRNA complexes show that by 30 minutes post-injection, the...OVISE using the following antibodies, Rabbit polyclonal anti-phosphorylated Ɣ-H2A, anti-RAD51, anti-PARP1, anti-p53. Preliminary data show increased

  7. Tumor Targeting of Polymeric Nanoparticles Conjugated with Peptides, Saccharides, and Small Molecules for Anticancer Drugs.

    Science.gov (United States)

    Bayram, Banu; Özgür, Aykut; Tutar, Lütfi; Tutar, Yusuf

    2017-06-07

    Targeting drugs or pharmaceutical compounds to tumor site increases cancer treatment efficiency and therapeutic outcome. Nanoparticles are unique delivery systems for site-targeting within an organism. Many novel technologies have been established in drug research and development area. Nanotechnology now offers nanometer size polymeric nanoparticles and these particles direct drugs to their targets, protect drugs against degradation, and release the drug in a controlled manner. Modification of nanoparticle surface by molecules leads to prolonged retention and accumulation in the target area of the organism. Current efforts of designing polymeric nanoparticles include drug activation in the target area, controlled drug release at the site upon stimulation, and increased drug loading capacity of drug polymer conjugates. Recent progress in molecular mechanism elucidation of cancer cell and rising research in nanoparticle designs may provide efficient cancer treatment modality and innovative nanoparticle designs in the near future. Recent years have seen many developments in the field of innovative peptide based drug nanoparticles. Although none of them approved to be used in clinic yet, peptides are promising structures due to their simple and non-antigenic nature. Biodegrable materials are also preferred materials in drug delivery. Polysaccharide-based micelle systems improve hydrophobic drug and protein delivery. Ease of saccharide structure modification improves pharmacokinetic and pharmacodynamic properties of drug molecules as well as their delivery to a specific site in a controlled manner and sustained rate. Small molecules, especially drugs, conjugated to nanoparticles and several nanoparticles of this type are in the clinical trials and at the market. This review provides recent developments of polymeric nanoparticles conjugated with peptides, saccharides, and small molecules in cancer theraphy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Biodegradable Micellar HPMA-Based Polymer-Drug Conjugates with Betulinic Acid for Passive Tumor Targeting.

    Science.gov (United States)

    Lomkova, Ekaterina A; Chytil, Petr; Janoušková, Olga; Mueller, Thomas; Lucas, Henrike; Filippov, Sergey K; Trhlíková, Olga; Aleshunin, Pavel A; Skorik, Yury A; Ulbrich, Karel; Etrych, Tomáš

    2016-11-14

    Here, we present the synthesis, physicochemical, and preliminary biological characterization of micellar polymer-betulinic acid (BA) conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers, enabling the controlled release of cytotoxic BA derivatives in solid tumors or tumor cells. Various HPMA copolymer conjugates differing in the structure of the spacer between the drug and the carrier were synthesized, all designed for pH-triggered drug release in tumor tissue or tumor cells. The high molecular weight of the micellar conjugates should improve the uptake of the drug in solid tumors due to the Enhanced permeability and retention (EPR) effect. Nevertheless, only the conjugate containing BA with methylated carboxyl groups enabled pH-dependent controlled release in vitro. Moreover, drug release led to the disassembly of the micellar structure, which facilitated elimination of the water-soluble HPMA copolymer carrier from the body by renal filtration. The methylated BA derivative and its polymer conjugate exhibited high cytostatic activity against DLD-1, HT-29, and HeLa carcinoma cell lines and enhanced tumor accumulation in HT-29 xenograft in mice.

  9. Polymeric immunonanoparticles for active tumor targeting: preparation, characterization and "in vivo" evaluation

    OpenAIRE

    Cirstoiu, Adriana

    2009-01-01

    L'objectif de cette thèse a été de développer et d'évaluer l'efficacité d'un nouveau traitement du cancer ovarien par ciblage actif de la tumeur, en utilisant des immunonanoparticules polymériques biodégradables chargées en paclitaxel. Dans un premier temps, on a mis au point des immunonanoparticules fonctionnalisées en surface par des anticorps monoclonaux: Herceptin® (trastuzumab, anti-HER2). Ensuite, des études in vitro et in vivo ont été menées pour déterminer l'efficacité de cette nouvel...

  10. EAG2 potassium channel with evolutionarily conserved function as a brain tumor target

    Science.gov (United States)

    Huang, Xi; He, Ye; Dubuc, Adrian M.; Hashizume, Rintaro; Zhang, Wei; Reimand, Jüri; Yang, Huanghe; Wang, Tongfei A.; Stehbens, Samantha J.; Younger, Susan; Barshow, Suzanne; Zhu, Sijun; Cooper, Michael K.; Peacock, John; Ramaswamy, Vijay; Garzia, Livia; Wu, Xiaochong; Remke, Marc; Forester, Craig M.; Kim, Charles C.; Weiss, William A.; James, C. David; Shuman, Marc A.; Bader, Gary D.; Mueller, Sabine; Taylor, Michael D.; Jan, Yuh Nung; Jan, Lily Yeh

    2015-01-01

    Over 20% of the drugs for treating human diseases target ion channels, however, no cancer drug approved by the U.S. Food and Drug Administration (FDA) is intended to target an ion channel. Here, we demonstrate the evolutionarily conserved function of EAG2 potassium channel in promoting brain tumor growth and metastasis, delineate downstream pathways and uncover a mechanism for different potassium channels to functionally corporate and regulate mitotic cell volume and tumor progression. We show that EAG2 potassium channel is enriched at the trailing edge of migrating MB cells to regulate local cell volume dynamics, thereby facilitating cell motility. We identify the FDA-approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings thus illustrate the potential of targeting ion channels in cancer treatment. PMID:26258683

  11. Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment.

    Science.gov (United States)

    Scarfò, Irene; Maus, Marcela V

    2017-01-01

    Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for haematological malignancies (i.e. B-ALL). However, the success of this type of treatment has not yet been achieved in solid tumors. One hypothesis is that the immunosuppressive nature of the tumor microenvironment (TME) influences and affects the efficacy of adoptive immunotherapy. Understanding the role of the TME and its interaction with CAR T-cells is crucial to improve the potency of adoptive immunotherapy. In this review, we discuss the strategies and potential combinatorial approaches recently developed in mouse models to enhance the efficacy of CAR T-cells, with particular emphasis on the translational potential of these approaches.

  12. Tumor Targeting Potential of Lipid-Based Nano-Pharmaceuticals (LNPs)

    Science.gov (United States)

    Gupta, Kshitij; Yavlovich, Amichai; Puri, Anu; Blumenthal, Robert

    2013-09-01

    Nanoparticle-mediated targeted drug delivery has become the modality of interest for cancer/tumor therapy as it reduces the undesirable delivery to normal cells and improves efficacy of the pharmaceuticals. Among all the nanosystems, lipid-based nano-pharmaceuticals (LNPs) have been most extensively studied for cancer therapy. Doxil formulation was the first LNP that has been approved for cancer treatment. When conjugated with ligands, LNPs can be targeted to tumor cells. This chapter focuses on the targeting potential of LNPs for cancer therapy. We will discuss the advantages of enhanced permeability and retention (EPR) effect (passive targeting) for preferential tumor accumulation of LNPs, the importance of pegylation to avoid reticulo-endothelial system uptake and active targeting strategies using various targeting ligands that can be coupled to the LNP surface to target the tumor region (tumor cells/tumor vasculature). Targeted LNPs show higher binding affinity, greater intracellular localization and thereby increased cancer cell killing in comparison to non targeted LNPs. However, contrasting reports exist that pose challenges to the notion that targeted LNPs are advantageous. Recent trends have also demonstrated the concept of dual targeting that simultaneously homes LNPs to receptors on the tumor cells and biomarkers expressed on the tumor vasculature. In addition, targeting with multiple ligands on the LNPs has also been explored. These approaches may prove to be a better answer for next generation of LNPs for delivery of anti-cancer agents. However, more extensive studies are required to get their clinical approval in anti-cancer therapy.

  13. Simple PEG modification of DNA aptamer based on copper ion coordination for tumor targeting.

    Science.gov (United States)

    Takafuji, Yoshimasa; Jo, Jun-ichiro; Tabata, Yasuhiko

    2011-01-01

    A simple modification of a DNA aptamer with poly(ethylene glycol) (PEG) based on metal coordination was developed. N,N-bis(carboxymethyl)-L-lysine (NTA) of a metal chelate residue was chemically introduced to one terminus of PEG. The NTA-introduced PEG (PEG-NTA) chelated Cu(2+) ions form a Cu(2+)-chelated PEG (PEG-Cu). When PEG-Cu was mixed with a DNA aptamer of anti-tumor activity (AS1411) in aqueous solution, a complex of PEG-Cu and AS1411 based on metal coordination was formed. The complex inhibited in vitro tumor growth in a dose-dependent manner. A body distribution study with tumor-bearing mice revealed that PEG-Cu-AS1411 complexes injected intravenously had a significant longer lifetime in the blood circulation and 1.5-2.0-fold higher accumulation in the tumor tissue than free AS1411. Intravenous injection of complexes suppressed the in vivo growth of tumor mass to a significantly greater extent compared with that of free AS1411. The Cu(2+)-coordinated PEG modification is a simple and promising method to enhance accumulation of the aptamer in the tumor, resulting in the augmented anti-tumor effect.

  14. An assessment tumor targeting ability of 177Lu labeled cyclic CCK analogue peptide by binding with cholecystokinin receptor

    Directory of Open Access Journals (Sweden)

    Eun-Ha Cho

    2016-07-01

    Full Text Available The cholecystokinin (CCK receptor is known as a receptor that is overexpressed in many human tumors. The present study was designed to investigate the targeting ability of cyclic CCK analogue in AR42J pancreatic cells. The CCK analogues, DOTA-K(glucose-Gly-Trp-Nle-Asp-Phe (DOTA-glucose-CCK and DOTA-Nle-cyclo(Glu-Trp-Nle-Asp-Phe-Lys-NH2 (DOTA-[Nle]-cCCK, were synthesized and radiolabeled with 177Lu, and competitive binding was evaluated. The binding appearance of synthesized peptide with AR42J cells was evaluated by confocal microscopy. And bio-distribution was performed in AR42J xenografted mice. Synthesized peptides were prepared by a solid phase synthesis method, and their purity was over 98%. DOTA is the chelating agent for 177Lu-labeling, in which the peptides were radiolabeled with 177Lu by a high radiolabeling yield. A competitive displacement of 125I-CCK8 on the AR42J cells revealed that the 50% inhibitory concentration value (IC50 was 12.3 nM of DOTA-glucose-CCK and 1.7 nM of DOTA-[Nle]-cCCK. Radio-labeled peptides were accumulated in AR42J tumor in vivo, and %ID/g of the tumor was 0.4 and 0.9 at 2 h p.i. It was concluded that 177Lu-DOTA-[Nle]-cCCK has higher binding affinity than 177Lu-DOTA-glucose-CCK and can be a potential candidate as a targeting modality for a CCK receptor over-expressing tumors.

  15. Clinical Safety and Immunogenicity of Tumor-Targeted, Plant-Made Id-KLH Conjugate Vaccines for Follicular Lymphoma

    Directory of Open Access Journals (Sweden)

    Daniel Tusé

    2015-01-01

    Full Text Available We report the first evaluation of plant-made conjugate vaccines for targeted treatment of B-cell follicular lymphoma (FL in a Phase I safety and immunogenicity clinical study. Each recombinant personalized immunogen consisted of a tumor-derived, plant-produced idiotypic antibody (Ab hybrid comprising the hypervariable regions of the tumor-associated light and heavy Ab chains, genetically grafted onto a common human IgG1 scaffold. Each immunogen was produced in Nicotiana benthamiana plants using twin magnICON vectors expressing the light and heavy chains of the idiotypic Ab. Each purified Ab was chemically linked to the carrier protein keyhole limpet hemocyanin (KLH to form a conjugate vaccine. The vaccines were administered to FL patients over a series of ≥6 subcutaneous injections in conjunction with the adjuvant Leukine (GM-CSF. The 27 patients enrolled in the study had previously received non-anti-CD20 cytoreductive therapy followed by ≥4 months of immune recovery prior to first vaccination. Of 11 patients who became evaluable at study conclusion, 82% (9/11 displayed a vaccine-induced, idiotype-specific cellular and/or humoral immune response. No patients showed serious adverse events (SAE related to vaccination. The fully scalable plant-based manufacturing process yields safe and immunogenic personalized FL vaccines that can be produced within weeks of obtaining patient biopsies.

  16. Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy

    Science.gov (United States)

    Kim, Kyoung Sub; Kim, Jiyoung; Lee, Joo Young; Matsuda, Shofu; Hideshima, Sho; Mori, Yasurou; Osaka, Tetsuya; Na, Kun

    2016-06-01

    Despite magnetic nanoparticles having shown great potential in cancer treatment, tremendous challenges related to diagnostic sensitivity and treatment efficacy for clinical application remain. Herein, we designed optimized multifunctional magnetite nanoparticles (AHP@MNPs), composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid (AHP), to achieve enhanced tumor diagnosis and therapy. Fe3O4 nanoparticles (MNPs) were synthesized by a facile hydrolysis method. MNPs have higher biocompatibility, controllable particle sizes, and desirable magnetic properties. The fabricated AHP@MNPs have enhanced water solubility (average size: 108.13 +/- 1.08 nm), heat generation properties, and singlet oxygen generation properties upon magnetic and laser irradiation. The AHP@MNPs can target tumors via CD44 receptor-mediated endocytosis, which have enhanced tumor therapeutic effects through photodynamic/hyperthermia-combined treatment without any drugs. We successfully detected tumors implanted in mice via magnetic resonance imaging and optical imaging. Furthermore, we demonstrated the photodynamic/hyperthermia-combined therapeutic efficacy of AHP@MNPs with synergistically enhanced efficacy against cancer.Despite magnetic nanoparticles having shown great potential in cancer treatment, tremendous challenges related to diagnostic sensitivity and treatment efficacy for clinical application remain. Herein, we designed optimized multifunctional magnetite nanoparticles (AHP@MNPs), composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid (AHP), to achieve enhanced tumor diagnosis and therapy. Fe3O4 nanoparticles (MNPs) were synthesized by a facile hydrolysis method. MNPs have higher biocompatibility, controllable particle sizes, and desirable magnetic properties. The fabricated AHP@MNPs have enhanced water solubility (average size: 108.13 +/- 1.08 nm), heat generation properties, and singlet oxygen generation properties upon magnetic and laser irradiation. The AHP@MNPs can target tumors via CD44 receptor-mediated endocytosis, which have enhanced tumor therapeutic effects through photodynamic/hyperthermia-combined treatment without any drugs. We successfully detected tumors implanted in mice via magnetic resonance imaging and optical imaging. Furthermore, we demonstrated the photodynamic/hyperthermia-combined therapeutic efficacy of AHP@MNPs with synergistically enhanced efficacy against cancer. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr02273a

  17. Role of Exosomes Released by Dendritic Cells and/or by Tumor Targets: Regulation of NK Cell Plasticity.

    Science.gov (United States)

    Reiners, Katrin S; Dassler, Juliane; Coch, Christoph; Pogge von Strandmann, Elke

    2014-01-01

    Exosomes are endosomal-derived nanovesicles released by normal and tumor cells, which transfer functionally active proteins, lipids, and nucleic acids between cells. They are important mediators of intercellular communication and act on the adjacent stroma as well as in the periphery. Recently, exosomes have been recognized to play a pathophysiological role in various diseases such as cancer or infectious diseases. Tumor cell-derived exosomes (Tex) have been shown to act as tumor promotors by educating non-malignant cells to provide a tumor supporting microenvironment, which helps to circumvent immune detection by the host and supports metastasis. However, Tex with anti-tumor, immune-activating properties were also described reflecting the complexity of exosomes. Here, we assess the role of extracellular microvesicles/exosomes as messengers affecting NK cell function in health and disease and discuss the molecular basis for the differential impact of exosomes on NK cell activity. The molecular composition/load of exosomes and the mechanisms regulating their release remain unclear and need to be further analyzed to facilitate the development of new treatment options targeting the exosomal machinery.

  18. High Affinity Binders to EphA2 Isolated from Abdurin Scaffold Libraries; Characterization, Binding and Tumor Targeting.

    Directory of Open Access Journals (Sweden)

    Christopher Ullman

    Full Text Available Abdurins are a novel antibody-like scaffold derived from the engineering of a single isolated CH2 domain of human IgG. Previous studies established the prolonged serum half-life of Abdurins, the result of a retained FcRn binding motif. Here we present data on the construction of large, diverse, phage-display and cell-free DNA display libraries and the isolation of high affinity binders to the cancer target, membrane-bound ephrin receptor tyrosine kinase class A2 (EphA2. Antigen binding regions were created by designing combinatorial libraries into the structural loops and Abdurins were selected using phage display methods. Initial binders were reformatted into new maturation libraries and low nanomolar binders were isolated using cell-free DNA display, CIS display. Further characterization confirmed binding of the Abdurins to both human and murine EphA2 proteins and exclusively to cell lines that expressed EphA2, followed by rapid internalization. Two different EphA2 binders were labeled with 64Cu, using a bifunctional MeCOSar chelator, and administered to mice bearing tumors from transplanted human prostate cancer cells, followed by PET/CT imaging. The anti-EphA2 Abdurins localized in the tumors as early as 4 hours after injection and continued to accumulate up to 48 hours when the imaging was completed. These data demonstrate the ability to isolate high affinity binders from the engineered Abdurin scaffold, which retain a long serum half-life, and specifically target tumors in a xenograft model.

  19. Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles: in vitro and in vivo studies.

    Science.gov (United States)

    Kaul, Goldie; Amiji, Mansoor

    2005-06-01

    To develop safe and effective systemically administered nonviral gene therapy vectors for solid tumors, DNA-containing poly(ethylene glycol)-modified (PEGylated) gelatin nanoparticles were fabricated and evaluated in vitro and in vivo. Reporter plasmid DNA encoding for beta-galactosidase (pCMV-beta) was encapsulated in gelatin and PEGylated gelatin nanoparticles using a water-ethanol solvent displacement method under controlled pH and temperature. Lewis lung carcinoma (LLC) cells in culture were transfected with the pCMV-beta in the control and nanoparticle formulations. Periodically, the expression of beta-galactosidase in the cells was measured quantitatively using an enzymatic assay for the conversion of o-nitrophenyl-beta-D: -galactopyranoside (ONPG) to o-nitrophenol (ONP). Qualitative expression of beta-galactosidase in LLC cells was observed by staining with 5-bromo-4-chloro-3-indolyl-beta-D: -galactopyranoside (X-gal). Additionally, the plasmid DNA-encapsulated gelatin and PEGylated gelatin nanoparticles were administered intravenously (i.v.) and intratumorally (i.t.) to LLC-bearing female C57BL/6J mice. At various time points postadministration, the animals were sacrificed and transgene expression in the tumor and liver was determined quantitatively by the ONPG to ONP enzymatic conversion assay and qualitatively by X-gal staining. Almost 100% of the pCMV-beta was encapsulated in gelatin and PEGylated gelatin nanoparticles (mean diameter 200 nm) at 0.5% (w/w) concentration. PEGylated gelatin nanoparticles efficiently transfected the LLC cells and the beta-galactosidase expression, as measured by the ONPG to ONP enzymatic conversion assay at 420 nm absorbance, increased starting from 12 h until 96 h post-transfection. The efficient expression of LLC cells was also evident by the X-gal staining method that shows blue color formation. The in vivo studies showed significant expression of beta-galactosidase in the tumor following administration of DNA-containing PEGylated gelatin nanoparticles to LLC-bearing mice by both i.v. and i.t. routes. Following i.v. administration of pCMV-beta in PEGylated gelatin nanoparticles, for instance, the absorbance at 420 nm per gram of tumor increased from 0.60 after 12 h to 0.85 after 96 h of transfection. After i.t. administration, the absorbance values increased from 0.90 after 12 h to almost 1.4 after 96 h. The in vitro and in vivo results of this study clearly show that a long-circulating, biocompatible and biodegradable, DNA-encapsulating nanoparticulate system would be highly desirable for systemic delivery of genetic constructs to solid tumors.

  20. Doxorubicin/gold-loaded core/shell nanoparticles for combination therapy to treat cancer through the enhanced tumor targeting.

    Science.gov (United States)

    Kim, Kyungim; Oh, Keun Sang; Park, Dal Yong; Lee, Jae Young; Lee, Beom Suk; Kim, In San; Kim, Kwangmeyung; Kwon, Ick Chan; Sang, Yoon Kim; Yuk, Soon Hong

    2016-04-28

    A combination therapy consisting of radiotherapy and chemotherapy is performed using the core/shell nanoparticles (NPs) containing gold NPs and doxorubicin (DOX). Gold NPs in the core/shell NPs were utilized as a radiosensitizer. To examine the morphology and size distribution of the core/shell NPs, transmittance electron microscopy and dynamic light scattering were used. The in vitro release behavior, cellular uptake and toxicity were also observed to verify the functionality of the core/shell NPs as a nanocarrier. To demonstrate the advantage of the core/shell NPs over traditional gold NPs reported in the combination therapy, we evaluated the accumulation behavior of the core/shell NPs at the tumor site using the biodistribution. Antitumor efficacy was observed with and without radiation to evaluate the role of gold NPs as a radiosensitizer. Copyright © 2016. Published by Elsevier B.V.

  1. Aminated β-Cyclodextrin-Modified-Carboxylated Magnetic Cobalt/Nanocellulose Composite for Tumor-Targeted Gene Delivery

    Directory of Open Access Journals (Sweden)

    Thayyath Sreenivasan Anirudhan

    2014-01-01

    Full Text Available Gene therapy is a new kind of medicine, which uses genes as drugs in order to treat life threatening diseases. In the present work, a nonviral vector, aminated β-cyclodextrin-modified-carboxylated magnetic cobalt/nanocellulose composite (ACDC-Co/NCC, was synthesized for efficient transfection of genes into tumour cells. The synthesized ACDC-Co/NCC was characterized by means of FTIR, XRD, SEM, and ESR techniques. DNA condensing ability of ACDC-Co/NCC was found to be increased with increase in amount of ACDC-Co/NCC and 84.9% of DNA (1.0 μg/mL inclusion was observed with 6.0 μg/mL of ACDC-Co/NCC. The cytotoxicity of ACDC-Co/NCC was observed to be minimal, even at higher concentration, with respect to the model transfecting agent, poly(ethyleneimine (PEI. 88.2% of the gene was transfected at high dose of DNA, as indicated by the highest luciferase expression. These results indicated that ACDC-Co/NCC might be a promising candidate for gene delivery with the characteristics of good biocompatibility, potential biodegradability, minimal cytotoxicity, and relatively high gene transfection efficiency.

  2. Comparative study on radiolabeling and biodistribution of core-shell silver/polymeric nanoparticles-based theranostics for tumor targeting.

    Science.gov (United States)

    Farrag, Nourihan S; El-Sabagh, Hanan A; Al-Mahallawi, Abdulaziz M; Amin, Abeer M; AbdEl-Bary, Ahmed; Mamdouh, Wael

    2017-08-30

    A simple and rapid method for radiolabeling of three types of Ag NPs has been performed using 125I isotope, with high labeling yields, >90% without disturbing the optical properties. All the factors affecting labeling yield were studied. In order to monitor the in-vivo tissue uptake of radiolabeled Ag NPs using γ-rays, Ag-based radioiodo-NPs with a maximum labeling yield were intravenously injected in normal and solid tumor bearing mice. The preliminary biodistribution study revealed that this new radioiodo-NPs have a high affinity to be localized in the tumor site for a long period of time. The reported highly efficient method provides new radiolabeled Ag-based NPs as tumor-specific agents for both diagnostic and therapeutic applications. Copyright © 2017. Published by Elsevier B.V.

  3. Theranostic tumor targeted nanoparticles combining drug delivery with dual near infrared and 19F magnetic resonance imaging modalities.

    Science.gov (United States)

    Vu-Quang, Hieu; Vinding, Mads Sloth; Nielsen, Thomas; Ullisch, Marcus Görge; Nielsen, Niels Chr; Kjems, Jørgen

    2016-10-01

    Combining imaging and drug delivery of "theranostic" nanoparticles has enabled concurrent diagnosis and therapy of diseases. Here, we describe a novel theranostic system that combines two imaging tracers, perfluorooctyl bromide (PFOB) for 19F magnetic resonance imaging (MRI) and indocyanine green (ICG) for near infrared (NIR) imaging, with the chemotherapeutic agent doxorubicin (Dox) into poly (lactic-co-glycolic acid)- poly (ethylene-glycol)-folate (PLGA-PEG-folate) nanoparticles. Cell culture studies using flow cytometry, confocal laser scanning microscope imaging, and 19F MRI showed enhanced uptake of nanoparticles via folate receptors expressed on human nasopharyngeal epidermal carcinoma (KB) cells. In vivo, higher MRI and fluorescence signals were obtained from tumors with 19F MRI and NIR, respectively, using folate-receptor-targeted nanoparticles compared with non-targeted equivalents. An in vitro cytotoxicity assay showed that folate-targeted nanoparticles were able to kill cancer cells more efficiently than non-folate conjugated particles. Our results suggest a potential use of PLGA-PEG-folate PFOB/ICG/Dox nanoparticles as a targeted chemotherapy agent traceable by either 19F MRI or NIR imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody

    Science.gov (United States)

    2014-05-01

    in May 2013, the difference between nude mice (which lack T- cells , but still have a partially functional adaptive and innate immune system) and NSG...Mangada J, Greiner DL, Handgretinger R. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human...Targeting of Cerebral Breast Cancer Metastases Using a T- Cell Receptor Mimic Antibody PRINCIPAL INVESTIGATOR: Ulrich Bickel

  5. Tumor targeting using {sup 67}Ga-DOTA-Bz-folate - investigations of methods to improve the tissue distribution of radiofolates

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Cristina, E-mail: cristina.mueller@psi.ch [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Vlahov, Iontcho R.; Santhapuram, Hari Krishna R.; Leamon, Christopher P. [Endocyte Inc., West Lafayette, IN 47906 (United States); Schibli, Roger [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich (Switzerland)

    2011-07-15

    Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [{sup 67}Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-({gamma})-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with {sup 67}GaCl{sub 3} according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: {sup 67}Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%{+-}0.75% ID/g, 1 h pi and 6.08%{+-}0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of {sup 67}Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel {sup 67}Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR-positive cancer and potentially inflammatory diseases. Due to its rapid blood clearance properties, this tracer is also a promising candidate for positron emission tomography imaging if radiolabeled with the short-lived [{sup 68}Ga]-gallium radionuclide.

  6. Engineering Intrinsically Zirconium‐89 Radiolabeled Self‐Destructing Mesoporous Silica Nanostructures for In Vivo Biodistribution and Tumor Targeting Studies

    National Research Council Canada - National Science Library

    Goel, Shreya; Chen, Feng; Luan, Shijie; Valdovinos, Hector F; Shi, Sixiang; Graves, Stephen A; Ai, Fanrong; Barnhart, Todd E; Theuer, Charles P; Cai, Weibo

    2016-01-01

    .... The as‐synthesized bMSNs are intrinsically radiolabeled with oxophilic zirconium‐89 ( 89 Zr, t 1/2 = 78.4 h) radionuclide to track their in vivo pharmacokinetics via positron emission tomography imaging...

  7. Multifunctional nanosheets based on hyaluronic acid modified graphene oxide for tumor-targeting chemo-photothermal therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hou, Lin; Feng, Qianhua; Wang, Yating; Zhang, Huijuan; Jiang, Guixiang; Yang, Xiaomin; Ren, Junxiao; Zhu, Xiali; Shi, Yuyang; Zhang, Zhenzhong, E-mail: zhangzz-pharm@163.com [Zhengzhou University, School of Pharmaceutical Sciences (China)

    2015-03-15

    Graphene oxide (GO) with strong optical absorption in the near-infrared (NIR) region has shown great potential both in photothermal therapy and drug delivery. In this work, hyaluronic acid (HA)-functionalized GO (HA-GO) was successfully synthesized and controlled loading of mitoxantrone (MIT) onto HA-GO via π–π stacking interaction was investigated. The results revealed that drug-loaded nanosheets with high loading efficiency of 45 wt% exhibited pH-sensitive responses to tumor environment. Owing to the receptor-mediated endocytosis, cellular uptake analysis of HA-GO showed enhanced internalization. In vivo optical imaging test demonstrated that HA-GO nanosheets could enhance the targeting ability and residence time in tumor site. Moreover, the anti-tumor activity of free MIT, MIT/GO, and MIT/HA-GO in combination with NIR laser was investigated using human MCF-7 cells. In vitro cytotoxicity study revealed that HA-GO could stand as a biocompatible nanocarrier and MIT/HA-GO demonstrated remarkably higher toxicity than free MIT and MIT/GO, with IC{sub 50} of 0.79 µg ml{sup −1}. Tumor cell-killing potency was enhanced when MIT/HA-GO were combined with NIR irradiation, and the IC{sub 50} of MIT/HA-GO plus laser irradiation was 0.38 µg ml{sup −1}. In vivo, MIT/HA-GO plus NIR laser irradiation with the tumor growth inhibition of 93.52 % displayed greater anti-tumor effect compared with free MIT and MIT/GO with or without laser irradiation. Therefore, the MIT/HA-GO nanosheets may potentially be useful for further development of synergistic cancer therapy.

  8. Tumor-targeted gene therapy using Adv-AFP-HRPC/IAA prodrug system suppresses growth of hepatoma xenografted in mice.

    Science.gov (United States)

    Dai, M; Liu, J; Chen, D-E; Rao, Y; Tang, Z-J; Ho, W-Z; Dong, C-Y

    2012-02-01

    Clinical efficacy of current therapies for hepatocellular carcinoma (HCC) treatment is limited. Indole-3-acetic acid (IAA) is non-toxic for mammalian cells. Oxidative decarboxylation of IAA by horseradish peroxidase (HRP) leads to toxic effects of IAA. The purpose of this study was to investigate the effects of a novel gene-targeted enzyme prodrug therapy with IAA on hepatoma growth in vitro and in vivo mouse hepatoma models. We generated a plasmid using adenovirus to express HRP isoenzyme C (HRPC) with the HCC marker, alpha-fetoprotein (AFP), as the promoter (pAdv-AFP-HRPC). Hepatocellular cells were infected with pAdv-AFP-HRPC and treated with IAA. Cell death was detected using MTT assay. Hepatoma xenografts were developed in mice by injection of mouse hepatoma cells. The size and weight of tumors and organs were evaluated. Cell death in tumors was assessed using hematoxylin and eosin-stained tissue sections. HRPC expression in tissues was detected using Reverse Transcriptase-Polymerase Chain Reaction. IAA stimulated death of hepatocellular cells infected with pAdv-AFP-HRPC, in a dose- and time-dependent manner, but not in control cells. Growth of hepatoma xenografts, including the size and weight, was inhibited in mice treated with pAdv-AFP-HRPC and IAA, compared with that in control group. pAdv-AFP-HRPC/IAA treatment induced cell death in hepatoma xenografts in mice. HRPC gene expressed only in hepatoma, but not in other normal organs of mice. pAdv-AFP-HRPC/IAA treatment did not cause any side effects on normal organs. These findings suggest that pAdv-AFP-HRPC/IAA enzyme/prodrug system may serve as a strategy for HCC therapy.

  9. Intracellular delivery and passive tumor targeting of a self-assembled nanogel containing carborane clusters for boron neutron capture therapy.

    Science.gov (United States)

    Kawasaki, Riku; Sasaki, Yoshihiro; Akiyoshi, Kazunari

    2017-01-29

    Boron neutron capture therapy, based on the release of thermal neutron irradiation from boron, is a targeted radiation therapy for cancer. Targeted and sufficient accumulation of boron in tumor cells to achieve cytotoxic efficacy and reduce off-target effects remains a challenge. Carborane has been investigated for use as a delivery agent in boron neutron capture therapy because of its high boron content and chemical stability; however, it is cytotoxic, making safe delivery difficult. The aim of this study was to investigate the potential of carborane-bearing pullulan nanogels to safely and effectively deliver boron to tumor cells in vitro and in vivo and, consequently, assess their potential as a boron neutron capture therapeutic. Murine fibrosarcoma cells (CMS5a) were used for in vitro investigations of nanogel cytotoxicity, cell uptake. A mouse fibrosarcoma xenograft model was used to investigate the bio-distribution of nanogels after intravenous administration. The nanogels produced no apparent cytotoxicity and underwent cell uptake in CMS5a cells after a 24 h incubation at up to 2000 μg/mL and 400 μg/mL, respectively. The internalized nanogels were localized around the nuclear membrane. The nanogels were administered intravenously to mice bearing fibrosarcoma xenografts. Nanogel tumor localization likely occurred through the enhanced permeation and retention effect. The nanogels successfully reduced the cytotoxicity of carborane, were internalized into tumor cells, acted as a dual-delivery therapeutic and accumulated in tumors in vivo. Consequently, they demonstrate significant potential as a boron neutron capture therapeutic. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Folate-conjugated pH-responsive nanocarrier designed for active tumor targeting and controlled release of doxorubicin

    Science.gov (United States)

    Wei, Lulu; Lu, Beibei; Cui, Lin; Peng, Xueying; Wu, Jianning; Li, Deqiang; Liu, Zhiyong; Guo, Xuhong

    2017-12-01

    A novel type of amphiphilic pH-responsive folate-poly(ɛ-caprolactone)- block-poly(2-hydroxyethylmethacrylate)- co-poly(2-(dimethylamino)-ethylmethacrylate) (FA-PCL- b-P(HEMA- co-DMAEMA)) (MFP) block copolymers were designed and synthesized via atom transfer radical polymerization (ATRP) and ring opening polymerization (ROP) techniques. The molecular structures of the copolymers were confirmed with 1H NMR, FTIR and GPC measurements. The critical micelle concentration (CMC) of MFP in aqueous solution was extremely low (about 6.54 mg/L). The in vitro release behavior of DOX-loaded micelles was significantly accelerated when the pH value of solution decreased from 7.4 to 5.0. In vitro antitumor efficiency was evaluated by incubating DOX-loaded micelles with Hela cells. The results demonstrated that this copolymer possessed excellent biocompatibility, and FA-decorated micelles MFP showed higher cellular uptake than those micelles without the FA moiety, indicating their unique targetability. These folate-conjugated biodegradable micelles are highly promising for targeted cancer chemothe-rapy.

  11. Iron oxide core oil-in-water emulsions as a multifunctional nanoparticle platform for tumor targeting and imaging

    NARCIS (Netherlands)

    Jarzyna, Peter A.; Skajaa, Torjus; Gianella, Anita; Cormode, David P.; Samber, Daniel D.; Dickson, Stephen D.; Chen, Wei; Griffioen, Arjan W.; Fayad, Zahi A.; Mulder, Willem J. M.

    2009-01-01

    Nanoemulsions are increasingly investigated for the delivery of hydrophobic drugs to improve their bioavailability or make their administration possible. In the current study, oil-in-water emulsions with three different mean diameters (30, 60, and 95 nm) were developed as a new multimodality

  12. Folate-conjugated pH-responsive nanocarrier designed for active tumor targeting and controlled release of doxorubicin

    Science.gov (United States)

    Wei, Lulu; Lu, Beibei; Cui, Lin; Peng, Xueying; Wu, Jianning; Li, Deqiang; Liu, Zhiyong; Guo, Xuhong

    2017-11-01

    A novel type of amphiphilic pH-responsive folate-poly(ɛ-caprolactone)-block-poly(2-hydroxyethylmethacrylate)-co-poly(2-(dimethylamino)-ethylmethacrylate) (FA-PCL-b-P(HEMA-co-DMAEMA)) (MFP) block copolymers were designed and synthesized via atom transfer radical polymerization (ATRP) and ring opening polymerization (ROP) techniques. The molecular structures of the copolymers were confirmed with 1H NMR, FTIR and GPC measurements. The critical micelle concentration (CMC) of MFP in aqueous solution was extremely low (about 6.54 mg/L). The in vitro release behavior of DOX-loaded micelles was significantly accelerated when the pH value of solution decreased from 7.4 to 5.0. In vitro antitumor efficiency was evaluated by incubating DOXloaded micelles with Hela cells. The results demonstrated that this copolymer possessed excellent biocompatibility, and FA-decorated micelles MFP showed higher cellular uptake than those micelles without the FA moiety, indicating their unique targetability. These folate-conjugated biodegradable micelles are highly promising for targeted cancer chemothe-rapy.

  13. Dual-stimuli responsive and reversibly activatable theranostic nanoprobe for precision tumor-targeting and fluorescence-guided photothermal therapy

    Science.gov (United States)

    Zhao, Xu; Yang, Cheng-Xiong; Chen, Li-Gong; Yan, Xiu-Ping

    2017-05-01

    The integrated functions of diagnostics and therapeutics make theranostics great potential for personalized medicine. Stimulus-responsive therapy allows spatial control of therapeutic effect only in the site of interest, and offers promising opportunities for imaging-guided precision therapy. However, the imaging strategies in previous stimulus-responsive therapies are `always on' or irreversible `turn on' modality, resulting in poor signal-to-noise ratios or even `false positive' results. Here we show the design of dual-stimuli-responsive and reversibly activatable nanoprobe for precision tumour-targeting and fluorescence-guided photothermal therapy. We fabricate the nanoprobe from asymmetric cyanine and glycosyl-functionalized gold nanorods (AuNRs) with matrix metalloproteinases (MMPs)-specific peptide as a linker to achieve MMPs/pH synergistic and pH reversible activation. The unique activation and glycosyl targetibility makes the nanoprobe bright only in tumour sites with negligible background, while AuNRs and asymmetric cyanine give synergistic photothermal effect. This work paves the way to designing efficient nanoprobes for precision theranostics.

  14. Folate-decorated chitosan/doxorubicin poly(butyl)cyanoacrylate nanoparticles for tumor-targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Duan Jinghua [Xiangya Hospital, Central South University, Hepatobiliary and Enteric Surgery Research Center (China); Liu Mujun [Central South University, School of Biological Science and Technology (China); Zhang Yangde; Zhao Jinfeng; Pan Yifeng [Xiangya Hospital, Central South University, Hepatobiliary and Enteric Surgery Research Center (China); Yang Xiyun, E-mail: bax_2007@126.com [Central South University, School of Metallurgical Science and Engineering (China)

    2012-03-15

    A novel chitosan coated poly(butyl cyanoacrylate) (PBCA) nanoparticles loaded doxorubicin (DOX) were synthesized and then conjugated with folic acid to produce a folate-targeted drug carrier for tumor-specific drug delivery. Prepared nanoparticles were surface modified by folate for targeting cancer cells, which is confirmed by FTIR spectroscopy and characterized for shape, size, and zeta potential measurements. The size and zeta potential of prepared DOX-PBCA nanoparticles (DOX-PBCA NPs) were almost 174 {+-} 8.23 nm and +23.14 {+-} 4.25 mV, respectively with 46.8 {+-} 3.32% encapsulation capacity. The transmission electron microscopy study revealed that preparation allowed the formation of spherical nanometric and homogeneous. Fluorescent microscopy imaging and flow cytometry analysis revealed that DOX-PBCA NPs were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells. The results demonstrate that folate-conjugated DOX-PBCA NPs drug delivery system could provide increased therapeutic benefit by delivering the encapsulated drug to the folate receptor positive cancer cells.

  15. Application of ion exchange and extraction chromatography to the separation of actinium from proton-irradiated thorium metal for analytical purposes.

    Science.gov (United States)

    Radchenko, V; Engle, J W; Wilson, J J; Maassen, J R; Nortier, F M; Taylor, W A; Birnbaum, E R; Hudston, L A; John, K D; Fassbender, M E

    2015-02-06

    Actinium-225 (t1/2=9.92d) is an α-emitting radionuclide with nuclear properties well-suited for use in targeted alpha therapy (TAT), a powerful treatment method for malignant tumors. Actinium-225 can also be utilized as a generator for (213)Bi (t1/2 45.6 min), which is another valuable candidate for TAT. Actinium-225 can be produced via proton irradiation of thorium metal; however, long-lived (227)Ac (t1/2=21.8a, 99% β(-), 1% α) is co-produced during this process and will impact the quality of the final product. Thus, accurate assays are needed to determine the (225)Ac/(227)Ac ratio, which is dependent on beam energy, irradiation time and target design. Accurate actinium assays, in turn, require efficient separation of actinium isotopes from both the Th matrix and highly radioactive activation by-products, especially radiolanthanides formed from proton-induced fission. In this study, we introduce a novel, selective chromatographic technique for the recovery and purification of actinium isotopes from irradiated Th matrices. A two-step sequence of cation exchange and extraction chromatography was implemented. Radiolanthanides were quantitatively removed from Ac, and no non-Ac radionuclidic impurities were detected in the final Ac fraction. An (225)Ac spike added prior to separation was recovered at ≥ 98%, and Ac decontamination from Th was found to be ≥ 10(6). The purified actinium fraction allowed for highly accurate (227)Ac determination at analytical scales, i.e., at (227)Ac activities of 1-100 kBq (27 nCi to 2.7 μCi). Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Contemporary Journal of African Studies - Vol 4, No 1 (2016)

    African Journals Online (AJOL)

    The Trope of Apotheosis and Intimations of Self-Immolation: A Deconstructive Interpretation of Mother-Daughter Dynamics in Chika Unigwe's Night Dancer · EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. Sola Owonibi, Funmilayo Gaji, 129-153 ...

  17. Browse Title Index

    African Journals Online (AJOL)

    Items 1 - 49 of 49 ... Vol 4, No 1 (2016), The Trope of Apotheosis and Intimations of Self-Immolation: A Deconstructive Interpretation of Mother-Daughter Dynamics in Chika Unigwe's Night Dancer, Abstract. Sola Owonibi, Funmilayo Gaji. Vol 4, No 1 (2016), Traditional Earth Houses in Vittin, Tamale: Identity and perception of ...

  18. Teenage Suicide in Zimbabwe.

    Science.gov (United States)

    Lester, David; Wilson, C.

    1990-01-01

    The teenage suicide rate in Zimbabwe did not change much during the 1970s, though the rate rose for female teenagers. Female teenagers used poison as a method of suicide more often than did adults, and self-immolation had increased in frequency among young women by the mid-1980s. (Author)

  19. A DT-diaphorase responsive theranostic prodrug for diagnosis, drug release monitoring and therapy.

    Science.gov (United States)

    Liu, Peilian; Xu, Jiangsheng; Yan, Donghang; Zhang, Peisheng; Zeng, Fang; Li, Bowen; Wu, Shuizhu

    2015-06-11

    A DT-diaphorase-activatable theranostic prodrug, which contains camptothecin, a self-immolative linker and a trigger group, has been developed for the detection of DT-diaphorase, tracking of drug release and selectively killing cancer cells over-expressed with DT-diaphorase. This strategy may offer a new approach for the development of enzyme-catalyzed theranostic anticancer therapeutics.

  20. In vivo tumor targeting and imaging with anti-vascular endothelial growth factor antibody-conjugated dextran-coated iron oxide nanoparticles

    National Research Council Canada - National Science Library

    Hsieh, Wan-Ju; Liang, Chan-Jung; Chieh, Jen-Jie; Wang, Shu-Huei; Lai, I-Rue; Chen, Jyh-Horng; Chang, Fu-Hsiung; Tseng, Wei-Kung; Yang, Shieh-Yueh; Wu, Chau-Chung; Chen, Yuh-Lien

    2012-01-01

    ...). The aim of the present study is to investigate whether the systemic delivery of antivascular endothelial growth factor antibodies conjugating to the surface of functionalized supermagnetic iron oxide nanoparticles (anti-VEGF-NPs...

  1. Design and Fabrication of Multifunctional Sericin Nanoparticles for Tumor Targeting and pH-Responsive Subcellular Delivery of Cancer Chemotherapy Drugs.

    Science.gov (United States)

    Huang, Lei; Tao, Kaixiong; Liu, Jia; Qi, Chao; Xu, Luming; Chang, Panpan; Gao, Jinbo; Shuai, Xiaoming; Wang, Guobin; Wang, Zheng; Wang, Lin

    2016-03-01

    The severe cytotoxicity of cancer chemotherapy drugs limits their clinical applications. Various protein-based nanoparticles with good biocompatibility have been developed for chemotherapy drug delivery in hope of reducing drugs' side effects. Sericin, a natural protein from silk, has no immunogenicity and possesses diverse bioactivities that have prompted sericin's application studies. However, the potential of sericin as a multifunctional nanoscale vehicle for cancer therapy have not been fully explored. Here we report the successful fabrication and characterization of folate-conjugated sericin nanoparticles with cancer-targeting capability for pH-responsive release of doxorubicin (these nanoparticles are termed "FA-SND"). DOX is covalently linked to sericin through pH-sensitive hydrazone bonds that render a pH-triggered release property. The hydrophobicity of DOX and the hydrophilicity of sericin promote the self-assembly of sericin-DOX (SND) nanoconjugates. Folate (FA) is then covalently grafted to SND nanoconjugates as a binding unit for actively targeting cancer cells that overexpress folate receptors. Our characterization study shows that FA-SND nanoparticles exhibit negative surface charges that would reduce nonspecific clearance by circulation. These nanoparticles possess good cytotoxicity and hemocompatibiliy. Acidic environment (pH 5.0) triggers effective DOX release from FA-SND, 5-fold higher than does a neutral condition (pH 7.4). Further, FA-SND nanoparticles specifically target folate-receptor-rich KB cells, and endocytosed into lysosomes, an acidic organelle. The acidic microenvironment of lysosomes promotes a rapid release of DOX to nuclei, producing cancer specific chemo-cytotoxicity. Thus, FA-mediated cancer targeting and lysosomal-acidity promoting DOX release, two sequentially-occurring cellular events triggered by the designed components of FA-SND, form the basis for FA-SND to achieve its localized and intracellular chemo-cytotoxicity. Together, this study suggests that these FA-SND nanoparticles may be a potentially effective carrier particularly useful for delivering hydrophobic chemotherapeutic agents for treating cancers with high-level expression of folate receptors.

  2. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

    Science.gov (United States)

    Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

    2016-01-01

    Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.

  3. Monitoring Tumor Targeting and Treatment Effects of IRDye 800CW and GX1-Conjugated Polylactic Acid Nanoparticles Encapsulating Endostar on Glioma by Optical Molecular Imaging

    Directory of Open Access Journals (Sweden)

    Yaqian Li

    2015-07-01

    Full Text Available Molecular imaging used in cancer diagnosis and therapeutic response monitoring is important for glioblastoma (GBM research. Antiangiogenic therapy currently is one of the emerging approaches for GBM treatment. In this study, a multifunctional nanoparticle was fabricated that can facilitate the fluorescence imaging of tumor and deliver a therapeutic agent to the tumor region in vivo and therefore possesses broad application in cancer diagnosis and treatment. This particle was polylactic acid (PLA nanoparticles encapsulating Endostar, which was further conjugated with GX1 peptide and the near-infrared (NIR dye IRDye 800CW (IGPNE. We demonstrated noninvasive angiogenesis targeting and therapy of IGPNE on U87MG xenografts in vivo using dual-modality optical molecular imaging including NIR fluorescence molecular imaging (FMI and bioluminescence imaging (BLI. The NIR FMI results demonstrated that IGPNE had more accumulation to the tumor site compared to free IRDye 800CW. To further evaluate the antitumor treatment efficacy of IGPNE, BLI and immunohistochemistry analysis were performed on tumor-bearing mice. With the aid of molecular imaging, the results confirmed that IGPNE enhanced antitumor treatment efficacy compared to free Endostar. In conclusion, IGPNE realizes real-time imaging of U87MG tumors and improves the antiangiogenic therapeutic efficacy in vivo.

  4. Construction of expressing vectors including melanoma differentiation-associated gene-7 (mda-7 fused with the RGD sequences for better tumor targeting

    Directory of Open Access Journals (Sweden)

    Mahboobeh Khodadad

    2015-08-01

    Conclusion: Theoretically RGD tagged mda-7 would be able to induce apoptosis with more specificity and stronger than the standard one, therefore, these new constructs may have the potential for further researches.

  5. Conjugates of a novel 7-substituted camptothecin with RGD-peptides as α(v)β₃ integrin ligands: An approach to tumor-targeted therapy.

    Science.gov (United States)

    Dal Pozzo, Alma; Esposito, Emiliano; Ni, Minghong; Muzi, Laura; Pisano, Claudio; Bucci, Federica; Vesci, Loredana; Castorina, Massimo; Penco, Sergio

    2010-11-17

    Eight conjugates of a novel camptothecin derivative (Namitecan, NMT) with RGD peptides have been synthesized and biologically evaluated. This study focused on factors that optimize the drug linkage to the transport vector. The different linkages investigated consist of heterofunctional glycol fragments and a lysosomally cleavable peptide. The linkage length and conformation were systematically modified with the purpose to understand their effect on receptor affinity, systemic stability, cytotoxicity, and solubility of the corresponding conjugates. Among the new conjugates prepared, C6 and C7 showed high receptor affinity and tumor cell adhesion, acceptable stability in murine blood, and high cytotoxic activity (IC₅₀ = 8 nM). The rationale, synthetic strategy, and preliminary biological results will be presented.

  6. Tumor Targeting Using Anti–Epidermal Growth Factor Receptor (ior egf/r3 Immunoconjugate with a Tetraaza Macrocyclic Agent (DO3A-EA

    Directory of Open Access Journals (Sweden)

    Gauri Mishra

    2012-09-01

    Full Text Available Epidermal growth factor receptor (EGFR signaling inhibition represents a highly promising arena for the application of molecularly targeted cancer therapies. EGFR conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress EGFR receptors. Through improved understanding of EGFR biology in human cancers, there is anticipation that more tumor-selective therapy approaches with diminished collateral normal tissue toxicity can be advanced. We report here on the results with a thermodynamically stable chelate, 1,4,7-tris(carboxymethyl-10-(2-aminoethyl-1,4,7,10-tetraazacyclododecane (DO3A-EA and anti-EGFr (ior egf/r3 conjugate to develop immunospecifc imaging agent. Conjugation and labelling with anti-EGFr was performed using standard procedure and subjected to purification on size exclusion chromatography. The conjugated antibodies were labeled with a specific activity 20-30 mCi/mg of protein. Labeling efficiencies were measured by ascending paper chromatography on ITLC-SG strips. Radiolabeling of the immunoconjugate was found to be 98.5 ± 0.30%. 99mTc-DO3A-EA-EGFr conjugate was studied in athymic mice bearing U-87MG, MDA-MB-468 tumors following intravenous injection. Pharmacokinetic and biodistribution studies confirmed long circulation times (t1/2(fast= 45 min and t1/2(slow=4 hours 40 min and efficient accumulation in tumors. Biodistribution studies in athymic mice grafted with U-87MG human glioblastoma multiforme and Hela human cervical carcinoma tumors revealed significant localization of 99mTc-labeled antibodies conjugate in tumors and reduced accumulation in normal organs. This new chelating agent is promising for immunoscintigraphy since good tumour-to-normal organ contrast could be demonstrated. These properties can be exploited for immunospecifc contrast agents in nuclear medicine and SPECT imaging.

  7. Tumor-targeting nanogel that can function independently for both photodynamic and photothermal therapy and its synergy from the procedure of PDT followed by PTT.

    Science.gov (United States)

    Kim, Ja-Young; Choi, Won Il; Kim, Manse; Tae, Giyoong

    2013-10-28

    A dual-function nano-system for synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) was constructed. Gold nanorods (GNRs) as a PTT agent and chlorin e6 (Ce6) as a photosensitizer (PS) for PDT were loaded into a chitosan-functionalized, Pluronic-based nanogel that was proven to be an efficient delivery vehicle to the tumor site in vivo. Previously reported combined therapy systems relied on quenching and de-quenching of PS for PDT upon thermo-impact of PTT, thus only PTT followed by PDT procedure was possible. In contrast, the present dual-acting system has no quenching between PS and GNRs by preventing direct contact and self-aggregation of photo-sensitizers, allowing independent PDT or PTT procedure. In both in vitro cell culture and in vivo tumor-bearing mice experiments, a remarkably enhanced tumor ablation compared to the treatment of PDT or PTT only was observed by the treatment of PDT followed by PTT, but not significantly by the treatment of PTT followed by PDT. Thus, the present study demonstrated the synergistic effect of PDT and PTT in a sequence-dependent manner, and our system is a promising dual function nano system to achieve the enhanced phototherapy in vivo. © 2013.

  8. Preparation, Characterization, and Optimization of Folic Acid-Chitosan-Methotrexate Core-Shell Nanoparticles by Box-Behnken Design for Tumor-Targeted Drug Delivery.

    Science.gov (United States)

    Naghibi Beidokhti, Hamid Reza; Ghaffarzadegan, Reza; Mirzakhanlouei, Sasan; Ghazizadeh, Leila; Dorkoosh, Farid Abedin

    2017-01-01

    The objective of this study was to investigate the combined influence of independent variables in the preparation of folic acid-chitosan-methotrexate nanoparticles (FA-Chi-MTX NPs). These NPs were designed and prepared for targeted drug delivery in tumor. The NPs of each batch were prepared by coaxial electrospray atomization method and evaluated for particle size (PS) and particle size distribution (PSD). The independent variables were selected to be concentration of FA-chitosan, ratio of shell solution flow rate to core solution flow rate, and applied voltage. The process design of experiments (DOE) was obtained with three factors in three levels by Design expert software. Box-Behnken design was used to select 15 batches of experiments randomly. The chemical structure of FA-chitosan was examined by FTIR. The NPs of each batch were collected separately, and morphologies of NPs were investigated by field emission scanning electron microscope (FE-SEM). The captured pictures of all batches were analyzed by ImageJ software. Mean PS and PSD were calculated for each batch. Polynomial equation was produced for each response. The FE-SEM results showed the mean diameter of the core-shell NPs was around 304 nm, and nearly 30% of the produced NPs are in the desirable range. Optimum formulations were selected. The validation of DOE optimization results showed errors around 2.5 and 2.3% for PS and PSD, respectively. Moreover, the feasibility of using prepared NPs to target tumor extracellular pH was shown, as drug release was greater in the pH of endosome (acidic medium). Finally, our results proved that FA-Chi-MTX NPs were active against the human epithelial cervical cancer (HeLa) cells.

  9. Multifunctional Chitosan Magnetic-Graphene (CMG) Nanoparticles: a Theranostic Platform for Tumor-targeted Co-delivery of Drugs, Genes and MRI Contrast Agents

    OpenAIRE

    Wang, Chunyan; Ravi, Sowndharya; Garapati, Ujjwala Sree; Das, Mahasweta; Howell, Mark; MallelaMallela, Jaya; Alwarapan, Subbiah; Mohapatra, Shyam S; Mohapatra, Subhra

    2013-01-01

    Combing chemotherapy with gene therapy has been one of the most promising strategies for the treatment of cancer. The noninvasive MRI with superparamagnetic iron oxide (SPIO) as contrast agent is one of the most effecitve techniques for evaluating the antitumor therapy. However, to construct a single system that can deliver efficiently gene, drug and SPIO to the cancer site remains a challenge. Herein, we report a chitosan functionalized magnetic graphene nanoparticle (CMG) platform for simul...

  10. Multifunctional Chitosan Magnetic-Graphene (CMG) Nanoparticles: a Theranostic Platform for Tumor-targeted Co-delivery of Drugs, Genes and MRI Contrast Agents.

    Science.gov (United States)

    Wang, Chunyan; Ravi, Sowndharya; Garapati, Ujjwala Sree; Das, Mahasweta; Howell, Mark; MallelaMallela, Jaya; Alwarapan, Subbiah; Mohapatra, Shyam S; Mohapatra, Subhra

    2013-09-21

    Combing chemotherapy with gene therapy has been one of the most promising strategies for the treatment of cancer. The noninvasive MRI with superparamagnetic iron oxide (SPIO) as contrast agent is one of the most effecitve techniques for evaluating the antitumor therapy. However, to construct a single system that can deliver efficiently gene, drug and SPIO to the cancer site remains a challenge. Herein, we report a chitosan functionalized magnetic graphene nanoparticle (CMG) platform for simultaneous gene/drug and SPIO delivery to tumor. The phantom and ex vivo MRI images suggest CMG as a strong T2 contrast-enhancing agent. The CMGs are biocompatible as evaluated by the WST assay and predominantly accumulate in tumors as shown by biodistribution studies and MRI. The anticancer drug doxorubicin (DOX) loaded CMGs (DOX-CMGs) release DOX faster at pH 5.1 than at pH 7.4, and more effective (IC50 = 2 μM) in killing A549 lung cancer cells than free DOX (IC50 = 4 μM). CMGs efficiently deliver DNA into A549 lung cancer cells and C42b prostate cancer cells. In addition, i.v. administration of GFP-plasmid encapsulated within DOX-CMGs into tumor-bearing mice has showed both GFP expression and DOX accumulation at the tumor site at 24 and 48 hrs after administration. These results indicate CMGs provide a robust and safe theranostic platform, which integrates targeted delivery of both gene medicine and chemotherapeutic drug(s), and enhanced MR imaging of tumors. The integrated chemo- and gene- therapeutic and diagnostic design of CMG nanoparticles shows promise for simultaneous targeted imaging, drug delivery and real -time monitoring of therapeutic effect for cancer.

  11. Noninvasive 89Zr-Transferrin PET Shows Improved Tumor Targeting Compared with 18F-FDG PET in MYC-Overexpressing Human Triple-Negative Breast Cancer.

    Science.gov (United States)

    Henry, Kelly E; Dilling, Thomas R; Abdel-Atti, Dalya; Edwards, Kimberly J; Evans, Michael J; Lewis, Jason S

    2018-01-01

    The current standard for breast PET imaging is 18F-FDG. The heterogeneity of 18F-FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. 18F-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm3 MYC is a protein involved in oncogenesis and is overexpressed in triple-negative breast cancer (TNBC). Increased surface expression of transferrin receptor (TfR) is a downstream event of MYC upregulation and has been validated as a clinically relevant target for molecular imaging. Transferrin labeled with 89Zr has successfully identified MYC status in many cancer subtypes preclinically and been shown to predict response and changes in oncogene status via treatment with small-molecule inhibitors that target MYC and PI3K signaling pathways. We hypothesized that 89Zr-transferrin PET will noninvasively detect MYC and TfR and improve upon the current standard of 18F-FDG PET for MYC-overexpressing TNBC. Methods: In this study, 89Zr-transferrin and 18F-FDG imaging were compared in preclinical models of TNBC. TNBC cells (MDA-MB-157, MDA-MB-231, and Hs578T) were treated with bromodomain-containing protein 4 (BRD4) inhibitors JQ1 and OTX015 (0.5-1 μM). Cell proliferation, gene expression, and protein expression were assayed to explore the effects of these inhibitors on MYC and TfR. Results: Head-to-head comparison showed that 89Zr-transferrin targets TNBC tumors significantly better (P PET imaging and biodistribution studies in MDA-MB-231 and MDA-MB-157 xenografts and a patient-derived xenograft model of TNBC. c-Myc and TfR gene expression was decreased upon treatment with BRD4 inhibitors and c-MYC small interfering RNA (P PET imaging and biodistribution studies. 89Zr-transferrin is a useful tool to interrogate MYC via TfR-targeted PET imaging in TNBC. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

  12. Comparative evaluation of tumor targeting using the anti-HER2 ADAPT scaffold protein labeled at the C-terminus with indium-111 or technetium-99m.

    Science.gov (United States)

    Garousi, Javad; Lindbo, Sarah; Mitran, Bogdan; Buijs, Jos; Vorobyeva, Anzhelika; Orlova, Anna; Tolmachev, Vladimir; Hober, Sophia

    2017-11-07

    ABD-Derived Affinity Proteins (ADAPTs) is a novel class of engineered scaffold proteins derived from an albumin-binding domain of protein G. The use of ADAPT6 derivatives as targeting moiety have provided excellent preclinical radionuclide imaging of human epidermal growth factor 2 (HER2) tumor xenografts. Previous studies have demonstrated that selection of nuclide and chelator for its conjugation has an appreciable effect on imaging properties of scaffold proteins. In this study we performed a comparative evaluation of the anti-HER2 ADAPT having an aspartate-glutamate-alanine-valine-aspartate-alanine-asparagine-serine (DEAVDANS) N-terminal sequence and labeled at C-terminus with (99m)Tc using a cysteine-containing peptide based chelator, glycine-serine-serine-cysteine (GSSC), and a similar variant labeled with (111)In using a maleimido derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. Both (99m)Tc-DEAVDANS-ADAPT6-GSSC and (111)In-DEAVDANS-ADAPT6-GSSC-DOTA accumulated specifically in HER2-expressing SKOV3 xenografts. The tumor uptake of both variants did not differ significantly and average values were in the range of 19-21%ID/g. However, there was an appreciable variation in uptake of conjugates in normal tissues that resulted in a notable difference in the tumor-to-organ ratios. The (111)In-DOTA label provided 2-6 fold higher tumor-to-organ ratios than (99m)Tc-GSSC and is therefore the preferable label for ADAPTs.

  13. Self-Assembled Polymeric Micelles Based on Hyaluronic Acid-g-Poly(d,l-lactide-co-glycolide Copolymer for Tumor Targeting

    Directory of Open Access Journals (Sweden)

    Gyung Mo Son

    2014-09-01

    Full Text Available Graft copolymer composed hyaluronic acid (HA and poly(d,l-lactide-co-glycolide (PLGA (HAgLG was synthesized for antitumor targeting via CD44 receptor of tumor cells. The carboxylic end of PLGA was conjugated with hexamethylenediamine (HMDA to have amine end group in the end of chain (PLGA-amine. PLGA-amine was coupled with carboxylic acid of HA. Self-assembled polymeric micelles of HAgLG have spherical morphologies and their sizes were around 50–200 nm. Doxorubicin (DOX-incorporated polymeric micelles were prepared by dialysis procedure. DOX was released over 4 days and its release rate was accelerated by the tumoric enzyme hyaluronidase. To assess targetability of polymeric micelles, CD44-positive HepG2 cells were employed treated with fluorescein isothiocyanate (FITC-labeled polymeric micelles. HepG2 cells strongly expressed green fluorescence at the cell membrane and cytosol. However, internalization of polymeric micelles were significantly decreased when free HA was pretreated to block the CD44 receptor. Furthermore, the CD44-specific anticancer activity of HAgLG polymeric micelles was confirmed using CD44-negative CT26 cells and CD44-positive HepG2 cells. These results indicated that polymeric micelles of HaLG polymeric micelles have targetability against CD44 receptor of tumor cells. We suggest HAgLG polymeric micelles as a promising candidate for specific drug targeting.

  14. 3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation.

    Science.gov (United States)

    Sethi, Pallavi; Jyoti, Amar; Swindell, Elden P; Chan, Ryan; Langner, Ulrich W; Feddock, Jonathan M; Nagarajan, Radhakrishnan; O'Halloran, Thomas V; Upreti, Meenakshi

    2015-11-01

    An appropriate representation of the tumor microenvironment in tumor models can have a pronounced impact on directing combinatorial treatment strategies and cancer nanotherapeutics. The present study develops a novel 3D co-culture spheroid model (3D TNBC) incorporating tumor cells, endothelial cells and fibroblasts as color-coded murine tumor tissue analogs (TTA) to better represent the tumor milieu of triple negative breast cancer in vitro. Implantation of TTA orthotopically in nude mice, resulted in enhanced growth and aggressive metastasis to ectopic sites. Subsequently, the utility of the model is demonstrated for preferential targeting of irradiated tumor endothelial cells via radiation-induced stromal enrichment of galectin-1 using anginex conjugated nanoparticles (nanobins) carrying arsenic trioxide and cisplatin. Demonstration of a multimodal nanotherapeutic system and inclusion of the biological response to radiation using an in vitro/in vivo tumor model incorporating characteristics of tumor microenvironment presents an advance in preclinical evaluation of existing and novel cancer nanotherapies. Existing in-vivo tumor models are established by implanting tumor cells into nude mice. Here, the authors described their approach 3D spheres containing tumor cells, enodothelial cells and fibroblasts. This would mimic tumor micro-environment more realistically. This interesting 3D model should reflect more accurately tumor response to various drugs and would enable the design of new treatment modalities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Macromolecular HPMA-based nanoparticles with cholesterol for solid-tumor targeting: detailed study of the inner structure of a highly efficient drug delivery system.

    Science.gov (United States)

    Filippov, Sergey K; Chytil, Petr; Konarev, Petr V; Dyakonova, Margarita; Papadakis, Christinem; Zhigunov, Alexander; Plestil, Josef; Stepanek, Petr; Etrych, Tomas; Ulbrich, Karel; Svergun, Dmitri I

    2012-08-13

    We report a rigorous investigation into the detailed structure of nanoparticles already shown to be successful drug delivery nanocarriers. The basic structure of the drug conjugates consists of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer bearing the anticancer drug doxorubicin (Dox) bound via a pH-sensitive hydrazone bond and a defined amount of cholesterol moieties that vary in hydrophobicity. The results show that size, anisotropy, and aggregation number N(aggr) of the nanoparticles grows with increasing cholesterol content. From ab initio calculations, we conclude that the most probable structure of HPMA copolymer-cholesterol nanoparticles is a pearl necklace structure, where ellipsoidal pearls mainly composed of cholesterol are covered by a HPMA shell; pearls are connected by bridges composed of hydrophilic HPMA copolymer chains. Using a combination of techniques, we unambiguously show that the Dox moieties are not impregnated inside a cholesterol core but are instead uniformly distributed across the whole nanoparticle, including the hydrophilic HPMA shell surface.

  16. Tumor-Targeted Silencing of Bcl-2/Bcl-xl by Self-Assembled Sirna-Nanovectors as a Novel Molecular Therapy for Breast Cancer

    National Research Council Canada - National Science Library

    Xu, Liang

    2007-01-01

    The major goal of this Concept Award project is to explore the anti-Her-2 antibody as targeting ligand to establish the self-assembled nanovectors for targeted siRNA delivery to Her-2(+) breast cancer. Our hypothesis is (1...

  17. An NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles for tumor targeted drug delivery in vitro and in vivo

    Science.gov (United States)

    Gayam, Srivardhan Reddy; Venkatesan, Parthiban; Sung, Yi-Ming; Sung, Shuo-Yuan; Hu, Shang-Hsiu; Hsu, Hsin-Yun; Wu, Shu-Pao

    2016-06-01

    The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this smart biocompatible carrier system showed obvious uptake and consequent release of the drug in tumor cells, could selectively induce the tumor cell death and enhance the capability of inhibition of tumor growth in vivo. The controlled drug delivery system demonstrated its use as a potential theranostic material.The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this smart biocompatible carrier system showed obvious uptake and consequent release of the drug in tumor cells, could selectively induce the tumor cell death and enhance the capability of inhibition of tumor growth in vivo. The controlled drug delivery system demonstrated its use as a potential theranostic material. Electronic supplementary information (ESI) available: Synthesis and characterization of the functional molecules and MSNPs is available in the ESI. See DOI: 10.1039/c6nr03525f

  18. Tumor-targeting magnetic lipoplex delivery of short hairpin RNA suppresses IGF-1R overexpression of lung adenocarcinoma A549 cells in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chunmao; Ding, Chao; Kong, Minjian [Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China); Dong, Aiqiang, E-mail: dr_dongaiqiang@sina.com [Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China); Qian, Jianfang; Jiang, Daming; Shen, Zhonghua [Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China)

    2011-07-08

    Highlights: {yields} We compared lipofection with magnetofection about difference of transfection efficiency on delivery a therapeutic gene in vitro and in vivo. {yields} We investigated the difference of shRNA induced by magnetofection and lipofection into A549 cell and subcutaneous tumor to knockdown IGF-1R overexpressed in A549 cell and A549 tumor. {yields} We investigated in vivo shRNA silenced IGF-1R overexpression 24, 48, and 72 h after shRNA intravenous injection into tumor-bearing mice by way of magnetofection and lipofection. {yields} Our results showed that magnetofection could achieve therapeutic gene targeted delivery into special site, which contributed to targeted gene therapy of lung cancers. -- Abstract: Liposomal magnetofection potentiates gene transfection by applying a magnetic field to concentrate magnetic lipoplexes onto target cells. Magnetic lipoplexes are self-assembling ternary complexes of cationic lipids with plasmid DNA associated with superparamagnetic iron oxide nanoparticles (SPIONs). Type1insulin-like growth factor receptor (IGF-1R), an important oncogene, is frequently overexpressed in lung cancer and mediates cancer cell proliferation and tumor growth. In this study, we evaluated the transfection efficiency (percentage of transfected cells) and therapeutic potential (potency of IGF-1R knockdown) of liposomal magnetofection of plasmids expressing GFP and shRNAs targeting IGF-1R (pGFPshIGF-1Rs) in A549 cells and in tumor-bearing mice as compared to lipofection using Lipofectamine 2000. Liposomal magnetofection provided a threefold improvement in transgene expression over lipofection and transfected up to 64.1% of A549 cells in vitro. In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1 {+-} 6% and by liposomal magnetofection by 85.1 {+-} 3%. In vivo delivery efficiency of the pGFPshIGF-1R plasmid into the tumor was significantly higher in the liposomal magnetofection group than in the lipofection group. In vivo IGF-1R specific-shRNA by lipofection inhibited IGF-1R protein by an average of 43.8 {+-} 5.3%; that by liposomal magnetofection inhibited IGF-1R protein by 43.4 {+-} 5.7%, 56.3 {+-} 9.6%, and 72.2 {+-} 6.8%, at 24, 48, and 72 h, respectively, after pGFPshIGF-1R injection. Our findings indicate that liposomal magnetofection may be a promising method that allows the targeting of gene therapy to lung cancer.

  19. The effect of nanoparticle polyethylene glycol surface density on ligand-directed tumor targeting studied in vivo by dual modality imaging

    NARCIS (Netherlands)

    Hak, Sjoerd; Helgesen, Emily; Hektoen, Helga H.; Huuse, Else Marie; Jarzyna, Peter A.; Mulder, Willem J. M.; Haraldseth, Olav; de Lange Davies, Catharina

    2012-01-01

    The development and application of nanoparticles as in vivo delivery vehicles for therapeutic and/or diagnostic agents has seen a drastic growth over the last decades. Novel imaging techniques allow real-time in vivo study of nanoparticle accumulation kinetics at the level of the cell and targeted

  20. PET-based compartmental modeling of {sup 124}I-A33 antibody: quantitative characterization of patient-specific tumor targeting in colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zanzonico, Pat; O' Donoghue, Joseph A.; Humm, John L. [Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Carrasquillo, Jorge A.; Pandit-Taskar, Neeta; Ruan, Shutian; Larson, Steven M. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Smith-Jones, Peter [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Stony Brook School of Medicine, Departments of Psychiatry and Radiology, Stony Brook, NY (United States); Divgi, Chaitanya [Columbia University Medical Center, New York, NY (United States); Scott, Andrew M. [La Trobe University, Olivia Newton-John Cancer Research Institute, Melbourne (Australia); Kemeny, Nancy E.; Wong, Douglas; Scheinberg, David [Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY (United States); Fong, Yuman [Memorial Sloan Kettering Cancer Center, Department of Surgery, New York, NY (United States); City of Hope, Department of Surgery, Duarte, CA (United States); Ritter, Gerd; Jungbluth, Achem; Old, Lloyd J. [Memorial Sloan Kettering Cancer Center, Ludwig Institute for Cancer Research, New York, NY (United States)

    2015-10-15

    The molecular specificity of monoclonal antibodies (mAbs) directed against tumor antigens has proven effective for targeted therapy of human cancers, as shown by a growing list of successful antibody-based drug products. We describe a novel, nonlinear compartmental model using PET-derived data to determine the ''best-fit'' parameters and model-derived quantities for optimizing biodistribution of intravenously injected {sup 124}I-labeled antitumor antibodies. As an example of this paradigm, quantitative image and kinetic analyses of anti-A33 humanized mAb (also known as ''A33'') were performed in 11 colorectal cancer patients. Serial whole-body PET scans of {sup 124}I-labeled A33 and blood samples were acquired and the resulting tissue time-activity data for each patient were fit to a nonlinear compartmental model using the SAAM II computer code. Excellent agreement was observed between fitted and measured parameters of tumor uptake, ''off-target'' uptake in bowel mucosa, blood clearance, tumor antigen levels, and percent antigen occupancy. This approach should be generally applicable to antibody-antigen systems in human tumors for which the masses of antigen-expressing tumor and of normal tissues can be estimated and for which antibody kinetics can be measured with PET. Ultimately, based on each patient's resulting ''best-fit'' nonlinear model, a patient-specific optimum mAb dose (in micromoles, for example) may be derived. (orig.)

  1. A Mild, Ferrocene-Catalyzed C?H Imidation of (Hetero)Arenes

    OpenAIRE

    Foo, Klement; Sella, Eran; Thom?, Isabelle; Eastgate, Martin D.; Baran, Phil S.

    2014-01-01

    A simple method for direct C?H imidation is reported using a new perester-based self-immolating reagent and a base-metal catalyst. The succinimide products obtained can be easily deprotected in situ (if desired) to reveal the corresponding anilines directly. The scope of the reaction is broad, the conditions are extremely mild, and the reaction is tolerant of oxidizable and acid-labile functionality, multiple heteroatoms, and aryl iodides. Mechanistic studies indicate that ferrocene (Cp2Fe) p...

  2. Investigation of the outcomes and varieties of violent suicides during a period of twenty years in Ilam, Iran

    Directory of Open Access Journals (Sweden)

    Yosra Azizpour

    2017-10-01

    Conclusion: One of the main objectives of this study was identification of high risk groups who used the invasive methods for suicide commitments, based on their epidemiological characteristics such as gender and age. The results showed that women and elderly individuals were among the high-risk groups who committed completed suicide using the invasive methods and self-immolation attributed the most frequent method among invasive methods for suicide in Ilam province which resulted in death.

  3. Gold-coated lanthanide phosphate nanoparticles for an {sup 225}Ac in vivo alpha generator

    Energy Technology Data Exchange (ETDEWEB)

    McLaughlin, M.F. [Missouri Univ., Columbia, MO (United States). Dept. of Chemistry; Oak Ridge National Lab., TN (United States); Woodward, J.; Boll, R.A.; Rondinone, A.J.; Mirzadeh, S. [Oak Ridge National Lab., TN (United States); Robertson, J.D. [Missouri Univ., Columbia, MO (United States). Dept. of Chemistry

    2013-11-01

    Retaining radioactive daughter products at a clinically relevant target site remains one of the major challenges in development of in vivo {alpha} generators with radionuclides such as {sup 225}Ac and {sup 223}Ra. In this work, we examine the ability of layered nanoparticle constructs to retain {sup 225}Ac and the first decay daughter, {sup 221}Fr. Actinium-225 is cocrystalized in a lanthanide phosphate nanoparticle consisting of varying amounts of La and Gd. Additional lanthanide phosphate layers improve retention capability while an outer layer of gold facilitates the attachment of targeting moieties for in vivo use. Retention of {sup 225}Ac in the nanoparticles is near quantitative while the {sup 221}Fr retention varies from 60-89% as a function of time, the number of layers, and nanoparticle composition. Decay corrected radiochemical yield in the multi-shell syntheses are high (76%) and comparable to or better than existing delivery approaches. (orig.)

  4. Two-year hospital records of burns from a referral center in Western Iran: March 2010-March 2012

    Science.gov (United States)

    Ahmadijouybari, Touraj; Najafi, Farid; Moradinazar, Mehdi; Karami-matin, Behzad; Karami-matin, Reza; Ataie, Maria; Hatami, Masoumeh; Purghorbani, Samira; Amee, Vahid

    2014-01-01

    Abstract: Background: Burns are among the most common injuries affecting a great number of people worldwide annually. In Iran, especially in its western region and in Kermanshah province, burns have a relatively high incidence. The present study was aimed at investigating epidemiological characteristics in Western Iran. Methods: Within a cross-sectional study, the data on all patients attending the Burns Center at Imam Khomeini Hospital (Kermanshah, Iran) during 2010-2011 and 2011-2012 (24 months) were collected. Then, age, gender, cause of burns, total body surface area, and time of the occurrence were extracted from the hospital records. The data were analyzed using the SPSS statistical package (Version 19, for Windows). We used chi-squared test when we compared the categorical responses between two or more groups. For comparing means between two groups we used t-test. In addition, trends were investigated using linear regression. Results: Overall 13 248 people were referred to the Burns Center at Imam Khomeini Hospital (Kermanshah, Iran) during the period of study, including 328 cases of self-immolation. The mean age of the patients was 27±19 years and 29±13 years for unintentional burns and self-immolation respectively. Out of the total number of unintentional cases, 6 519 (50.5%) were men, while the corresponding percentage of men among the self-immolation cases was 16.6% (p less than 0.001). Trends in the number of cases were cyclic, with the highest and lowest number of burns cases being in March and May. Overall, hot liquids and flammable materials were the two most important causes of unintentional burns. However, flammable materials were the main cause of burns among self-immolation cases. During hospital admission, 168 (51%) self-immolation victims and 43 (0.33%) unintentional burn victims died. Conclusions: While major preventive measures are not adequately used in developing countries, burns and their burden can be significantly reduced by increasing

  5. Factors associated with the choice of suicide method in Kermanshah Province, Iran.

    Science.gov (United States)

    Rostami, Mehran; Jalilian, Abdollah; Rezaei-Zangeneh, Ramin; Salari, Arash

    2016-01-01

    Identification of factors in the choice of suicide methods is important in understanding the phenomenon. We aimed to quantify the effect of gender, age, living area, education level and marital status on the choice of suicide method among residents of Kermanshah province in the west of Iran. A cross-sectional study of all completed suicides from March 2006 to September 2013. Kermanshah Province, Iran. Data were extracted from suicide forms in the electronic files of the Forensic Medicine Organization. A total of 1901 (1138 men), suicide cases were identified. After preliminary analysis, a multinomial logistic model was fitted to the data to test and quantify the impact of each influential factor on the choice of suicide method. The relative risk of each suicide method over hanging as the reference method was estimated by calculating relative-risk ratios from the multinomial logistic model. Relative risk of suicide by self-immolation, drug and toxic poisoning and firearms. We found that women are at a higher relative risk than men for suicide by self-immolation, intentional drug poisoning and toxic poisoning. The relative risk of suicide by self-immolation and intentional drug poisoning was higher for urban residents and young individuals. On the other hand, men and rural residents were at higher relative risk of suicide by firearm. In Kermanshah province, the impact of rapid social changes on women and the availability of firearms in rural areas and drugs in urban households require more attention in any suicide prevention planning. The lack of data prevented analysis of factors that may be more influential in choosing suicide.

  6. Trends of Suicidal Poisoning In Ahmedabad (Retrospective Study)

    OpenAIRE

    Kartik Prajapati; Saumil Merchant; Pratik Patel

    2012-01-01

    The suicide rate in India is 10.3. In the last three decades, the suicide rate has increased by 43% but the male female ratio has been stable at 1.4: 1. Majority (71%) of suicide in India are by persons below the age of 44 years which imposes a huge social, emotional and economic burden. Several studies reveal that suicidal behaviours are much more prevalent than what is officially reported. (1) Poisoning, hanging and self immolation (particularly women) were the methods to commit suicide. Ph...

  7. A Mild, Ferrocene-Catalyzed C–H Imidation of (Hetero)Arenes

    Science.gov (United States)

    2015-01-01

    A simple method for direct C–H imidation is reported using a new perester-based self-immolating reagent and a base-metal catalyst. The succinimide products obtained can be easily deprotected in situ (if desired) to reveal the corresponding anilines directly. The scope of the reaction is broad, the conditions are extremely mild, and the reaction is tolerant of oxidizable and acid-labile functionality, multiple heteroatoms, and aryl iodides. Mechanistic studies indicate that ferrocene (Cp2Fe) plays the role of an electron shuttle in the decomposition of the perester reagent, delivering a succinimidyl radical ready to add to an aromatic system. PMID:24654983

  8. A mild, ferrocene-catalyzed C-H imidation of (hetero)arenes.

    Science.gov (United States)

    Foo, Klement; Sella, Eran; Thomé, Isabelle; Eastgate, Martin D; Baran, Phil S

    2014-04-09

    A simple method for direct C-H imidation is reported using a new perester-based self-immolating reagent and a base-metal catalyst. The succinimide products obtained can be easily deprotected in situ (if desired) to reveal the corresponding anilines directly. The scope of the reaction is broad, the conditions are extremely mild, and the reaction is tolerant of oxidizable and acid-labile functionality, multiple heteroatoms, and aryl iodides. Mechanistic studies indicate that ferrocene (Cp2Fe) plays the role of an electron shuttle in the decomposition of the perester reagent, delivering a succinimidyl radical ready to add to an aromatic system.

  9. Indian research on suicide

    OpenAIRE

    Vijayakumar, Lakshmi

    2010-01-01

    The suicide rate in India is 10.3. In the last three decades, the suicide rate has increased by 43% but the male female ratio has been stable at 1.4 : 1. Majority (71%) of suicide in India are by persons below the age of 44 years which imposes a huge social, emotional and economic burden. Fifty four articles on suicides have been published in IJP. Several studies reveal that suicidal behaviours are much more prevalent than what is officially reported. Poisoning, hanging and self immolation (p...

  10. The availability of a functional tumor targeting T-cell repertoire determines the anti-tumor efficiency of combination therapy with anti-CTLA-4 and anti-4-1BB antibodies

    DEFF Research Database (Denmark)

    Jensen, Benjamin Anderschou Holbech; Pedersen, Sara Ram; Christensen, Jan Pravsgaard

    2013-01-01

    It has previously been found that combination therapy with anti-CTLA-4 and anti-4-1BB antibodies may enhance tumor immunity. However, this treatment is not efficient against all tumors, and it has been suggested that variations in tumor control may reflect differences in the immunogenicity...

  11. The tumor-targeting immunocytokine F16-IL2 in combination with doxorubicin: dose escalation in patients with advanced solid tumors and expansion into patients with metastatic breast cancer.

    Science.gov (United States)

    Catania, Chiara; Maur, Michela; Berardi, Rossana; Rocca, Andrea; Giacomo, Anna Maria Di; Spitaleri, Gianluca; Masini, Cristina; Pierantoni, Chiara; González-Iglesias, Reinerio; Zigon, Giulia; Tasciotti, Annaelisa; Giovannoni, Leonardo; Lovato, Valeria; Elia, Giuliano; Menssen, Hans D; Neri, Dario; Cascinu, Stefano; Conte, Pier Franco; Braud, Filippo de

    2015-01-01

    A phase Ib/II trial was performed to evaluate safety, tolerability, recommended dose (RD) and efficacy of F16-IL2, a recombinant antibody-cytokine fusion protein, in combination with doxorubicin in patients with solid tumors (phase Ib) and metastatic breast cancer (phase II). Six patient cohorts with progressive solid tumors (n = 19) received escalating doses of F16-IL2 [5-25 Million International Units (MIU) of IL2 equivalent dose] in combination with escalating doses of doxorubicin (0-25 mg/m(2)) on day 1, 8 and 15 every 4 weeks. Subsequently, patients with metastatic breast cancer (n = 10) received the drug combination at the RD. Clinical data and laboratory findings were analyzed for safety, tolerability, and activity. F16-IL2 could be administered up to 25 MIU, in combination with the RD of doxorubicin (25 mg/m(2)). No human anti-fusion protein antibodies (HAFA) response was detected. Pharmacokinetics of F16-IL2 was dose-dependent over the tested range, with half-lives of ca. 13 and ca. 8 hours for cohorts dosed at lower and higher levels, respectively. Toxicities were controllable and reversible, with no combination treatment-related death. After 8 weeks, 57% and 67% disease control rates were observed for Phase I and II, respectively (decreasing to 43% and 33% after 12 weeks), considering 14 and 9 patients evaluable for efficacy. One patient experienced a long lasting partial response (45 weeks), still on-going at exit of study. F16-IL2 can be safely and repeatedly administered at the RD of 25 MIU in combination with 25 mg/m(2) doxorubicin; its safety and activity are currently being investigated in combination with other chemotherapeutics, in order to establish optimal therapy settings.

  12. Dual fluorescent HPMA copolymers for passive tumor targeting with pH-sensitive drug release: synthesis and characterization of distribution and tumor accumulation in mice by noninvasive multispectral optical imaging.

    Science.gov (United States)

    Hoffmann, Stefan; Vystrčilová, Lucie; Ulbrich, Karel; Etrych, Tomáš; Caysa, Henrike; Mueller, Thomas; Mäder, Karsten

    2012-03-12

    Preclinical in vivo characterization of new polymeric drug conjugate candidates is crucial for understanding the effects of certain chemical modifications on distribution and elimination of these carrier systems, which is the basis for rational drug design. In our study we synthesized dual fluorescent HPMA copolymers of different architectures and molecular weights, containing one fluorescent dye coupled via a stable hydrazide bond functioning as the carrier label and the other one modeling the drug bound to a carrier via a pH-sensitive hydrolytically cleavable hydrazone bond. Thus, it was possible to track the in vivo fate, namely distribution, elimination and tumor accumulation, of the polymer drug carrier and a cleavable model drug simultaneously and noninvasively in nude mice using multispectral optical imaging. We confirmed our in vivo results by more detailed ex vivo characterization (imaging and microscopy) of autopsied organs and tumors. There was no significant difference in relative biodistribution in the body between the 30 KDa linear and 200 KDa star-like polymer, but the star-like polymer circulated much longer. We observed a moderate accumulation of the polymeric carriers in the tumors. The accumulation of the pH-sensitive releasable model drug was even higher compared to the polymer accumulation. Additionally, we were able to follow the long-term in vivo fate and to prove a time-dependent tumor accumulation of HPMA copolymers over several days.

  13. Case fatality rates of different suicide methods within Ilam province of Iran.

    Science.gov (United States)

    Razaeian, Mohsen; Sharifirad, Gholamreza

    2012-01-01

    There are few diverse studies that have reported the case fatality rates of different methods of suicide, none of them are originated from developing countries. The aim of the present article is to report the case fatality rates of different methods of suicide in Ilam province of Iran. Data on 611 cases of suicide and 1807 cases of deliberate self harm (DSH) that were recorded in a comprehensive registry during 1995 through 2002 were analyzed for both genders together and for males and females, separately. For both genders together, the two most fatal methods were hanging (75.4%) and self-immolation (68.3%); for males, hanging (76.3%) and self-immolation (64.7%); and for females, firearms (75%) and hanging (73.7%), respectively. The least fatal methods for both genders together and for females and males separately were drug ingestion and cutting. The results of present study, which for the first time has reported the case fatality rates of suicide methods in a developing world, would not only help to better plan the local suicide prevention strategies and clinical assessment of suicidal cases but to shed light on overall understanding of this mysterious human phenomenon.

  14. Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization.

    Directory of Open Access Journals (Sweden)

    Jaspreet Singh Jaggi

    2007-03-01

    Full Text Available Abnormal regulation of angiogenesis in tumors results in the formation of vessels that are necessary for tumor growth, but compromised in structure and function. Abnormal tumor vasculature impairs oxygen and drug delivery and results in radiotherapy and chemotherapy resistance, respectively. Alpha particles are extraordinarily potent, short-ranged radiations with geometry uniquely suitable for selectively killing neovasculature.Actinium-225 ((225Ac-E4G10, an alpha-emitting antibody construct reactive with the unengaged form of vascular endothelial cadherin, is capable of potent, selective killing of tumor neovascular endothelium and late endothelial progenitors in bone-marrow and blood. No specific normal-tissue uptake of E4G10 was seen by imaging or post-mortem biodistribution studies in mice. In a mouse-model of prostatic carcinoma, (225Ac-E4G10 treatment resulted in inhibition of tumor growth, lower serum prostate specific antigen level and markedly prolonged survival, which was further enhanced by subsequent administration of paclitaxel. Immunohistochemistry revealed lower vessel density and enhanced tumor cell apoptosis in (225Ac-E4G10 treated tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following (225Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following (225Ac-E4G10 therapy.The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy.

  15. Tumor Immunotargeting Using Innovative Radionuclides

    Directory of Open Access Journals (Sweden)

    Françoise Kraeber-Bodéré

    2015-02-01

    Full Text Available This paper reviews some aspects and recent developments in the use of antibodies to target radionuclides for tumor imaging and therapy. While radiolabeled antibodies have been considered for many years in this context, only a few have reached the level of routine clinical use. However, alternative radionuclides, with more appropriate physical properties, such as lutetium-177 or copper-67, as well as alpha-emitting radionuclides, including astatine-211, bismuth-213, actinium-225, and others are currently reviving hopes in cancer treatments, both in hematological diseases and solid tumors. At the same time, PET imaging, with short-lived radionuclides, such as gallium-68, fluorine-18 or copper-64, or long half-life ones, particularly iodine-124 and zirconium-89 now offers new perspectives in immuno-specific phenotype tumor imaging. New antibody analogues and pretargeting strategies have also considerably improved the performances of tumor immunotargeting and completely renewed the interest in these approaches for imaging and therapy by providing theranostics, companion diagnostics and news tools to make personalized medicine a reality.

  16. DNA and aptamer stabilized gold nanoparticles for targeted delivery of anticancer therapeutics

    Science.gov (United States)

    Latorre, Alfonso; Posch, Christian; Garcimartín, Yolanda; Celli, Anna; Sanlorenzo, Martina; Vujic, Igor; Ma, Jeffrey; Zekhtser, Mitchell; Rappersberger, Klemens; Ortiz-Urda, Susana; Somoza, Álvaro

    2014-06-01

    Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further reduce toxicity by increasing targeted delivery towards malignant cells.Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further

  17. Improved (225)Ac daughter retention in InPO4 containing polymersomes.

    Science.gov (United States)

    de Kruijff, R M; Drost, K; Thijssen, L; Morgenstern, A; Bruchertseifer, F; Lathouwers, D; Wolterbeek, H T; Denkova, A G

    2017-10-01

    Alpha-emitting radionuclides like actinium-225 ((225)Ac) are ideal candidates for the treatment of small metastasised tumours, where the long half-life of (225)Ac enables it to also reach less accessible tumours. The main challenge lies in retaining the recoiled alpha-emitting daughter nuclides, which are decoupled from targeting agents upon emission of an alpha particle and can subsequently cause unwanted toxicity to healthy tissue. Polymersomes, vesicles composed of amphiphilic block copolymers, are capable of transporting (radio)pharmaceuticals to tumours, and are ideal candidates for the retention of these daughter nuclides. In this study, the Geant4 Monte Carlo simulation package was used to simulate ideal vesicle designs. Vesicles containing an InPO4 nanoparticle in the core were found to have the highest recoil retention, and were subsequently synthesized in the lab. The recoil retention of two of the daughter nuclides, namely francium-221 ((221)Fr) and bismuth-213 ((213)Bi) was determined at different vesicle sizes. Recoil retention was found to have improved significantly, from 37 ± 4% and 22 ± 1% to 57 ± 5% and 40 ± 2% for (221)Fr and (213)Bi respectively for 100nm polymersomes, as compared to earlier published results by Wang et al. where (225)Ac was encapsulated using a hydrophilic chelate (Wang et al. 2014). To better understand the different parameters influencing daughter retention, simulation data was expanded to include vesicle polydispersity and nanoparticle position within the polymersome. The high retention of the recoiling daughters and the (225)Ac itself makes this vesicle design very suitable for future in vivo verification. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Efforts to control the errant products of a targeted in vivo generator.

    Science.gov (United States)

    Jaggi, Jaspreet Singh; Kappel, Barry J; McDevitt, Michael R; Sgouros, George; Flombaum, Carlos D; Cabassa, Catalina; Scheinberg, David A

    2005-06-01

    Alpha-particle immunotherapy by targeted alpha-emitters or alpha-emitting isotope generators is a novel form of extraordinarily potent cancer therapy. A major impediment to the clinical use of targeted actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter radionuclides. The daughters, especially bismuth-213 (213Bi), tend to accumulate in the kidneys. We tested the efficacy of various pharmacologic agents and the effect of tumor burden in altering the pharmacokinetics of the 225Ac daughters to modify their renal uptake. Pharmacologic treatments in animals were started before i.v. administration of the HuM195-225Ac generator. 225Ac, francium-221 (221Fr), and 213Bi biodistributions were calculated in each animal at different time points after 225Ac generator injection. Oral metal chelation with 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) caused a significant reduction (P < 0.0001) in the renal 213Bi uptake; however, DMPS was more effective than DMSA (P < 0.001). The results with DMPS were also confirmed in a monkey model. The renal 213Bi and 221Fr activities were significantly reduced by furosemide and chlorothiazide treatment (P < 0.0001). The effect on renal 213Bi activity was further enhanced by the combination of DMPS with either chlorothiazide or furosemide (P < 0.0001). Competitive antagonism by bismuth subnitrate moderately reduced the renal uptake of 213Bi. The presence of a higher target-tumor burden significantly prevented the renal 213Bi accumulation (P = 0.003), which was further reduced by DMPS treatment (P < 0.0001). Metal chelation, diuresis with furosemide or chlorothiazide, and competitive metal blockade may be used as adjuvant therapies to modify the renal accumulation of 225Ac daughters.

  19. Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: Decoy, trap and kill chemotherapy moves toward the clinic.

    Science.gov (United States)

    Igarashi, Kentaro; Kawaguchi, Kei; Kiyuna, Tasuku; Miyake, Kentaro; Miyake, Masuyo; Li, Shukuan; Han, Qinghong; Tan, Yuying; Zhao, Ming; Li, Yunfeng; Nelson, Scott D; Dry, Sarah M; Singh, Arun S; Elliott, Irmina A; Russell, Tara A; Eckardt, Mark A; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Tsuchiya, Hiroyuki; Eilber, Fritz C; Hoffman, Robert M

    2018-01-29

    In the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimurium A1-R (S. typhimurium A1-R), which decoys chemoresistant quiescent cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G2, and chemotherapy. The PDOX models were randomized into the following groups 14 days after implantation: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks). G4, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G6, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks) and CDDP (6 mg/kg, i.p. injection, weekly, for 2 weeks). On day 14 after initiation, all treatments except CDDP alone, significantly inhibited tumor growth compared to untreated control: (CDDP: p = 0.586; rMETase: p = 0.002; S. typhimurium A1-R: p = 0.002; S. typhimurium A1-R combined with rMETase: p = 0.0004; rMETase combined with both S. typhimurium A1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimurium A1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.

  20. DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy.

    Directory of Open Access Journals (Sweden)

    Franziska Graf

    Full Text Available RATIONALE: Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to the beta-particle emitter Lutetium-177 labeled somatostatin-analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of γH2AX-foci formation. METHODS: To determine the relative biological effectiveness (RBE between the two isotopes (as - biological consequence of different ionisation-densities along a particle-track, somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks (DSB were quantified by immunofluorescence staining of γH2AX-foci. Cell cycle was analyzed by flow cytometry. In vivo uptake of both radiolabeled somatostatin-analogues into subcutaneously growing AR42J tumors and the number of cells displaying γH2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities estimated from in vitro cytotoxicity. RESULTS: Ac-225-DOTATOC resulted in ED50 values of 14 kBq/ml after 48 h, whereas Lu-177-DOTATOC displayed ED50 values of 10 MBq/ml. The number of DSB grew with increasing concentration of Ac-225-DOTATOC and similarly with Lu-177-DOTATOC when applying a factor of 700-fold higher activity compared to Ac-225. Already 24 h after incubation with 2.5-10 kBq/ml, Ac-225-DOTATOC cell-cycle studies showed up to a 60% increase in the percentage of tumor cells in G2/M phase. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical (7.5%ID/g, though the overall number of cells with γH2AX-foci was higher in tumors treated with 48 kBq Ac-225-DOTATOC compared to tumors treated with 30 MBq Lu-177-DOTATOC (35% vs. 21%. Tumors with a volume of 0.34 ml reached delayed exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC and after 21 days (34 MBq Lu-177-DOTATOC. CONCLUSION: γH2AX-foci formation, triggered

  1. TRASH TO TREASURE: CONVERTING COLD WAR LEGACY WASTE INTO WEAPONS AGAINST CANCER

    Energy Technology Data Exchange (ETDEWEB)

    Nicholas, R.G.; Lacy, N.H.; Butz, T.R.; Brandon, N.E.

    2004-10-06

    As part of its commitment to clean up Cold War legacy sites, the U.S. Department of Energy (DOE) has initiated an exciting and unique project to dispose of its inventory of uranium-233 (233U) stored at Oak Ridge National Laboratory (ORNL), and extract isotopes that show great promise in the treatment of deadly cancers. In addition to increasing the supply of potentially useful medical isotopes, the project will rid DOE of a nuclear concern and cut surveillance and security costs. For more than 30 years, DOE's ORNL has stored over 1,200 containers of fissile 233U, originally produced for several defense-related projects, including a pilot study that looked at using 233U as a commercial reactor fuel. This uranium, designated as special nuclear material, requires expensive security, safety, and environmental controls. It has been stored at an ORNL facility, Building 3019A, that dates back to the Manhattan Project. Down-blending the material to a safer form, rather than continuing to store it, will eliminate a $15 million a year financial liability for the DOE and increase the supply of medical isotopes by 5,700 percent. During the down-blending process, thorium-229 (229Th) will be extracted. The thorium will then be used to extract actinium-225 (225Ac), which will ultimately supply its progeny, bismuth-213 (213Bi), for on-going cancer research. The research includes Phase II clinical trials for the treatment of acute myelogenous leukemia at Sloan-Kettering Memorial Cancer Center in New York, as well as other serious cancers of the lungs, pancreas, and kidneys using a technique known as alpha-particle radioimmunotherapy. Alpha-particle radioimmunotherapy is based on the emission of alpha particles by radionuclides. 213Bi is attached to a monoclonal antibody that targets specific cells. The bismuth then delivers a high-powered but short-range radiation dose, effectively killing the cancerous cells but sparing the surrounding tissue. Production of the actinium and

  2. Epidemiology of burns throughout the World. Part II: intentional burns in adults.

    Science.gov (United States)

    Peck, Michael D

    2012-08-01

    A significant number of burns and deaths from fire are intentionally wrought. Rates of intentional burns are unevenly distributed throughout the world; India has a particularly high rate in young women whereas in Europe rates are higher in men in mid-life. Data from hospitalized burn patients worldwide reveal incidence rates for assault by fire and scalds ranging from 3% to 10%. The average proportion of the body surface area burned in an assault by fire or scalds is approximately 20%. In different parts of the world, attempted burning of others or oneself can be attributed to different motives. Circumstances under which assaults occur fall largely into the categories of interpersonal conflict, including spousal abuse, elder abuse, or interactions over contentious business transactions. Contributing social factors to assaults by burning include drug and alcohol abuse, non-constructive use of leisure time, non-participation in religious and community activities, unstable relationships, and extramarital affairs. Although the incidence of self-mutilation and suicide attempts by burning are relatively low, deliberate self-harm carries a significant risk of death, with an overall mortality rate of 65% worldwide. In those who resort to self-immolation, circumstantial themes reflect domestic discord, family dysfunction, and the social ramifications of unemployment. Preventing injurious burn-related violence requires a multifaceted approach, including legislation and enforcement, education, and advocacy. Better standardized assessment tools are needed to screen for risks of abuse and for psychiatric disorders in perpetrators. Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.

  3. Chemical signal activation of an organocatalyst enables control over soft material formation.

    Science.gov (United States)

    Trausel, Fanny; Maity, Chandan; Poolman, Jos M; Kouwenberg, D S J; Versluis, Frank; van Esch, Jan H; Eelkema, Rienk

    2017-10-12

    Cells can react to their environment by changing the activity of enzymes in response to specific chemical signals. Artificial catalysts capable of being activated by chemical signals are rare, but of interest for creating autonomously responsive materials. We present an organocatalyst that is activated by a chemical signal, enabling temporal control over reaction rates and the formation of materials. Using self-immolative chemistry, we design a deactivated aniline organocatalyst that is activated by the chemical signal hydrogen peroxide and catalyses hydrazone formation. Upon activation of the catalyst, the rate of hydrazone formation increases 10-fold almost instantly. The responsive organocatalyst enables temporal control over the formation of gels featuring hydrazone bonds. The generic design should enable the use of a large range of triggers and organocatalysts, and appears a promising method for the introduction of signal response in materials, constituting a first step towards achieving communication between artificial chemical systems.Enzymes regulated by chemical signals are common in biology, but few such artificial catalysts exist. Here, the authors design an aniline catalyst that, when activated by a chemical trigger, catalyses formation of hydrazone-based gels, demonstrating signal response in a soft material.

  4. Suicide in children and adolescents: a Tunisian perspective from 2009 to 2015.

    Science.gov (United States)

    Majdoub, Wael; Mosbahi, Amal; Naouar, Maroua; Beji, Meriem; Mannai, Jihene; Turki, Elyes

    2017-12-01

    This study presents the characteristics of child and adolescent suicides which occurred in Kairouan, Tunisia. Data were collected from autopsy records of the Forensic Department of the University Hospital Ibn El Jazzar of Kairouan. General characteristics of suicides among children and adolescents (under the age of 18) between 2009 and 2015 were retrospectively reviewed. A total of 49 cases, with a female predominance (61.2%) and a mean age of 15.4 ± 2.1, were registered. Most of the victims were from rural areas (93.1%). In most cases, suicide occurred in the victim's home or the surrounding area (73.4%). The identified precipitating factors were family problems in 55.1%, and school issues in 12.2%. The most common suicide method was hanging (69.38%) for both genders, followed by self-immolation for males and poisoning for females, the majority using pesticides. This study offers useful information to understand the risk factors in Tunisian child and adolescent suicides and provides a basis for the development of urgently needed preventive strategies.

  5. Impact of the Tunisian Revolution on homicide and suicide rates in Tunisia.

    Science.gov (United States)

    Ben Khelil, Mehdi; Gharbaoui, Meriem; Farhani, Fethia; Zaafrane, Malek; Harzallah, Hana; Allouche, Mohamed; Zhioua, Mongi; Hamdoun, Moncef

    2016-12-01

    To analyze the impact of the Tunisian Revolution on suicide and homicide patterns in Tunisia. It is a retrospective, cross-sectional study, including all the cases of homicides and suicides that occurred during an 8-year period (2007-2014) in Northern Tunisia. We compared data before and after the revolution. After the revolution, the number of suicides rose 1.7 times, with a prevalence rising from 1.8 to 3.12 suicides per 100,000 persons per year. Homicides rose 1.3 times after the revolution. For both manner of death, victims were mostly males, aged between 20 and 39 years, living in urban areas. Hanging and self-immolation rose, respectively, 1.8 and 3 times after 2011. We observed suicide cases most frequently occurred in public places and in front of public administration after 2011. Homicide victims' profile and circumstances showed a single variation which is an increase in number of cases happening in rural areas. Our results proved a short-term impact of the transition period on homicides and suicides. Urgent preventive measures are needed especially to decrease the suicide rates.

  6. “I could still see her in my mind’s eye”: Water and Maternal Imagery in Uwe Johnson’s Anniversaries: From the Life of Gesine Cresspahl

    Directory of Open Access Journals (Sweden)

    Caroline Rupprecht

    2010-01-01

    Full Text Available This article analyzes the writings of East German author Uwe Johnson (1934-84 in terms of his experimental style—specifically transitions between descriptive passages—in conjunction with maternal imagery, as discussed through reference to Susan Suleiman’s concept of a “1.5 generation” of Holocaust survivors. A non-Jewish German author, Johnson addresses German history from the position of the perpetrators, yet born in 1934, he experienced National Socialism from the point of view of a child. In his tetralogy, Anniversaries: From the Life of Gesine Cresspahl (1970-83, feelings of guilt and attempts to understand the German past are negotiated through the maternal figure. This figure is linked, in turn, to water as both a structural and symbolic element throughout the novel. As this article demonstrates, the effect of “blurred boundaries” is achieved through water, which functions as paradigm for the mother-daughter relationship: the narrator-protagonist Gesine’s memory is shaped by the experience of near-drowning before the eyes of her mother, Lisbeth, who commits suicide via self-immolation during Reichskristallnacht . As this article concludes, the author himself seems caught in the predicament of Suleiman’s 1.5 Generation, where perception is blurred, and immersing oneself in (imaginary bodies of water becomes a response to the madness of fascism.

  7. Comparative genomic analyses of the cyanobacterium, Lyngbya aestuarii BL J, a powerful hydrogen producer.

    Directory of Open Access Journals (Sweden)

    Ankita eKothari

    2013-12-01

    Full Text Available The filamentous, non-heterocystous cyanobacterium Lyngbya aestuarii is an important contributor to marine intertidal microbial mats system worldwide. The recent isolate L. aestuarii BL J, is an unusually powerful hydrogen producer. Here we report a morphological, ultrastructural and genomic characterization of this strain to set the basis for future systems studies and applications of this organism. The filaments contain circa 17 μm wide trichomes, composed of stacked disk-like short cells (2 μm long, encased in a prominent, laminated exopolysaccharide sheath. Cellular division occurs by transversal centripetal growth of cross-walls, where several rounds of division proceed simultaneously. Filament division occurs by cell self-immolation of one or groups of cells (necridial cells at the breakage point. Short, sheath-less, motile filaments (hormogonia are also formed. Morphologically and phylogenetically L. aestuarii belongs to a clade of important cyanobacteria that include members of the marine Trichodesmiun and Hydrocoleum genera, as well as terrestrial Microcoleus vaginatus strains, and alkalyphilic strains of Arthrospira. A draft genome of strain BL J was compared to those of other cyanobacteria in order to ascertain some of its ecological constraints and biotechnological potential. The genome had an average GC content of 41.1 %. Of the 6.87 Mb sequenced, 6.44 Mb was present as large contigs (>10,000 bp. It contained 6515 putative protein-encoding genes, of which, 43 % encode proteins of known functional role, 26 % corresponded to proteins with domain or family assignments, 19.6 % encode conserved hypothetical proteins, and 11.3 % encode apparently unique hypothetical proteins. The strain’s genome reveals its adaptations to a life of exposure to intense solar radiation and desiccation. It likely employs the storage compounds, glycogen and cyanophycin but no polyhydroxyalkanoates, and can produce the osmolytes, trehalose and glycine

  8. Epidemiology and financial implications of self-inflicted burns.

    Science.gov (United States)

    George, S; Javed, M; Hemington-Gorse, S; Wilson-Jones, N

    2016-02-01

    The cost of the treatment of burns is high especially in self-inflicted burns with prolonged treatment. We performed a retrospective review of the self-inflicted burns at our regional burns centre to determine the costs incurred in their management and to identify factors which could reduce the financial burden in the future. The data was collected retrospectively of all the inpatient and outpatient self-inflicted burns presenting to our regional burns centre in the year 2011. Twenty one patients (out of a total of 870 patients) presented with self-inflicted burns to our centre in 2011. Five (23.8%) were major burns with an average of 53.2% Total Body Surface Area (TBSA) and 16 (76.2%) were minor burns with an average of 0.5% TBSA. 11 (52.4%) patients had flame burns including 4 self-immolation burns. The mortality rate was 4.8% (n=1). Five (23.8%) patients underwent surgical treatment. Seven (33.3%) patients were treated in intensive care and with average stay of 46.85 days. Critical care and theatre attendances made up most of the costs with average ICU stay per patient calculated at £313,131/day. The total cost of all 21 patients was £1,581,856. Burns are preventable injuries, early detection and intervention in patients with propensity to self-inflict burns can possibly reduce the costs of treatment in the future. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

  9. Epidemiology and outcome of burns in Esteqlal Hospital of Kabul, Afghanistan.

    Science.gov (United States)

    Padovese, V; De Martino, R; Eshan, M A; Racalbuto, V; Oryakhail, M A

    2010-11-01

    Burns are a major public health issue in Afghanistan, at least in terms of morbidity and long term disability. Little data exists to document the extent of the problem. This study reports the epidemiology and outcome of burns seen in Esteqlal Hospital of Kabul, a regional referral and teaching hospital run jointly by the Afghan Ministry of Public Health and the Italian Cooperation. It furthermore aims to investigate the underlying conditions which lead to this dramatically widespread event in order to develop effective burn prevention programmes. A total of 532 patients admitted for burns between March 1, 2007 and June 30, 2008 in Esteqlal Hospital were studied retrospectively through the review of medical records. Male to female ratio was 0.7:1 and the median age at presentation was 19 years. The mean total body surface area (TBSA) burned was 36.5%. Overall mortality rate was 28% with a prevalence of death among females (68%). The most common cause of burn was flame (46.2%), followed by gas cylinder explosion (36.4%). Self-immolation was reported in 21 patients, 76% of whom resulted in death. A large number of burn injuries occur in domestic settings and are preventable. Strategies might include implementation of educational programs through mass communications and development of policies for the commerce of unadulterated petroleum products. Other goals such as disability prevention and mortality reduction might be achieved building burns centres and training healthcare professionals working at the peripheral level. Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.

  10. Immolation of p-Aminobenzyl Ether Linker and Payload Potency and Stability Determine the Cell-Killing Activity of Antibody-Drug Conjugates with Phenol-Containing Payloads.

    Science.gov (United States)

    Zhang, Donglu; Le, Hoa; Cruz-Chuh, Josefa Dela; Bobba, Sudheer; Guo, Jun; Staben, Leanna; Zhang, Chenghong; Ma, Yong; Kozak, Katherine R; Lewis Phillips, Gail D; Vollmar, Breanna S; Sadowsky, Jack D; Vandlen, Richard; Wei, BinQing; Su, Dian; Fan, Peter; Dragovich, Peter S; Khojasteh, S Cyrus; Hop, Cornelis E C A; Pillow, Thomas H

    2018-02-07

    The valine-citrulline (Val-Cit) dipeptide and p-aminobenzyl (PAB) spacer have been commonly used as a cleavable self-immolating linker in ADC design including in the clinically approved ADC, brentuximab vedotin (Adcetris). When the same linker was used to connect to the phenol of the cyclopropabenzindolone (CBI) (P1), the resulting ADC1 showed loss of potency in CD22 target-expressing cancer cell lines (e.g., BJAB, WSU-DLCL2). In comparison, the conjugate (ADC2) of a cyclopropapyrroloindolone (CPI) (P2) was potent despite the two corresponding free drugs having similar picomolar cell-killing activity. Although the corresponding spirocyclization products of P1 and P2, responsible for DNA alkylation, are a prominent component in buffer, the linker immolation was slow when the PAB was connected as an ether (PABE) to the phenol in P1 compared to that in P2. Additional immolation studies with two other PABE-linked substituted phenol compounds showed that electron-withdrawing groups accelerated the immolation to release an acidic phenol-containing payload (to delocalize the negative charge on the anticipated anionic phenol oxygen during immolation). In contrast, efficient immolation of LD4 did not result in an active ADC4 because the payload (P4) had a low potency to kill cells. In addition, nonimmolation of LD5 did not affect the cell-killing potency of its ADC5 since immolation is not required for DNA alkylation by the center-linked pyrrolobenzodiazepine. Therefore, careful evaluation needs to be conducted when the Val-Cit-PAB linker is used to connect antibodies to a phenol-containing drug as the linker immolation, as well as payload potency and stability, affects the cell-killing activity of an ADC.

  11. Mathematics and Humor: John Allen Paulos and the Numeracy Crusade

    Directory of Open Access Journals (Sweden)

    Paul H. Grawe

    2015-07-01

    Full Text Available John Allen Paulos at minimum gave the Numeracy movement a name through his book Innumeracy: Mathematical Illiteracy and Its Consequences. What may not be so obvious was Paulos’ strong interest in the relationship between mathematics and mathematicians on the one hand and humor and stand-up-comedian joke structures on the other. Innumeracy itself could be seen as a typically mathematical Gotcha joke on American culture generally. In this perspective, a Minnesotan acculturated to Minnesota-Nice Humor of Self-Immolation Proclivities (SImP looks at the more raw-boned, take-no-prisoners humor style Paulos outlined in Mathematics and Humor and implemented in Innumeracy. Despite the difference in humor styles, there is much to applaud in Paulos’ analysis of the relationship between certain types of humor and professional interests of mathematicians in Mathematics and Humor. Much humor relies on the sense of incongruity which Paulos’ claims to be central to all humor and key to mathematical reductio ad absurdum. Mathematics is rightfully famous for a sense of combinatorial playfulness in its most elegant proofs, as humor often relies on clashing combinations of word play. And a great range of mathematical lore is best understood within a concept of a sudden drop from one sense of certainty to another (essentially a Gotcha on the audience. Innumeracy repeatedly exemplifies Gotchas on the great unwashed and unmathematical majority. Extensive empirical evidence over the last quarter century allows us to synthesize these Paulos observations into the idea that inculcated mathematical humor has strong propensities to complex Intellectual, Advocate, and Crusader humor forms. However, the Paulos humors do not include the Sympathetic Pain humor form, the inclusion of which may increase teaching effectiveness.

  12. Epidemiology and Outcome of Self-Inflicted Burns at Pakistan Institute of Medical Sciences, Islamabad

    Science.gov (United States)

    Saaiq, Muhammad; Ashraf, Bushra

    2014-01-01

    BACKGROUND Self-inflicted burn injuries carry considerable mortality and morbidity among otherwise fit young individuals. This study assessed the epidemiologic pattern and outcome of these injuries in a burn care facility in Pakistan. METHODS The study was carried out at Pakistan Institute of Medical Sciences (PIMS) Burn Care Centre in Islamabad over a period of 2 years. It included all adult patients of either gender, aged over 14 years who presented as cases of burn suicides and attempted burn suicides during the study period. Convenience sampling technique was employed. The sociodemographic profile of the patients, motives underlying the act of self-immolation, any underlying psychiatric illness, alcohol abuse, total body surface area (TBSA) burnt, depth of burn injury, associated inhalation injury, duration of hospital stay, and mortality were all recorded. RESULTS Seventy five patients (80.64%) were female while 18 patients (19.35%) were male. The overall mean age was 26.89±6.1 years (range=15-52 years). The affected TBSA ranged from 15%-100% with an overall mean of 69.30±25.42%. The hospital stay ranged from 1-37 days with a mean of 7.16±6.60 days. Marital conflicts constituted the most frequent motive underlying the suicidal attempts (n=57; 61.29%) followed by failed love affairs (n=9; 9.67%). There was an overall mortality of 84.95%. The most common sufferers of self inflicted burn injuries were young, married, illiterate housewives who were resident of rural area. Getting marriage was the most common triggering cause for such injuries. CONCLUSION There is need to institute appropriate preventive measures to address the issue in a national perspective. PMID:25489533

  13. Therapeutic mechanism and efficacy of the antibody-drug conjugate BAY 79-4620 targeting human carbonic anhydrase 9.

    Science.gov (United States)

    Petrul, Heike M; Schatz, Christoph A; Kopitz, Charlotte C; Adnane, Lila; McCabe, Timothy J; Trail, Pamela; Ha, Sha; Chang, Yong S; Voznesensky, Andrei; Ranges, Gerald; Tamburini, Paul P

    2012-02-01

    Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein that is expressed in many different tumors and yet restricted in normal tissues to the gastrointestinal tract. It is upregulated by hypoxia and correlates with tumor grade and poor survival in several tumor indications. Monoclonal antibodies (mAb) with single digit nanomolar binding affinity for CAIX were derived by panning with the recombinant ectodomain of CAIX against the MorphoSys HUCAL Gold library of human Fabs. Highest affinity Fabs were converted to full-length IgGs and subjected to further characterization based upon their avidity and selectivity for CAIX, their capacity to undergo internalization in CAIX-expressing cell lines, and their selective localization to CAIX-positive human xenografted tumors when administered to mice as fluorescent conjugates. Through this selection process, the 3ee9 mAb was identified, which upon conjugation to monomethyl auristatin E through a self-immolative enzyme-cleavable linker yielded the potent and selective CAIX antibody-drug conjugate CAIX-ADC (BAY 79-4620). In preclinical human xenograft models in mice representing several tumor indications, BAY 79-4620 showed potent antitumor efficacy and in some models showed partial and complete tumor shrinkage even following a single dose. The mechanism of action was shown by histology to involve the sequelae of events typical of antitubulin agents. Efficacy in murine preclinical models correlated semiquantitatively, with CAIX expression levels as determined by immunohistochemistry and ELISA. These preclinical data collectively support the development of BAY 79-4620 for the treatment of cancer patients with CAIX overexpressing tumors.

  14. Epidemiologic Study of Suicidal Attempt Cases in Fars Province, South of Iran, 2010-2011

    Directory of Open Access Journals (Sweden)

    Mojtaba Naghshvarian

    2016-01-01

    Full Text Available Background: The reduction of suicidal attempts as one of the most important goals is improvement of societies’ health status. The present study aimed to assess the epidemiologic aspects of suicide cases in Fars province in 2010-2011. Methods: A total of 9714 suicide cases in Fars province, south of Iran, in 2010-2011 were enrolled in this cross-sectional study through census. The study data were collected using suicide registry forms in the health centers affiliated to Fars province department of health services and analyzed using SPSS, version 17. Results: The rate of suicide attempts was 116.5 per 100,000 population in Fars province (93per 100,000 among men and 141.5 per 100,000 among women. The results showed significant differences between the suicide rates based on sex, age group, place of living, and season of the year (P<0.001. Most of these cases were female (59.4%, single (52.9%, 15-24 years old (56.4%, had high school education (25.8%, lived in urban areas (69.6% and were female homemakers (30.3%. Based on the data, however, the largest number of suicide deaths resulted from self-immolation (56.7%. Conclusion: The present study findings revealed different rates of suicidal attempts based on sex and age group. Also, the importance of education and mental support, especially among women and singles, and also preventive measures in the context of uncontrolled immigration from the countryside to the large cities seems to essential more than ever. Yet, defects in some findings, particularly information about etiology, suggest that more researches should be conducted and suicide data registry and reporting systems should be improved

  15. Suicide Methods in Asia: Implications in Suicide Prevention

    Science.gov (United States)

    Wu, Kevin Chien-Chang; Chen, Ying-Yeh; Yip, Paul S. F.

    2012-01-01

    As the largest continent in the World, Asia accounts for about 60% of World suicides. Preventing suicide by restricting access to suicide methods is one of the few evidence-based suicide prevention strategies. However, there has been a lack of systematic exploration of suicide methods in Asian countries. To amend this shortage, the current review examines the leading suicide methods in different Asian countries, their trend, their age- and sex- specific characteristics, and their implications for suicide prevention. In total, 42 articles with leading suicide methods data in 17 Asian countries/regions were retrieved. The epidemiologic characteristics and recent trends of common suicide methods reflect specific socio-cultural, economic, and religious situations in the region. Common suicide methods shift with the introduction of technologies and constructions, and have specific age- or sex-characteristics that may render the restriction of suicide methods not equally effective for all sex and age sub-groups. Charcoal burning, pesticide poisoning, native plant poisoning, self-immolation, and jumping are all prominent examples. In the information society, suicide prevention that focuses on suicide methods must monitor and control the innovation and spread of knowledge and practices of suicide “technologies”. It may be more cost-effective to design safety into technologies as a way of suicide prevention while there is no rash of suicides yet by the new technologies. Further research on suicide methods is important for public health approaches to suicide prevention with sensitivity to socio-cultural, economic, and religious factors in different countries. PMID:22690187

  16. Suicide Methods in Asia: Implications in Suicide Prevention

    Directory of Open Access Journals (Sweden)

    Paul S. F. Yip

    2012-03-01

    Full Text Available As the largest continent in the World, Asia accounts for about 60% of World suicides. Preventing suicide by restricting access to suicide methods is one of the few evidence-based suicide prevention strategies. However, there has been a lack of systematic exploration of suicide methods in Asian countries. To amend this shortage, the current review examines the leading suicide methods in different Asian countries, their trend, their age- and sex- specific characteristics, and their implications for suicide prevention. In total, 42 articles with leading suicide methods data in 17 Asian countries/regions were retrieved. The epidemiologic characteristics and recent trends of common suicide methods reflect specific socio-cultural, economic, and religious situations in the region. Common suicide methods shift with the introduction of technologies and constructions, and have specific age- or sex-characteristics that may render the restriction of suicide methods not equally effective for all sex and age sub-groups. Charcoal burning, pesticide poisoning, native plant poisoning, self-immolation, and jumping are all prominent examples. In the information society, suicide prevention that focuses on suicide methods must monitor and control the innovation and spread of knowledge and practices of suicide “technologies”. It may be more cost-effective to design safety into technologies as a way of suicide prevention while there is no rash of suicides yet by the new technologies. Further research on suicide methods is important for public health approaches to suicide prevention with sensitivity to socio-cultural, economic, and religious factors in different countries.

  17. Cytotoxic Mechanisms of Tumor Specific Antibodies

    National Research Council Canada - National Science Library

    Clynes, Raphael

    2001-01-01

    ... and effector-cell-mediated cytotoxicity, we have demonstrated (Clynes RA, Towers TL, Presta LG, Ravetch JV, Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nature Medicine 6:443-446 (2000...

  18. Cytotoxic Mechanisms of Tumor Specific Antibodies

    National Research Council Canada - National Science Library

    Clynes, Raphael

    2000-01-01

    ... and effector-cell-mediated cytotoxicity, we have demonstrated (clynes RA, Towers TL, Presta LG, Ravetch JV, Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nature Medicine 6:443-446 (2000...

  19. Preparation of Two Types of Polymeric Micelles Based on Poly(β-L-Malic Acid) for Antitumor Drug Delivery

    National Research Council Canada - National Science Library

    Yang, Tiehong; Li, Wei; Duan, Xiao; Zhu, Lin; Fan, Li; Qiao, Youbei; Wu, Hong

    2016-01-01

    .... In this work, two types of CPT-conjugated polymers were synthesized based on poly(β-L-malic acid) (PMLA) derivatives. Folic acid (FA) was introduced into the polymers as tumor targeting group...

  20. The targeting mechanism of DHA ligand and its conjugate with Gemcitabine for the enhanced tumor therapy

    Science.gov (United States)

    Li, Siwen; Qin, Jingyi; Tian, Caiping; Cao, Jie; Fida, Guissi; Wang, Zhaohui; Chen, Haiyan; Qian, Zhiyu; Chen, Wei R; Gu, Yueqing

    2014-01-01

    Docosahexaenoic acid (DHA), an omega-3 C22 natural fatty acid serving as a precursor for metabolic and biochemical pathways, was reported as a targeting ligand of anticancer drugs. However, its tumor targeting ability and mechanism has not been claimed. Here we hypothesized that the uptake of DHA by tumor cells is related to the phosphatidylethanolamine (PE) contents in cell membranes. Thus, in this manuscript, the tumor-targeting ability of DHA was initially demonstrated in vitro and in vivo on different tumor cell lines by labeling DHA with fluorescence dyes. Subsequently, the tumor targeting ability was then correlated with the contents of PE in cell membranes to study the uptake mechanism. Further, DHA was conjugated with anticancer drug gemcitabine (DHA-GEM) for targeted tumor therapy. Our results demonstrated that DHA exhibited high tumor targeting ability and PE is the main mediator, which confirmed our hypothesis. The DHA-GEM displayed enhanced therapeutic efficacy than that of GEM itself, indicating that DHA is a promising ligand for tumor targeted therapy. PMID:25004114

  1. A new targeted delivery approach by functionalizing drug nanocrystals through polydopamine coating.

    Science.gov (United States)

    Zhan, Honglei; Jagtiani, Tina; Liang, Jun F

    2017-05-01

    Tumor target specificity via chemotherapy is widely considered to be very effective on tumor treatment. For an ideal chemotherapeutic agent like Camptothecin (CPT) (CPT is the abbreviation for Camptothecin), improved therapeutic efficacy and high selectivity are equally important. Inspired by adhesive proteins in mussels, here we developed a novel tumor targeting peptide XQ1 grafted CPT nanocrystals with polydopamine coating as a spacer. In this study, CPT nanocrystals were coated by polymerization of dopamine that was induced by plasma-activated water under an acidic environment, and then the tumor targeting peptide was grafted onto polydopamine (PDA) (PDA is the abbreviation for polydopamine) coated CPT nanocrystals through catechol chemistry. The PDA layer had negligible effects on drug crystallinity and structure but resulted in drug nanocrystals with excellent dispersion properties, improved dissolution rate and drug stability by preventing water hydrolysis. More importantly, tumor targeting peptide XQ1 facilitated a rapid cross-membrane translocation of drug nanocrystals via receptor-mediated endocytosis, leading to efficient intracellular drug delivery. Moreover, this novel drug formulation demonstrated more potent anti-cancer activity against tumor cells in comparison with free CPT and naked CPT nanocrystals and exhibited high selectivity, all of which are attributed to the tumor target specificity property and inherent pH-dependent drug release behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Development of a transferrin receptor-targeting HVJ-E vector.

    Science.gov (United States)

    Shimbo, Takashi; Kawachi, Masako; Saga, Kotaro; Fujita, Hiroshi; Yamazaki, Takehiko; Tamai, Katsuto; Kaneda, Yasufumi

    2007-12-21

    The development of more effective cancer treatments is anticipated. Tumor-targeted drug delivery is an important strategy in cancer therapy. We have developed an HVJ (hemagglutinating virus of Japan; Sendai virus) envelope (HVJ-E) vector using inactivated Sendai virus. The HVJ-E vector has been observed to target a number of cell lines since its hemagglutinin-neuraminidase (HN) protein recognizes the sialic acids of host cells. Thus, to reduce non-specific binding of the HVJ-E vector, we eliminated HN protein using HN-specific short interfering RNA (siRNA). Then, to further increase its tumor-targeting ability, we constructed HN-depleted HVJ containing the F-transferrin chimeric protein. The modified vectors containing Q-dots demonstrated 32-fold greater tumor-targeting efficiency than wild-type HVJ-E.

  3. Mechanism for Clastogenic Activity of Naphthalene

    Energy Technology Data Exchange (ETDEWEB)

    Buchholz, Bruce A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-09-29

    Naphthalene incubations form DNA adducts in vitro in a dose dependent manner in both mouse and rat tissues. Rodent tissue incubations with naphthalene indicate that naphthalene forms as many DNA adducts as Benzo(a)pyrene, a known DNA binding carcinogen. The mouse airway has the greatest number of DNA adducts, corresponding to the higher metabolic activation of naphthalene in this location. Both rat tissues, the rat olfactory (tumor target) and the airways (non-tumor target), have similar levels of NA-DNA adducts, indicating that short term measures of initial adduct formation do not directly correlate with sites of tumor formation in the NTP bioassays.

  4. CAR-T cells are serial killers.

    Science.gov (United States)

    Davenport, Alexander J; Jenkins, Misty R; Ritchie, David S; Prince, H Miles; Trapani, Joseph A; Kershaw, Michael H; Darcy, Phillip K; Neeson, Paul J

    2015-12-01

    Chimeric antigen receptor (CAR) T cells have enjoyed unprecedented clinical success against haematological malignancies in recent years. However, several aspects of CAR T cell biology remain unknown. We recently compared CAR and T cell receptor (TCR)-based killing in the same effector cell and showed that CAR T cells can not only efficiently kill single tumor targets, they can also kill multiple tumor targets in a sequential manner. Single and serial killing events were not sustained long term due to CAR down-regulation after 20 hours.

  5. Multi-functional nanoparticles for cancer therapy

    Directory of Open Access Journals (Sweden)

    Dev Kumar Chatterjee and Yong Zhang

    2007-01-01

    Full Text Available Many immunotherapeutic strategies developed in recent years involve the targeting of immune cells to tumors. In this study, we synthesized and characterized modified fluorescent nanoparticles as a targeting and delivery system, by conjugating both tumor targeting agent and chemokines to the nanoparticles, to attract immune cells to tumor cells. Biodegradable chitosan nanoparticles encapsulating quantum dots were prepared, with suitable surface modification to immobilize both tumor targeting agent and chemokine on their surfaces. The interactions between immune cells and tumor cells were visualized using optical microscope.

  6. Mechanism for Clastogenic Activity of Naphthalene

    Energy Technology Data Exchange (ETDEWEB)

    Buchholz, Bruce A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2016-06-24

    Naphthalene incubations form DNA adducts in vitro in a dose dependent manner in both mouse and rat tissues. Rodent tissue incubations with naphthalene indicate that naphthalene forms as many DNA adducts as Benzo(a)pyrene, a known DNA binding carcinogen. The mouse airway has the greatest number of DNA adducts, corresponding to the higher metabolic activation of naphthalene in this location. Both rat tissues, the rat olfactory (tumor target) and the airways (non-tumor target), have similar levels of NA-DNA adducts, indicating that short term measures of initial adduct formation do not directly correlate with sites of tumor formation in the NTP bioassays.

  7. New Strategies in Cancer Nanomedicine.

    Science.gov (United States)

    Tong, Rong; Kohane, Daniel S

    2016-01-01

    We review recent progress in cancer nanomedicine, including stimulus-responsive drug delivery systems and nanoparticles responding to light for phototherapy or tumor imaging. In addition, several new strategies to improve the circulation of nanoparticles in vivo, tumor penetration, and tumor targeting are discussed. The application of nanomedicine in cancer immunology, a relatively new type of cancer therapy, is also highlighted.

  8. Nanomedicine in veterinary oncology.

    Science.gov (United States)

    Lin, Tzu-Yin; Rodriguez, Carlos O; Li, Yuanpei

    2015-08-01

    Nanomedicine is an interdisciplinary field that combines medicine, engineering, chemistry, biology and material sciences to improve disease management and can be especially valuable in oncology. Nanoparticle-based agents that possess functions such as tumor targeting, imaging and therapy are currently under intensive investigation. This review introduces the basic concept of nanomedicine and the classification of nanoparticles. Because of their favorable pharmacokinetics, tumor targeting properties, and resulting superior efficacy and toxicity profiles, nanoparticle-based agents can overcome several limitations associated with conventional diagnostic and therapeutic protocols in veterinary oncology. The two most important tumor targeting mechanisms (passive and active tumor targeting) and their dominating factors (i.e. shape, charge, size and nanoparticle surface display) are discussed. The review summarizes published clinical and preclinical studies that utilize different nanoformulations in veterinary oncology, as well as the application of nanoparticles for cancer diagnosis and imaging. The toxicology of various nanoformulations is also considered. Given the benefits of nanoformulations demonstrated in human medicine, nanoformulated drugs are likely to gain more traction in veterinary oncology. Published by Elsevier Ltd.

  9. Effects of linker variation on the in vitro and in vivo characteristics of an 111In-labeled RGD peptide.

    NARCIS (Netherlands)

    Dijkgraaf, I.; Liu, S.; Kruijtzer, J.A.; Soede, A.C.; Oyen, W.J.G.; Liskamp, R.M.; Corstens, F.H.M.; Boerman, O.C.

    2007-01-01

    INTRODUCTION: Due to the selective expression of the alpha(v)beta3 integrin in tumors, radiolabeled arginine-glycine-aspartic acid (RGD) peptides are attractive candidates for tumor targeting. Minor modifications of these peptides could have a major impact on in vivo characteristics. In this study,

  10. Symposia Summary of the International RES Congress (10th) held at Ito, Japan on 2-7 September 1984.

    Science.gov (United States)

    1984-11-28

    independently genetically regulated. In the presence of antibody, some activated macro- phages can kill certain tumor targets by release of reactive...hat t he dpressed Pf ’, f uni(ion, ( ia u’,ed by depresed ht~- iliir cioirtl tmetabol isrrn a% wel 1s dec(1,reased funct innmnq PES m,,% in iisan mpri

  11. An Adenovirus Vector Incorporating Carbohydrate Binding Domains Utilizes Glycans for Gene Transfer

    NARCIS (Netherlands)

    Kim, Julius W.; Glasgow, Joel N.; Nakayama, Masaharu; Ak, Ferhat; Ugai, Hideyo; Curiel, David T.

    2013-01-01

    Background: Vectors based on human adenovirus serotype 5 (HAdV-5) continue to show promise as delivery vehicles for cancer gene therapy. Nevertheless, it has become clear that therapeutic benefit is directly linked to tumor-specific vector localization, highlighting the need for tumor-targeted gene

  12. Biomarkers in the Detection of Prostate Cancer in African Americans

    Science.gov (United States)

    2012-09-01

    cell activation. Cancer Res 70:1668. doi:10.1158/0008– 5472.CAN-09-2470 114. Morelli AE, Larregina AT, Shufesky WJ, Sullivan MMLG, Sullivan DBS ...and Receptors as Targets for Cancer Radiotherapy , Tumor Targeting 3 (1998), 122–137. (Not found in PubMed). [26] M.N. Saleh, A.B. Tilden, R.F

  13. An off-on fluorescence probe targeting mitochondria based on oxidation-reduction response for tumor cell and tissue imaging

    Science.gov (United States)

    Yao, Hanchun; Cao, Li; Zhao, Weiwei; Zhang, Suge; Zeng, Man; Du, Bin

    2017-10-01

    In this study, a tumor-targeting poly( d, l-lactic-co-glycolic acid) (PLGA) loaded "off-on" fluorescent probe nanoparticle (PFN) delivery system was developed to evaluate the region of tumor by off-on fluorescence. The biodegradability of the nanosize PFN delivery system readily released the probe under tumor acidic conditions. The probe with good biocompatibility was used to monitor the intracellular glutathione (GSH) of cancer cells and selectively localize to mitochondria for tumor imaging. The incorporated tumor-targeting probe was based on the molecular photoinduced electron transfer (PET) mechanism preventing fluorescence ("off" state) and could be easily released under tumor acidic conditions. However, the released tumor-targeting fluorescence probe molecule was selective towards GSH with high selectivity and an ultra-sensitivity for the mitochondria of cancer cells and tissues significantly increasing the probe molecule fluorescence signal ("on" state). The tumor-targeting fluorescence probe showed sensitivity to GSH avoiding interference from cysteine and homocysteine. The PFNs could enable fluorescence-guided cancer imaging during cancer therapy. This work may expand the biological applications of PFNs as a diagnostic reagent, which will be beneficial for fundamental research in tumor imaging. [Figure not available: see fulltext.

  14. The role of cell-mediated cytolysis in antitumor responses

    NARCIS (Netherlands)

    C. Gravekamp (Claudia)

    1988-01-01

    textabstractThe purpose of the work described in this thesis was (1) to study the effector cell types involved in antitumor responses; (2) to investigate whether of the immune system in cancer patient may occur at tumor-target or at lymphocyte-effector cell level; and (3) to explore new

  15. Evaluation, characterization and validation in micro-MRI and micro-PET with [{sup 18}F]-F.D.G. of two heterologous murine models of endometrium carcinoma; Mise au point, caracterisation et validation en micro-IRM et micro-TEP au [{sup 18}F]-FDG de 2 modeles murins heterologues de cancer de l'endometre

    Energy Technology Data Exchange (ETDEWEB)

    Lefebvre-Lacoeuille, C.; Descamps, P. [Pole gynecologie-obstetrique, CHU d' Angers, (France); Lacoeuille, C.; Couturier, F.O. [service de medecine nucleaire, CHU d' Angers, (France); Scarwell, B.; Bouchet, F. [Inserm U646, universite d' Angers, (France); Lemaire, L.; Hindre, F.; Fusellier, M. [ecole nationale veterinaire de Nantes, (France)

    2009-05-15

    The two murine models of endometrium cancer validated in this work and whom growth can be quantified by {mu}Tep could be used to evaluate the interest of oestrogens labelled with {sup 18}F in the anti tumoral targeted therapies. (N.C.)

  16. Targeted Dual-Modality Imaging in Renal Cell Carcinoma: An Ex Vivo Kidney Perfusion Study

    NARCIS (Netherlands)

    Hekman, M.C.H.; Boerman, O.C.; Weijert, M. de; Bos, D.L.; Oosterwijk, E.; Langenhuijsen, H.F.; Mulders, P.F.A.; Rijpkema, M.

    2016-01-01

    PURPOSE: Antibodies labeled with both a near-infrared fluorescent dye and a radionuclide can be used for tumor-targeted intraoperative dual-modality imaging. Girentuximab is a chimeric monoclonal antibody against carbonic anhydrase IX (CAIX), an antigen expressed in 95% of clear cell renal cell

  17. Cisplatin Loaded Hyaluronic Acid Modified TiO2 Nanoparticles for Neoadjuvant Chemotherapy of Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Enling Liu

    2015-01-01

    Full Text Available Novel tumor-targeting titanium dioxide (TiO2 nanoparticles modified with hyaluronic acid (HA were developed to explore the feasibility of exploiting the pH-responsive drug release property of TiO2 and the tumor-targeting ability of HA to construct a tumor-targeting cisplatin (CDDP delivery system (HA-TiO2 for potential neoadjuvant chemotherapy of ovarian cancer. The experimental results indicated that CDDP release from the HA-TiO2 nanoparticles was significantly accelerated by decreasing pH from 7.4 to 5.0, which is of particular benefit to cancer therapy. CDDP-loaded HA-TiO2 nanoparticles increased the accumulation of CDDP in A2780 ovarian cancer cells via HA-mediated endocytosis and exhibited superior anticancer activity in vitro. In vivo real-time imaging assay revealed that HA-TiO2 nanoparticles possessed preferable tumor-targeting ability which might potentially minimize the toxic side effects of CDDP in clinical application.

  18. Synthesis and characterization of folate-poly(ethylene glycol ...

    African Journals Online (AJOL)

    polyethylenimine as a non-viral carrier for tumor-targeted gene delivery. ... It was concluded that FA-PEG-CHI-g-PEI, which has improved transfection efficiency and FRs specificity in vitro and in vivo, may be useful in gene therapy. Key words: Folate ...

  19. In vitro evaluation of avidin antibody pretargeting using 211At-labeled and biotinylated poly-L-lysine as effector molecule

    DEFF Research Database (Denmark)

    Frost, Sofia H L; Jensen, Holger Lau; Lindegren, Sture

    2010-01-01

    Pretargeting is an approach for enhancing the therapeutic index of radioimmunotherapy by separating the administrations of tumor-targeting substance and radiolabel. In this study, a pretargeting model system of avidin-conjugated monoclonal antibody trastuzumab and biotinylated, (211)At-labeled po...

  20. The Nature of Magnetic State of Small Fe3O4 Nanoparticles

    Directory of Open Access Journals (Sweden)

    J. Dolinšek

    2011-12-01

    Full Text Available We have investigated the nature of the magnetic state of 4 nm and 7 nm magnetite Fe3O4 nanoparticles and show that they form a collective superspin glass state. Magnetic force on the nanoparticles relevant to the tumor targeting application was determined as well.

  1. Absolute MR thermometry using nanocarriers

    NARCIS (Netherlands)

    Deckers, Roel; Sprinkhuizen, Sara M; Crielaard, Bart J; Ippel, Johannes H; Boelens, Rolf; Bakker, Chris J G; Storm, Gert; Lammers, Twan; Bartels, Lambertus W

    2014-01-01

    Accurate time-resolved temperature mapping is crucial for the safe use of hyperthermia-mediated drug delivery. We here propose a magnetic resonance imaging temperature mapping method in which drug delivery systems serve not only to improve tumor targeting, but also as an accurate and absolute

  2. Enhancing Tumor Penetration of Nanomedicines

    NARCIS (Netherlands)

    Sun, Qingxue; Ojha, Tarun; Kiessling, Fabian; Lammers, Twan; Shi, Yang

    2017-01-01

    Tumor-targeted nanomedicines have been extensively applied to alter the drawbacks and enhance the efficacy of chemotherapeutics. Despite the large number of preclinical nanomedicine studies showing initial success, their therapeutic benefit in the clinic has been rather modest, which is partially

  3. Connexin 43 Gene Therapy Delivered by Polymer-Modified Salmonella in Murine Tumor Models

    Directory of Open Access Journals (Sweden)

    Wei-Kuang Wang

    2014-04-01

    Full Text Available The use of preferentially tumor-targeting bacteria as vectors is one of the most innovative approaches for the treatment of cancer. This method is based on the observation that some obligate or facultative anaerobic bacteria are capable of selectively multiplying in tumors and inhibiting their growth. Previously, we found that the tumor-targeting efficiency of Salmonella could be modulated by modifying the immune response to these bacteria by coating them with poly(allylamine hydrochloride (PAH, and these organisms are designated PAH-S.C. (S. choleraesuis. PAH can provide a useful platform for the chemical modification of Salmonella, perhaps by allowing a therapeutic gene to bind to tumor-targeting Salmonella. This study aimed to investigate the benefits of the use of PAH-S.C. for gene delivery. To evaluate this modulation, the invasion activity and gene transfer of DNA-PAH-S.C. were measured in vitro and in vivo. Treatment with PAH-S.C. carrying a tumor suppressor gene (connexin 43 resulted in inhibition of tumor growth, which suggested that tumor-targeted gene therapy using PAH-S.C. carrying a therapeutic gene could exert antitumor activities. This technique represents a promising strategy for the treatment of tumors.

  4. (89)Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art (89)Zr Radiochemistry

    NARCIS (Netherlands)

    Heskamp, S.; Raavé , R.; Boerman, O.C.; Rijpkema, M.J.P.; Goncalves, V.; Denat, F.

    2017-01-01

    Immuno-positron emission tomography (immunoPET) with (89)Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore,

  5. 89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry

    NARCIS (Netherlands)

    Heskamp, S.; Raave, R.; Boerman, O.C.; Rijpkema, M.J.P.; Goncalves, V.; Denat, F.

    2017-01-01

    Immuno-positron emission tomography (immunoPET) with 89Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it

  6. Liposome-mediated targeting of enzymes to cancer cells for site-specific activation of prodrugs : Comparison with the corresponding antibody-enzyme conjugate

    NARCIS (Netherlands)

    Fonseca, Maria José; Jagtenberg, Joycelyn C.; Haisma, Hidde J.; Storm, Gert

    Purpose. Immunoenzymosomes are tumor-targeted immunoliposomes bearing enzymes on their surface. These enzymes are capable of converting relatively nontoxic prodrugs into active cytostatic agents. The aims of this study were to compare the enzyme delivery capability of immunoenzymosomes with that of

  7. Effects of tumor microenvironments on targeted delivery of glycol chitosan nanoparticles.

    Science.gov (United States)

    Yhee, Ji Young; Jeon, Sangmin; Yoon, Hong Yeol; Shim, Man Kyu; Ko, Hyewon; Min, Jiwoong; Na, Jin Hee; Chang, Hyeyoun; Han, Hyounkoo; Kim, Jong-Ho; Suh, Minah; Lee, Hyukjin; Park, Jae Hyung; Kim, Kwangmeyung; Kwon, Ick Chan

    2017-12-10

    In cancer theranostics, the main strategy of nanoparticle-based targeted delivery system has been understood by enhanced permeability and retention (EPR) effect of macromolecules. Studies on diverse nanoparticles provide a better understanding of different EPR effects depending on their structure, physicochemical properties, and chemical modifications. Recently the tumor microenvironment has been considered as another important factor for determining tumor-targeted delivery of nanoparticles, but the correlation between EPR effects and tumor microenvironment has not yet been fully elucidated. Herein, ectopic subcutaneous tumor models presenting different tumor microenvironments were established by inoculation of SCC7, U87, HT29, PC3, and A549 cancer cell lines into athymic nude mice, respectively. In the five different types of tumor-bearing mice, tumor-targeted delivery of self-assembled glycol chitosan nanoparticles (CNPs) were comparatively evaluated to identify the correlation between the tumor microenvironments and targeted delivery of CNPs. As a result, neovascularization and extents of intratumoral extracellular matrix (ECM) were both important in determining the tumor targeted delivery of CNPs. The EPR effect was maximized in the tumors which include large extent of angiogenic blood vessels and low intratumoral ECM content. This comprehensive study provides substantial evidence that the EPR effects based tumor-targeted delivery of nanoparticles can be different depending on the tumor microenvironment in individual tumors. To overcome current limitations in clinical nanomedicine, the tumor microenvironment of the patients and EPR effects in clinical tumors should also be carefully studied. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting Efficiency of Tumor.

    Science.gov (United States)

    Yoon, Hong Yeol; Shin, Min Lee; Shim, Man Kyu; Lee, Sangmin; Na, Jin Hee; Koo, Heebeom; Lee, Hyukjin; Kim, Jong-Ho; Lee, Kuen Yong; Kim, Kwangmeyung; Kwon, Ick Chan

    2017-05-01

    Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) and integrin α v β 3 with cyclic RGD-conjugated CNPs (cRGD-CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN-CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD-CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN-CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD-CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.

  9. Anticancer nanomedicine and tumor vascular permeability; Where is the missing link?

    Science.gov (United States)

    Taurin, Sebastien; Nehoff, Hayley; Greish, Khaled

    2012-12-28

    Anticancer nanomedicine was coined to describe anticancer delivery systems such as polymer conjugates, liposomes, micelles, and metal nanoparticles. These anticancer delivery platforms have been developed with the enhanced permeability and retention (EPR) effect as a central mechanism for tumor targeting. EPR based nanomedicine has demonstrated, beyond doubt, to selectively target tumor tissues in animal models. However, over the last two decades, only nine anticancer agents utilizing this targeting strategy have been approved for clinical use. In this review, we systematically analyze various aspects that explain the limited clinical progress yet achieved. The influence of nanomedicine physicochemical characteristics, animal tumor models, and variations in tumor biology, on EPR based tumor targeting is closely examined. Furthermore, we reviewed results from over one hundred publications to construct patterns of factors that can influence the transition of EPR based anticancer nanomedicine to the clinic. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Manganese dioxide nanosheets-based redox/pH-responsive drug delivery system for cancer theranostic application.

    Science.gov (United States)

    Hao, Yongwei; Wang, Lei; Zhang, Bingxiang; Li, Dong; Meng, Dehui; Shi, Jinjin; Zhang, Hongling; Zhang, Zhenzhong; Zhang, Yun

    2016-01-01

    The aim of this study was to construct redox- and pH-responsive degradable manganese dioxide (MnO2) nanosheets for cancer theranostic application. The small MnO2 nanosheets were synthesized, and then functionalized by hyaluronic acid (HA), demonstrating excellent stability and tumor-targeting ability. Cisplatin (cis-diamminedichloroplatinum [CDDP]) was absorbed by the nanosheets through a physical action, which was designed as MnO2/HA/CDDP. The prepared MnO2/HA/CDDP formulation was able to efficiently deliver CDDP to tumor cells in vitro and in vivo, resulting in improved therapeutic efficiency. Subsequently, they were triggered by lower pH and higher level of reduced glutathione to generate Mn(2+), enabling magnetic resonance imaging. The smart multifunctional system combining efficient magnetic resonance imaging and chemotherapy has the potential to be used as a tumor-targeting theranostic nanomedicine.

  11. Biophotonics and biotechnology in pancreatic cancer: cyclic RGD-peptide-conjugated type II quantum dots for in vivo imaging.

    Science.gov (United States)

    Yong, Ken-Tye

    2010-01-01

    This work introduces a novel, facile and straightforward approach to produce cyclic-RGD-peptide-conjugated type II CdTe/CdS quantum dot (QD) formulation for pancreatic tumor targeting and imaging in live animals. The ultra-small QDs were prepared by a hot colloidal synthesis method. Phospholipid micelles were then used to encapsulate the QDs, allowing them to be stably dispersed in biological fluids and able to conjugate with cyclic-RGD peptides. The QD complex had shown low cytotoxicity on Panc-1 human pancreatic cancer cell lines. In addition, the tissue sections and biodistribution of QD complexes were imaged and analyzed in mice bearing pancreatic tumor xenografts, confirming specific tumor targeting. These studies support further evaluation of type II QDs as potential probes for early pancreatic cancer assessment and detection. Copyright © 2010 S. Karger AG, Basel.

  12. Glycoengineered mesenchymal stem cells as an enabling platform for two-step targeting of solid tumors.

    Science.gov (United States)

    Layek, Buddhadev; Sadhukha, Tanmoy; Prabha, Swayam

    2016-05-01

    Current tumor targeted drug and diagnostic delivery systems suffer from a lack of selectivity for tumor cells. Here, we propose a two-step tumor targeting strategy based on mesenchymal stem cells (MSCs), which actively traffic to tumors. We developed glycoengineering protocols to induce expression of non-natural azide groups on the surface of MSCs without affecting their viability or tumor homing properties. Glycoengineered MSCs demonstrated active tumor homing in subcutaneous and orthotopic lung and ovarian tumor models. Subsequent systemic administration of dibenzyl cyclooctyne (DBCO)-labeled fluorophores or nanoparticles to MSC pretreated mice resulted in enhanced tumor accumulation of these agents through bio-orthogonal copper-free click chemistry. Further, administration of glycoengineered MSCs along with paclitaxel-loaded DBCO-functionalized nanoparticles resulted in significant (p step targeting strategy to improve the tumor specificity of diagnostic agents and drugs, and thus potentially improve the treatment outcomes for patients diagnosed with cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Biodistribution and Gamma Camera Image of Anti-VEGF-2 Humanized Antibody, TTAC0001 in Xenografted Tumor Models

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Tae Sup; Son, Jin Ju; Jung, Jae Ho; Woo, Kwnag Sun; Jung, Wee Sup; Kang, Joo Hyun; Cheon, Gi Jeong [KIRAMS, Seoul (Korea, Republic of); Yoo, Jin San [KRIBB, Daejeon (Korea, Republic of); Park, Young Seo [Kyungwn University, Sungnam (Korea, Republic of)

    2009-05-15

    Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) have been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis. Recently, antiangiogenic therapies that interfere with the VEGF/VEGFR pathway may represent novel approaches to effective treatment. This study is aimed to evaluate tumor targeting of VEGFR-2 Ab in melanoma and chronic myelogenous leukemia (CML) tumor model for the feasibility of treatment using anti- VEGFR-2 antibody, TTAC-0001.

  14. Development of Biodegradable Zinc Oxide Nanowires Targeting Breast Cancer Metastasis

    Science.gov (United States)

    2013-09-01

    of highly-specificity anti-CD146 monoclonal antibody . 2. Bioconjugation of YY146 to a chelating moiety (NOTA) for the radiolabeling with 64Cu and...metastasis, and to optimize its optical property and conjugation chemistry for non-invasive dual-modality tracking (PET and optical). The overarching...hypothesis is that suitably functionalized ZnO NWs can have long circulation lifetime and efficient tumor targeting for future drug delivery

  15. Folate Receptor-Targeting Gold Nanoclusters as Fluorescence Enzyme Mimetic Nanoprobes for Tumor Molecular Colocalization Diagnosis

    OpenAIRE

    Hu, Dehong; Sheng, Zonghai; Fang, Shengtao; Wang, Yanan; Gao, Duyang; Zhang, Pengfei; Gong, Ping; Ma, Yifan; Cai, Lintao

    2014-01-01

    Nanoprobes with enzyme-like properties attracted a growing interest in early screening and diagnosis of cancer. To achieve high accuracy and specificity of tumor detection, the design and preparation of enzyme mimetic nanoprobes with high enzyme activity, tumor targeting and excellent luminescence property is highly desirable. Herein, we described a novel kind of fluorescence enzyme mimetic nanoprobe based on folate receptor-targeting Au nanoclusters. The nanoprobes exhibited excellent stabil...

  16. The Use of Therapeutic Peptides to Target and to Kill Cancer Cells

    OpenAIRE

    Boohaker, R J; Lee, M. W.; Vishnubhotla, P.; Perez, J M; Khaled, A.R.

    2012-01-01

    Peptide therapeutics is a promising field for emerging anti-cancer agents. Benefits include the ease and rapid synthesis of peptides and capacity for modifications. An existing and vast knowledge base of protein structure and function can be exploited for novel peptide design. Current research focuses on developing peptides that can (1) serve as tumor targeting moieties and (2) permeabilize membranes with cytotoxic consequences. A survey of recent findings reveals significant trends. Amphiphi...

  17. Peptide-targeted polymer cancerostatics

    Czech Academy of Sciences Publication Activity Database

    Böhmová, Eliška; Pola, Robert

    2016-01-01

    Roč. 65, Suppl. 2 (2016), S153-S164 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : HPMA copolymers * tumor targeting * peptides Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.461, year: 2016 http://www.biomed.cas.cz/physiolres/pdf/65%20Suppl%202/65_S153.pdf

  18. Cytolytic T-cell clones against an autologous human melanoma: specificity study and definition of three antigens by immunoselection.

    OpenAIRE

    Knuth, A; Wölfel, T; Klehmann, E; Boon, T.; Meyer zum Büschenfelde, K H

    1989-01-01

    Cytolytic T-lymphocyte (CTL) clones against an autologous melanoma (SK-MEL-29) were generated by mixed lymphocyte tumor culture and subsequent cloning of responder lymphocytes at limiting dilutions. These CTL clones lysed autologous melanoma but not autologous Epstein-Barr virus-transformed B cells and none of the allogeneic tumor targets included in the specificity analysis. The lysis of autologous melanoma targets could be inhibited by monoclonal antibodies against monomorphic HLA class I d...

  19. The Effect of Superparamagnetic Iron Oxide with iRGD Peptide on the Labeling of Pancreatic Cancer Cells In Vitro: A Preliminary Study

    OpenAIRE

    Zuo, Hou Dong; Yao, Wei Wu; Chen, Tian Wu; Zhu, Jiang; Zhang, Juan Juan; Pu, Yu; Liu, Gang; Zhang, Xiao Ming

    2014-01-01

    The iRGD peptide loaded with iron oxide nanoparticles for tumor targeting and tissue penetration was developed for targeted tumor therapy and ultrasensitive MR imaging. Binding of iRGD, a tumor homing peptide, is mediated by integrins, which are widely expressed on the surface of cells. Several types of small molecular drugs and nanoparticles can be transfected into cells with the help of iRGD peptide. Thus, we postulate that SPIO nanoparticles, which have good biocompatibility, can also be t...

  20. Highly Specific Targeting of the TMPRSS2/ERG Fusion Gene in Prostate Cancer Using Liposomal Nanotechnology

    Science.gov (United States)

    2013-06-01

    tumor targeting PEGylated liposomesconjugated high affinity ligands, such as RGD , folate, IGFR1 binding peptide to PEG-2000 arm that is bound to...nanoliposomes coated with PEG2000 attached to RGD , folate, IGFR1 binding peptide were tested in in vitro setting using VCAP prostate cell line. This tumor...DSPE. We first tried this strategy in integrin alphaVbeta 3 expressing SKOV3 tumors using RGD - peptied expressing liposomes. Although αVβ3 (the

  1. Myeloid-derived suppressor cells as a Trojan horse: A cellular vehicle for the delivery of oncolytic viruses.

    Science.gov (United States)

    Pan, Ping-Ying; Chen, Hui-Ming; Chen, Shu-Hsia

    2013-08-01

    We have recently demonstrated that oncolytic vesicular stomatitis viruses can be efficiently and selectively delivered to neoplastic lesions by myeloid-derived suppressor cells (MDSCs). Importantly, the loading of viruses onto MDSCs inhibited their immunosuppressive properties and endowed them with immunostimulatory and tumoricidal functions. Our study demonstrates the potential use of MDSCs as a Trojan horse for the tumor-targeted delivery of various anticancer therapeutics.

  2. Enhancing Tumor Penetration of Nanomedicines

    OpenAIRE

    Sun, Qingxue; Ojha, Tarun; Kiessling, Fabian; Lammers, Twan; Shi, Yang

    2017-01-01

    Tumor-targeted nanomedicines have been extensively applied to alter the drawbacks and enhance the efficacy of chemotherapeutics. Despite the large number of preclinical nanomedicine studies showing initial success, their therapeutic benefit in the clinic has been rather modest, which is partially due to the inefficient tumor penetration caused by tumor microenvironment (high density of cells and extracellular matrix, increased interstitial fluid pressure). Furthermore, tumor penetration of na...

  3. Obtention et caractérisation d’anticorps monoclonaux dirigés contre les récepteurs des endothélines, ETAR et ETBR, surexprimés dans de nombreux cancers et impliqués dans la progression tumorale

    OpenAIRE

    Borrull, Aurélie

    2015-01-01

    It has been admitted that endothelin axis (endothelins ET-1, -2 and -3 and related GPCRs ETAR and ETBR) is involved in tumor progression. For instance, while ETAR is overexpressed in ovarian cancer, ETBR is in melanoma. This overexpression, as well as ETA/BR involvement in carcinogenesis, make these GPCRs a relevant tumor target. Because of their high specificity, various cytotoxic actions, possibilities of coupling, the monoclonal antibodies (mAbs) are useful tools in diagnosis and anti-canc...

  4. Consortia for Improving Medicine with Innovation and Technology

    Science.gov (United States)

    2016-12-01

    nanoparticles for tumor-targeted drug delivery to prevent lymph node metastases in breast cancer 2010 Out - 000703 09-433 Award Closed Cunningham...and perfusion to ensure successful kidney transplantation 2010 Out - 001008 10-582 Award Closed Unlu, M. Selim BU/CIMIT Applied Healthcare Engineering...coloring pigments and TiO2 powder to add opacity and skin tinting to the block to provide flesh tones rather than the earlier iterations that used clear

  5. The Platin-X Series: Activation, Targeting, and Delivery

    OpenAIRE

    Basu, Uttara; Banik, Bhabatosh; Wen, Ru; Pathak, Rakesh K.; Dhar, Shanta

    2016-01-01

    Anticancer platinum (Pt) complexes have long been pronounced as one of the biggest success stories in the history of medicinal inorganic chemistry. Yet there still remains the hunt for the “magic bullet” which can satiate the requisites of an effective chemotherapeutic drug formulation. Pt(IV) complexes are kinetically more inert that the Pt(II) congeners and offer the opportunity to append additional functional groups/ligands for prodrug activation, tumor targeting or drug delivery. The ulti...

  6. Study on radiation-inducible genes

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Sang Yong; Kim, Dong Ho; Joe, Min Ho; Song, Hyu Npa

    2012-01-15

    Transcription of previously identified radiation-inducible genes, uscA and cyoA, was examined responding to radiation. The putative promoter regions of both genes were cloned into pRS415 vector containing lacZ, and the core promoter region necessary for radiation response were determined through promoter deletion method. To investigate the role of uscA, which is assumed to be small RNA related with radiation response, a deletion mutant strain of uscA was constructed. However, uscA deletion did not affect bacterial survival against radiation exposure. The use of bacteria as anticancer agents has attracted interest. In this study, we tried to develop tumor targeting bacteria in which the radiation-inducible promoter activate a transgene encoding a cytotoxic protein. For outward secretion of anticancer protein produced inside bacteria, the N-terminal 140 amino acid of SspH1 was found to function as a secretion signal peptide. To create an attenuated tumor-targeting bacteria, Salmonella ptsI mutant strain was constructed, and we found that its virulence decreased. Finally, the tumor-targeting ability of ptsI mutant was verified by the use of in-vivo imaging analysis.

  7. Pharmacokinetics, tissue distribution and anti-tumor effect of low density lipoprotein peptide conjugated submicron emulsions.

    Science.gov (United States)

    Zhang, Nan; Miao, Jinhong; Sun, Pengchao; Liang, Qian; Hua, Haiying; Xu, Yusheng; Zhao, Yongxing

    2016-08-01

    Docetaxel (Doc) is a potent chemotherapy for cancer but its application is limited by poor water solubility and high risk of side effects. To improve these issues, low density lipoprotein receptor (LDLR) targeted peptide-RLT (CEKLKEAFRLTRKRGLKLA) modified Docetaxel-loaded submicron emulsions (RLT-DocSEs) had been developed. Docetaxel-loaded SEs (DocSEs) and cationic DocSEs (DocCSEs) were also prepared for comparison. To evaluate the tumor-targeting ability and anti-tumor efficacy, DocSEs, DocCSEs, and RLT-DocSEs were administrated intravenously to rats respectively. The pharmacokinetic parameters of three formulations were significantly different. In vivo distribution study was conducted in mice and the results indicated that RLT-DocSEs possessed increased tumor targeting ability than DocSEs and DocCSEs. RLT-DocSEs also resulted in a higher tumor inhibition rate and a better anti-tumor efficacy in mice. All the results suggested that RLT-DocSEs could be a potential formulation for the injection of Doc with enhanced tumor targeting and anti-tumor efficacy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  8. Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro.

    Science.gov (United States)

    Yang, Wanhua; Meng, Li; Wang, Hui; Chen, Rui; Wang, Rui; Ma, Xiangyi; Xu, Gang; Zhou, Jianfeng; Wang, Shixuan; Lu, Yunping; Ma, Ding

    2006-01-01

    The Arg-Gly-Asp (RGD) sequence was selected by using phage-display peptides to target tumors, focusing on targeting alpha(v) integrins in tumor blood vessels. Recent studies suggest that peptides containing the RGD sequence can bind to tumor cells, as well as tumor endothelial cells. To investigate whether the RGD peptide has other effects on tumor cells expressing alpha(v) integrins, besides its tumor targeting capability, we designed and synthesized a 10-amino peptide that contained the RGD sequence in a cyclic conformation with a disulfide bond, which specifically bound to breast cancer cell lines MDA-MB-231 and MCF-7. We found that this RGD peptide, GCGGRGDGGC, inhibited tumor cell proliferation in a dose-dependent manner, and also induced apoptosis and G1-phase cell cycle arrest in both of the cell lines that bound and internalized the peptide. Normal ovarian epithelial cells, which did not bind the RGD peptide, were unaffected. RGD peptide treatment also reduced cell invasiveness in both cell lines in vitro. This study suggests that the RGD peptide not only possesses tumor targeting capacity, but also has direct tumor cytotoxic and invasiveness inhibition effects dependent on the blockage of alpha(v) integrin activity, which would make it more efficient in tumor targeting therapy.

  9. MR imaging perfusion mismatch: a technique to verify successful targeting of liver tumors during transcatheter arterial chemoembolization.

    Science.gov (United States)

    Lewandowski, Robert J; Tepper, Joshua; Wang, Dingxin; Ibrahim, Saad; Miller, Frank H; Kulik, Laura; Mulcahy, Mary; Ryu, Robert K; Sato, Kent; Larson, Andrew C; Salem, Riad; Omary, Reed A

    2008-05-01

    To evaluate the combined use of transcatheter intraarterial perfusion (TRIP) magnetic resonance (MR) imaging and dynamic contrast-enhanced MR imaging to determine complete tumor targeting during transcatheter arterial chemoembolization (TACE) when performed within an integrated MR imaging-interventional radiology (IR) angiography suite. Between October 2006 and March 2007, eight consecutive patients with unresectable hepatocellular carcinoma (HCC) successfully underwent TACE in a combined MR imaging-IR suite. All patients were male, with a mean age of 59 years (range, 41-71 years). Tumor enhancement on TRIP MR images before and after TACE were qualitatively compared with dynamic contrast-enhanced MR images obtained after TACE. The authors computed the prevalence of perfusion mismatch. The presence of a perfusion mismatch was judged in a binary fashion. A perfusion match, confirming complete tumor targeting, occurred in six of the eight patients (75%). There was a perfusion mismatch in two patients (25%). Subsequent interrogation showed that the underlying cause of the mismatch was secondary to an unexpected collateral vessel in the first patient and watershed location of the tumor in the second patient. Performing TACE in an MR imaging-IR suite can facilitate complete tumor targeting. By comparing perfusion images from TRIP and contrast-enhanced MR sequences, the operator gains confidence and can potentially obtain more selective catheter placement during TACE.

  10. Imaging tumor hypoxia by near-infrared fluorescence tomography.

    Science.gov (United States)

    Biswal, Nrusingh C; Pavlik, Christopher; Smith, Michael B; Aguirre, Andres; Xu, Yan; Zanganeh, Saeid; Kuhn, Liisa T; Claffey, Kevin P; Zhu, Quing

    2011-06-01

    We have developed a novel nitroimidazole indocyanine dye conjugate for tumor-targeted hypoxia fluorescence tomography. The hypoxia probe has been evaluated in vitro using tumor cell lines and in vivo with tumor targeting in mice. The in vitro cell studies were performed to assess fluorescence labeling differences between hypoxia and normoxia conditions. When treated with the hypoxia probe, a fluorescence emission ratio of 2.5-fold was found between the cells incubated under hypoxia compared to the cells in normoxia condition. Hypoxia specificity was also confirmed by comparing the cells treated with indocyanine dye alone. In vivo tumor targeting in mice showed that the fluorescence signals measured at the tumor site were twice those at the normal site after 150 min post-injection of the hypoxia probe. On the other hand, the fluorescence signals measured after injection of indocyanine dye were the same at tumor and normal sites. In vivo fluorescence tomography images of mice injected with the hypoxia probe showed that the probe remained for more than 5 to 7 h in the tumors, however, the images of mice injected with indocyanine only dye confirmed that the unbound dye washed out in less than 3 h. These findings are supported with fluorescence images of histological sections of tumor samples using a Li-COR scanner and immunohistochemistry technique for tumor hypoxia.

  11. Facile synthesis of near-infrared CuInS2/ZnS quantum dots and glycol-chitosan coating for in vivo imaging

    Science.gov (United States)

    Kim, Eun-Mi; Lim, Seok Tae; Sohn, Myung-Hee; Jeong, Hwan-Jeong

    2017-07-01

    This study describes the synthesis method of water-soluble, low-toxicity, photostable highly luminescent probes based on I-III-VI2 type semiconductor quantum dots (QDs) and the possibility of tumor targeting in living animals. Cd-free high-quality CuInS2/ZnS core/shell QDs were synthesized, and their surfaces were reacted with mercaptoundecanoic acid for aqueous phase transfer followed by reaction with glycol-chitosan; lastly, Arg-Gly-Asp (RGD) integrin-binding peptide was covalently attached for in vivo tumor targeting. Dowtherm A, a highly viscous heat-transfer organic fluid, was used to control semiconductor crystal growth at high temperature (>230 °C) during organic synthesis. The structural and optical properties of the resulting CuInS2/ZnS QDs were investigated. The average diameters of CuInS2 and CuInS2/ZnS QDs were 3.0 and 3.7 nm, respectively. Cell toxicity and in vivo tumor targetability in RR1022 cancer cell-xenografted mice were further evaluated using cRGDyk-tagged glycol-chitosan-coated CuInS2/ZnS QDs. Glycol-chitosan-coated MUA-QDs displayed a Z-average diameter of 203.8 ± 7.67 nm in water by dynamic light scattering.

  12. A One-Pot Three-Component Double-Click Method for Synthesis of [67Cu]-Labeled Biomolecular Radiotherapeutics.

    Science.gov (United States)

    Fujiki, Katsumasa; Yano, Shinya; Ito, Takeshi; Kumagai, Yuki; Murakami, Yoshinori; Kamigaito, Osamu; Haba, Hiromitsu; Tanaka, Katsunori

    2017-05-15

    A one-pot three-component double-click process for preparing tumor-targeting agents for cancer radiotherapy is described here. By utilizing DOTA (or NOTA) containing tetrazines and the TCO-substituted aldehyde, the two click reactions, the tetrazine ligation (an inverse electron-demand Diels-Alder cycloaddition) and the RIKEN click (a rapid 6π-azaelectrocyclization), could simultaneously proceed under mild conditions to afford covalent attachment of the metal chelator DOTA or NOTA to biomolecules such as to albumin and anti-IGSF4 antibody without altering their activities. Subsequently, radiolabeling of DOTA- or NOTA-attached albumin and anti-IGSF4 antibody (an anti-tumor-targeting antibody) with [67Cu], a β--emitting radionuclide, could be achieved in a highly efficient manner via a simple chelation with DOTA proving to be a more superior chelator than NOTA. Our work provides a new and operationally simple method for introducing the [67Cu] isotope even in large quantities to biomolecules, thereby representing an important process for preparations of clinically relevant tumor-targeting agents for radiotherapy.

  13. Dual delivery systems based on polyamine analog BENSpm as prodrug and gene delivery vectors

    Science.gov (United States)

    Zhu, Yu

    -SS-BEN) capable of intracellular release of BENSpm using thiolytically sensitive dithiobenzyl carbamate linker. Similar activity on SSAT enzyme induction by Lipo-SS-BEN compared with BENSpm free drug verified the success of this prodrug design. Biodegradability of Lipo-SS-BEN contributed to decreased toxicity compared with nondegradable control LipoBEN. However, decreased enhancement of TRAIL activity was observed for Lipo-SS-BEN when compared with BENSpm, indicating that the lipid-related toxicity diminished the synergism. In addition, compared with LipoBEN and DOTAP, decreased transfection efficiency of Lipo-SS-BEN demonstrated instability of Lipo-SS-BEN in extracellular environment. In order to design a dual delivery vector with reduced vector toxicity and improved linker stability, we employed dendritic polyglycerol (PG) as a safe carrier backbone, onto which BENSpm was conjugated through carbamate linkage (PG-BEN). Polymers with norspermine (PG-Nor) shell and amine-terminated PG (PG-NH2) were synthesized as controls. The BENSpm dual vector PG-BEN demonstrated superior gene delivery function, and showed decreased toxicity compared with the control polymers. However, compared with BENSpm, which depleted all natural polyamines, PG-BEN only down-regulated intracellular putrescine levels. In addition, no free BENSpm was detected in PG-BEN treated cells. These results suggested that in order to take full advantage of BENSpm anticancer activity, alternative linker chemistry needs to be further explored. We then incorporated bis(2-hydroxyethyl) disulfide as a self-immolative linker to synthesize polymer prodrugs of BENSpm (DSS-BEN). The proposed mechanism of BENSpm release from DSS-BEN contains two steps: disulfide bond is first cleaved in the reducing intracellular space, then the intermediate further undergoes slow intramolecular cyclization to release free BENSpm. Cell line-dependent BENSpm release after DSS-BEN treatment was observed using HPLC analysis, demonstrating the

  14. Versatile RNA interference nanoplatform for systemic delivery of RNAs.

    Science.gov (United States)

    Choi, Ki Young; Silvestre, Oscar F; Huang, Xinglu; Min, Kyung Hyun; Howard, Gregory P; Hida, Naoki; Jin, Albert J; Carvajal, Nicole; Lee, Sang Wook; Hong, Jong-In; Chen, Xiaoyuan

    2014-05-27

    Development of nontoxic, tumor-targetable, and potent in vivo RNA delivery systems remains an arduous challenge for clinical application of RNAi therapeutics. Herein, we report a versatile RNAi nanoplatform based on tumor-targeted and pH-responsive nanoformulas (NFs). The NF was engineered by combination of an artificial RNA receptor, Zn(II)-DPA, with a tumor-targetable and drug-loadable hyaluronic acid nanoparticle, which was further modified with a calcium phosphate (CaP) coating by in situ mineralization. The NF can encapsulate small-molecule drugs within its hydrophobic inner core and strongly secure various RNA molecules (siRNAs, miRNAs, and oligonucleotides) by utilizing Zn(II)-DPA and a robust CaP coating. We substantiated the versatility of the RNAi nanoplatform by demonstrating effective delivery of siRNA and miRNA for gene silencing or miRNA replacement into different human types of cancer cells in vitro and into tumor-bearing mice in vivo by intravenous administration. The therapeutic potential of NFs coloaded with an anticancer drug doxorubicin (Dox) and multidrug resistance 1 gene target siRNA (siMDR) was also demonstrated in this study. NFs loaded with Dox and siMDR could successfully sensitize drug-resistant OVCAR8/ADR cells to Dox and suppress OVCAR8/ADR tumor cell proliferation in vitro and tumor growth in vivo. This gene/drug delivery system appears to be a highly effective nonviral method to deliver chemo- and RNAi therapeutics into host cells.

  15. A fullerene-based multi-functional nanoplatform for cancer theranostic applications.

    Science.gov (United States)

    Shi, Jinjin; Wang, Lei; Gao, Jun; Liu, Yan; Zhang, Jing; Ma, Rou; Liu, Ruiyuan; Zhang, Zhenzhong

    2014-07-01

    Recently, nanomaterials with multiple functions, such as drug carrier, MRI and optical imaging, photothermal therapy etc, have become more and more popular in the domain of cancer research. In this study, a C60-IONP nanocomposite is synthesized via decorating iron oxide nanoparticles (IONP) onto fullerene (C60) and then functionalized by polyethylene glycol (PEG2000), giving C60-IONP-PEG with excellent stability in physiological solutions, finally folic acid (FA), a widely used tumor targeting molecule, was linked to C60-IONP-PEG in order to obtain an active tumor targeting effect to MCF-7 cells and malignant tumor in mice models. Herein, a hybrid nanoplatform with multi-functional characteristics for cancer diagnosis, photodynamic therapy (PDT), radiofrequency (RF) thermal therapy (RTT) and magnetic targeting applications was developed and explored its biofunctions in vitro and in vivo. C60-IONP-PEG-FA showed neglectable toxicity, not only served as a powerful tumor diagnostic magnetic resonance imaging (MRI) contrast agent, but also as a strong photosensitizer and powerful agent for photothermal ablation of tumor, furthermore a remarkable synergistic enhancement of PDT combination with RTT was also observed during the treatment both in vitro and in vivo. Moreover, the multi-functional nanoplatform also could selectively kill cancer cells in highly localized regions via the excellent active tumor targeting and magnetic targeted abilities. This work showed the multi-functional C60-IONP-PEG-FA nanoplatform had a great potential for cancer theranostic applications. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Ascorbyl palmitate/d-α-tocopheryl polyethylene glycol 1000 succinate monoester mixed micelles for prolonged circulation and targeted delivery of compound K for antilung cancer therapy in vitro and in vivo.

    Science.gov (United States)

    Zhang, Youwen; Tong, Deyin; Che, Daobiao; Pei, Bing; Xia, Xiaodong; Yuan, Gaofeng; Jin, Xin

    2017-01-01

    The roles of ginsenoside compound K (CK) in inhibiting tumor have been widely recognized in recent years. However, low water solubility and significant P-gp efflux have restricted its application. In this study, CK ascorbyl palmitate (AP)/d-α-tocopheryl polyethylene glycol 1000 succinate monoester (TPGS) mixed micelles were prepared as a delivery system to increase the absorption and targeted antitumor effect of CK. Consequently, the solubility of CK increased from 35.2±4.3 to 1,463.2±153.3 μg/mL. Furthermore, in an in vitro A549 cell model, CK AP/TPGS mixed micelles significantly inhibited cell growth, induced G0/G1 phase cell cycle arrest, induced cell apoptosis, and inhibited cell migration compared to free CK, all indicating that the developed micellar delivery system could increase the antitumor effect of CK in vitro. Both in vitro cellular fluorescence uptake and in vivo near-infrared imaging studies indicated that AP/TPGS mixed micelles can promote cellular uptake and enhance tumor targeting. Moreover, studies in the A549 lung cancer xenograft mouse model showed that CK AP/TPGS mixed micelles are an efficient tumor-targeted drug delivery system with an effective antitumor effect. Western blot analysis further confirmed that the marked antitumor effect in vivo could likely be due to apoptosis promotion and P-gp efflux inhibition. Therefore, these findings suggest that the AP/TPGS mixed micellar delivery system could be an efficient delivery strategy for enhanced tumor targeting and antitumor effects.

  17. In vitro and in vivo evaluation of antitumor drug-loaded aptamer targeted single-walled carbon nanotubes system.

    Science.gov (United States)

    Zhang, Huijuan; Hou, Lin; Jiao, Xiaojing; Yandan, Ji; Zhu, Xiali; Hongji, Li; Chen, Xiaozhe; Ren, Junxiao; Xia, Yadan; Zhang, Zhenzhong

    2014-01-01

    A multifunctional tumor-targeting drug delivery system employing single-walled carbon nanotubes (SWCNT) as drug carriers, AS1411 as targeting ligand and doxorubicine (DOX) as a model chemotherapy drug was constructed. Firstly, SWCNT were modified with F68 (4.0 mg/ml) by ultrasonic dispersing technology due to the action of hydrophobic force and Van der Waals force, endowing SWCNT water dispersions and biocompatibility. Meanwhile, DOX could be easily absorbed on the surface of SWCNT by the π-π stacking, electrostatic adsorption and hydrophobic interactions. Finally, AS1411 was attached to the surface of DOX-SWCNT by the π-π stacking and electrostatic adsorption to obtain a tumor-targeting delivery system. Cellular uptake, anti-tumor effect in vitro and in vivo, cell cycle and apoptosis and biodistribution of AS1411-DOX-SWCNT were investigated, compared with the DOX solution. This AS1411-mediated DOX-loaded SWCNT (AS1411-DOX-SWCNT) delivery system not only retained both optical properties of SWCNT and cytotoxicity of DOX but also could accumulate in tumors, which facilitated combination of chemotherapy and photothermal therapy. AS1411-DOX-SWCNT could effectively promote DOX cellular uptake and then increase intracellular accumulation as a targeting delivery system. AS1411-DOX-SWCNT by NIR laser excited could trigger S phase arrest and the late stage apoptotic on PC3 cancer cells. The investigation in vivo further confirmed that this system possessed higher tumor targeting capacity and antitumor efficacy than DOX, especially with NIR laser irradiation.

  18. Experimental radiotherapy and clinical radiobiology. Vol. 22. Proceedings; Experimentelle Strahlentherapie und Klinische Strahlenbiologie. Bd. 22. Proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Baumann, Michael; Cordes, Nils; Dikomey, Ekkehard; Krause, Mechthild; Petersen, Cordula; Rodemannn, H. Peter; Zips, Daniel (eds.)

    2013-03-01

    The proceedings of the 22th Symposium on experimental radiotherapy and clinical radiotherapy contain lectures and poster on the following issues: Radiation induced immuno-targeting of tumors; targeting in the radiotherapy; biomarkers; targeting; radio-oncological therapy of rectal carcinoma - contribution of radiobiology for therapy optimization; biomarkers for radiation sensibility; resistance mechanisms of tumors; resistance mechanisms of normal tissue; micro ambience, P13L inhibition in radiotherapy: improvement of the local tumor control by molecular mechanisms or the influence of the tumor micro-ambience? DNA repair; radiation effects and technical development.

  19. Synthetic lipoprotein as nano-material vehicle in the targeted drug delivery.

    Science.gov (United States)

    Zhang, Xueqin; Huang, Gangliang

    2017-12-01

    High-density lipoprotein (HDL) and low-density lipoprotein (LDL), as human endogenous lipoprotein particles, have low toxicity, high selectivity, and good safety. They can avoid the recognition and clearance of human reticuloendothelial system. These synthetic lipoproteins (sLPs) have been attracted extensive attention as the nanovectors for tumor-targeted drug and gene delivery. Herein, recent advances in the field of anticancer based on these two lipid proteins and recombinant lipoproteins (rLPs) as target delivery vectors were analyzed and discussed.

  20. Clearance Kinetics and External Dosimetry of Iodine-131-labeled Murine and Humanized Monoclonal Antibody A33 in Patients with Colon Cancer: Radiation Safety Implications

    OpenAIRE

    Dauer, Lawrence T.; Boylan, Daniel C; Williamson, Matthew J.; Germain, Jean St.; Steven M. Larson

    2009-01-01

    The monoclonal antibody (mAb) A33 detects a membrane antigen that is expressed on greater than 95% of metastatic human colorectal cancers. Previous studies have shown excellent tumor-targeting of iodine-131 labeled murine and humanized forms of the mAb. A retrospective analysis of whole body clearance in the murine form was performed for comparison to the humanized form. Serial whole-body dose rate measurements were obtained for 55 treatments on 30 patients participating in phase I/II dose es...

  1. New paradigms and future challenges in Radiation Oncology: An Update of Biological Targets and Technology*

    Science.gov (United States)

    Liauw, Stanley L.; Connell, Philip P.; Weichselbaum, Ralph R.

    2013-01-01

    The primary objective of radiation oncology is to exploit the biological interaction of radiation within tissue to promote tumor death while minimizing damage to surrounding normal tissue. The clinical delivery of radiation relies on principles of radiation physics that define how radiation energy is deposited in the body, as well as technology that facilitates accurate tumor targeting. This review will summarize the current landscape of recent biological and technological advances in radiation oncology, describe the challenges that exist, and offer potential avenues for improvement. PMID:23427246

  2. Theranostic CuS Nanoparticles Targeting Folate Receptors for PET Image-Guided Photothermal Therapy

    OpenAIRE

    Zhou, Min; Song, Shaoli; Zhao, Jun; Tian, Mei; Li, Chun

    2015-01-01

    Copper sulfide nanoparticles (CuS NPs) have been reported as a single-compartment theranostic nanosystem to visualize and treat tumors simultaneously. However, few studies have investigated the in vivo tumor-targeted delivery of this class of nanoparticles. In this study, we introduced a tumor-specific targeting ligand, folic acid (FA), onto the surface of CuS NPs as a model system to demonstrate the feasibility of actively targeted CuS NPs for positron emission tomography (PET) imaging and P...

  3. Vaccinia virus, a promising new therapeutic agent for pancreatic cancer.

    Science.gov (United States)

    Al Yaghchi, Chadwan; Zhang, Zhongxian; Alusi, Ghassan; Lemoine, Nicholas R; Wang, Yaohe

    2015-01-01

    The poor prognosis of pancreatic cancer patients signifies a need for radically new therapeutic strategies. Tumor-targeted oncolytic viruses have emerged as attractive therapeutic candidates for cancer treatment due to their inherent ability to specifically target and lyse tumor cells as well as induce antitumor effects by multiple action mechanisms. Vaccinia virus has several inherent features that make it particularly suitable for use as an oncolytic agent. In this review, we will discuss the potential of vaccinia virus in the management of pancreatic cancer in light of our increased understanding of cellular and immunological mechanisms involved in the disease process as well as our extending knowledge in the biology of vaccinia virus.

  4. Targeted Mesoporous Iron Oxide Nanoparticles-Encapsulated Perfluorohexane and a Hydrophobic Drug for Deep Tumor Penetration and Therapy

    OpenAIRE

    Su, Yu-Lin; Fang, Jen-Hung; Liao, Chia-Ying; Lin, Chein-Ting; Li, Yun-Ting; Hu, Shang-Hsiu

    2015-01-01

    A magneto-responsive energy/drug carrier that enhances deep tumor penetration with a porous nano-composite is constructed by using a tumor-targeted lactoferrin (Lf) bio-gate as a cap on mesoporous iron oxide nanoparticles (MIONs). With a large payload of a gas-generated molecule, perfluorohexane (PFH), and a hydrophobic anti-cancer drug, paclitaxel (PTX), Lf-MIONs can simultaneously perform bursting gas generation and on-demand drug release upon high-frequency magnetic field (MF) exposure. Bi...

  5. Preliminary study of the internal margin of the gross tumor volume in thoracic esophageal cancer.

    Science.gov (United States)

    Li, Jiancheng; Wang, Linhua; Wang, Xiaoliang; Zhao, Yunhui; Liu, Di; Chen, Cheng; Zhang, He Ping; Pan, Jianji

    2012-10-01

    To measure the displacement of the tumor of the gross tumor volume (GTV) of thoracic esophageal cancer in the calm states of end-inspiration and end-expiration for determining the internal margin of the GTV (IGTV). Twenty-two patients with thoracic esophageal cancer who were unable to undergo surgery were identified in our hospital. The patients received radiotherapy. By using 16-slice spiral computed tomography (CT), we acquired the calm states of end-inspiration and end-expiration. The displacement and volume changes in tumor target volume were measured, and the changes were analyzed to determine if these were associated with the tidal volume and the location and length of the target volume V. In the end, we analyzed the displacement of tumor target volume and calculated the internal margin of the GTV by empirical formula. The average tidal volume was 463.6 ml. The average GTV at end-inspiration was 33.3 ml and at end-expiration was 33.35 ml. Three was not any significant between two groups (T=-0.034, P>0.05). The IGTV (X-axis direction) was 3.09 mm for the right sector and 4.08 mm for the left border; the IGTV (Z-axis direction) was 3.96 mm for the anterior border and 2.83 mm for the posterior border; and the IGTV (Y-axis direction) was 7.31 mm for the upper boundary (head direction) and 10.16 mm for the lower boundary (feet direction). The motion of the GTV showed no significant correlation with the tidal volume of patients and the length of the tumor, but in relation to the tumor location, the displacement of the lower thoracic and the middle thoracic target volumes occurred in the direction of the anterior and right, which were not significantly different (T=0.859, 0.229, P>0.05) The significant differences were observed for the other directions (P<0.05). Because of respiratory and organ movements, the displacement of the tumor target volume was different in all directions. Therefore, we recommend that expansion of the planning target volume during clinical

  6. Bitargeted microemulsions based on coix seed ingredients for enhanced hepatic tumor delivery and synergistic therapy.

    Science.gov (United States)

    Qu, Ding; Sun, Wenjie; Liu, Mingjian; Liu, Yuping; Zhou, Jing; Chen, Yan

    2016-04-30

    A hepatic tumor bitargeted microemulsions drug delivery system using coix seed oil and coix seed polysaccharide (CP) acting as anticancer components, as well as functional excipients, was developed for enhanced tumor-specific accumulation by CP-mediated enhancement on passive tumor targeting and modification of galactose stearate (tumor-targeted ligand). In the physicochemical characteristics studies, galactose stearate-modified coix seed multicomponent microemulsions containing 30% CP (w%) (Gal-C-MEs) had a well-defined spherical shape with a small size (47.63 ± 1.41 nm), a narrow polydispersity index (PDI, 0.101 ± 0.002), and a nearly neutral surface charge (-4.37 ± 1.76 mV). The half-maximal inhibitory concentration (IC50) of Gal-C-MEs against HepG2 cells was 70.2 μg/mL, which decreased by 1.8-fold in comparison with that of coix seed multicomponent microemulsions (C-MEs). The fluorescence intensity of fluorescein isothiocyanate (FITC)-loaded Gal-C-MEs (FITC-Gal-C-MEs) internalized by HepG2 cells was 1.8-fold higher than that of FITC-loaded C-MEs (FIT C-C-MEs), but the cellular uptake of the latter became reduce by 1.6-fold when the weight ratio of CP decreased up to 10%. In the cell apoptosis studies, C-MEs (containing 30% CP) did not show a significant difference with Gal-C-MEs, but exhibited 3.3-fold and 1.5-fold increase relative to C-MEs containing 10% CP and 20% CP, respectively. In the in vivo tumor targeting studies, Cy5-loaded Gal-C-MEs (Cy5-Gal-C-MEs), notably distributed in the tumor sites and still found even at 48 h post-administration, displayed the strongest capability of tumor tissue accumulation and retention among all the test groups. Most importantly, Gal-C-MEs had stronger inhibition of tumor growth, prolonged survival time and more effectively tumor cell apoptosis induction in comparison with C-MEs containing different amounts of CP, which further confirmed that a certain amount of CP and tumor-targeted ligand were of great importance to

  7. High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody-Drug Conjugates

    DEFF Research Database (Denmark)

    de Goeij, Bart E.C.G.; Satijn, D.; Freitag, C. M.

    2015-01-01

    Antibody-drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor...... specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR-and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein...

  8. Multiscale Modeling of Virus Structure, Assembly, and Dynamics

    Science.gov (United States)

    May, Eric R.; Arora, Karunesh; Mannige, Ranjan V.; Nguyen, Hung D.; Brooks, Charles L.

    Viruses are traditionally considered as infectious agents that attack cells and cause illnesses like AIDS, Influenza, Hepatitis, etc. However, recent advances have illustrated the potential for viruses to play positive roles for human health, instead of causing disease [1, 2]. For example, viruses can be employed for a variety of biomedical and biotechnological applications, including gene therapy[3], drug delivery[4], tumor targeting[5], and medical imaging[6]. Therefore, it is important to understand quantitatively how viruses operate such that they can be engineered in a predictive manner for beneficial roles.

  9. From Diagnosis to Treatment: Clinical Applications of Nanotechnology in Thoracic Surgery.

    Science.gov (United States)

    Digesu, Christopher S; Hofferberth, Sophie C; Grinstaff, Mark W; Colson, Yolonda L

    2016-05-01

    Nanotechnology is an emerging field with potential as an adjunct to cancer therapy, particularly thoracic surgery. Therapy can be delivered to tumors in a more targeted fashion, with less systemic toxicity. Nanoparticles may aid in diagnosis, preoperative characterization, and intraoperative localization of thoracic tumors and their lymphatics. Focused research into nanotechnology's ability to deliver both diagnostics and therapeutics has led to the development of nanotheranostics, which promises to improve the treatment of thoracic malignancies through enhanced tumor targeting, controlled drug delivery, and therapeutic monitoring. This article reviews nanoplatforms, their unique properties, and the potential for clinical application in thoracic surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study

    Czech Academy of Sciences Publication Activity Database

    Islam, W.; Fang, J.; Etrych, Tomáš; Chytil, Petr; Ulbrich, Karel; Sakoguchi, A.; Kusakabe, K.; Maeda, H.

    2018-01-01

    Roč. 536, č. 1 (2018), s. 108-115 ISSN 0378-5173 R&D Projects: GA ČR(CZ) GA15-02986S; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Grant - others:AV ČR(CZ) JSPS-16-05 Program:Bilaterální spolupráce Institutional support: RVO:61389013 Keywords : EPR effect * HPMA copolymer * tumor-targeting Subject RIV: FR - Pharmacology ; Medidal Chemistry OBOR OECD: Pharmacology and pharmacy Impact factor: 3.649, year: 2016

  11. Trial Watch-Oncolytic viruses and cancer therapy.

    Science.gov (United States)

    Pol, Jonathan; Buqué, Aitziber; Aranda, Fernando; Bloy, Norma; Cremer, Isabelle; Eggermont, Alexander; Erbs, Philippe; Fucikova, Jitka; Galon, Jérôme; Limacher, Jean-Marc; Preville, Xavier; Sautès-Fridman, Catherine; Spisek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-02-01

    Oncolytic virotherapy relies on the administration of non-pathogenic viral strains that selectively infect and kill malignant cells while favoring the elicitation of a therapeutically relevant tumor-targeting immune response. During the past few years, great efforts have been dedicated to the development of oncolytic viruses with improved specificity and potency. Such an intense wave of investigation has culminated this year in the regulatory approval by the US Food and Drug Administration (FDA) of a genetically engineered oncolytic viral strain for use in melanoma patients. Here, we summarize recent preclinical and clinical advances in oncolytic virotherapy.

  12. Multifunctional Nucleic Acids for Tumor Cell Treatment

    DEFF Research Database (Denmark)

    Pofahl, Monika; Wengel, Jesper; Mayer, Günter

    2014-01-01

    -proliferative and antimiR function in one 37-nucleotide nucleic acid molecule. It inhibits cancer cell growth and induces gene expression that is pathologically damped by an oncomir. These findings will have a strong impact on future developments regarding aptamer- and antimiR-related applications for tumor targeting......We report on a multifunctional nucleic acid, termed AptamiR, composed of an aptamer domain and an antimiR domain. This composition mediates cell specific delivery of antimiR molecules for silencing of endogenous micro RNA. The introduced multifunctional molecule preserves cell targeting, anti...

  13. Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation

    OpenAIRE

    Reyes-Reyes, E. Merit; Šalipur, Francesca R.; Shams, Mitra; Forsthoefel, Matthew K.; Bates, Paula J.

    2015-01-01

    AS1411 is a G-rich quadruplex-forming oligodeoxynucleotide that binds specifically to nucleolin, a protein found on the surface and in the cytoplasm of most malignant cells but absent from the surface/cytoplasm of most normal cells. AS1411 has shown promising clinical activity and is being widely used as a tumor-targeting agent, but its mechanism of action is not fully understood. Previously, we showed that AS1411 is taken up in cancer cells by macropinocytosis (fluid phase endocytosis) and s...

  14. Core-shell nanocarriers with high paclitaxel loading for passive and active targeting

    Science.gov (United States)

    Jin, Zhu; Lv, Yaqi; Cao, Hui; Yao, Jing; Zhou, Jianping; He, Wei; Yin, Lifang

    2016-06-01

    Rapid blood clearance and premature burst release are inherent drawbacks of conventional nanoparticles, resulting in poor tumor selectivity. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide homing to αVβ3 integrins. Herein, core-shell nanocapsules (NCs) and iRGD-modified NCs (iRGD-NCs) with high drug payload for paclitaxel (PTX) were prepared to enhance the antitumor activities of chemotherapy agents with poor water solubility. Improved in vitro and in vivo tumor targeting and penetration were observed with NCs and iRGD-NCs; the latter exhibited better antitumor activity because iRGD enhanced the accumulation and penetration of NCs in tumors. The NCs were cytocompatible, histocompatible, and non-toxic to other healthy tissues. The endocytosis of NCs was mediated by lipid rafts in an energy-dependent manner, leading to better cytotoxicity of PTX against cancer cells. In contrast with commercial product, PTX-loaded NCs (PTX-NCs) increased area under concentration-time curve (AUC) by about 4-fold, prolonged mean resident time (MRT) by more than 8-fold and reduced the elimination rate constant by greater than 68-fold. In conclusion, the present nanocarriers with high drug-loading capacity represent an efficient tumor-targeting drug delivery system with promising potential for cancer therapy.

  15. Mesenchymal Stem Cells Aggregate and Deliver Gold Nanoparticles to Tumors for Photothermal Therapy.

    Science.gov (United States)

    Kang, Seokyung; Bhang, Suk Ho; Hwang, Sekyu; Yoon, Jeong-Kee; Song, Jaejung; Jang, Hyeon-Ki; Kim, Sungjee; Kim, Byung-Soo

    2015-10-27

    Gold nanoparticles (AuNPs) have been extensively studied for photothermal cancer therapy because AuNPs can generate heat upon near-infrared irradiation. However, improving their tumor-targeting efficiency and optimizing the nanoparticle size for maximizing the photothermal effect remain challenging. We demonstrate that mesenchymal stem cells (MSCs) can aggregate pH-sensitive gold nanoparticles (PSAuNPs) in mildly acidic endosomes, target tumors, and be used for photothermal therapy. These aggregated structures had a higher cellular retention in comparison to pH-insensitive, control AuNPs (cAuNPs), which is important for the cell-based delivery process. PSAuNP-laden MSCs (MSC-PSAuNPs) injected intravenously to tumor-bearing mice show a 37-fold higher tumor-targeting efficiency (5.6% of the injected dose) and 8.3 °C higher heat generation compared to injections of cAuNPs after irradiation, which results in a significantly enhanced anticancer effect.

  16. Study on radiation-inducible genes

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Sang Yong; Kim, Dong Ho; Joe, Min Ho; Park, Hae Jun; Song, Hyu Npa

    2012-01-15

    Radiation-inducible genes of E. coli, which is a model strain for bacterial study, and Salmonella, which is a typical strain for pathogenic bacteria were compared through omic analysis. Heat shock response genes and prophage genes were induced by radiation in Salmonella, not in E. coli. Among prophage genes tested, STM2628 showed the highest activation by radiation, and approximately 1 kb promoter region was turned out to be necessary for radiation response. To screen an artificial promoter showing activation by 2 Gy, the high-throughput screening method using fluorescent MUG substrate was established. The use of bacteria as anticancer agents has attracted interest. In this study, we tried to develop tumor targeting bacteria in which the radiation-inducible promoter activate a transgene encoding a cytotoxic protein. To do this, a tumor-targeting hfq Salmonella mutant strain was constructed, and we found that its virulence decreased. For outward secretion of anticancer protein produced inside bacteria, the signal peptide of SspH1 was determined and the signal peptide was proven to be able to secrete an anticancer protein. Tumor xenograft mouse model was secured, which can be used for efficiency evaluation of bacterial tumor therapy.

  17. Low density lipoprotein peptide conjugated submicron emulsions for combating prostate cancer.

    Science.gov (United States)

    Sun, Pengchao; Zhang, Nan; Hua, Haiying; Liang, Qian; Zhang, Xuexiao; Sun, Qian; Zhao, Yongxing

    2017-02-01

    Submicron emulsions (SEs) is an advanced formulation that possesses good biocompatibility, high loading of hydrophobic drugs, and good stability through autoclave sterilization. To enhance tumor targeting and tumor cell uptake, SEs could be modified with positive charge and targeting moieties. In the present study, three formulations were prepared: Docetaxel-loaded SEs (DocSEs), cationic DocSEs (DocCSEs), and low density lipoprotein receptor (LDLR) targeted peptide-RLT (CEKLKEAFRLTRKRGLKLA) modified DocCSEs (RLT-DocCSEs). The optimized RLT-DocCSEs showed a particle size 182.2±10nm, a zeta potential 39.62±2.41mV, and a loading efficiency of Docetaxel (Doc) 98%. RLT-DocCSEs demonstrated sustained release in 96h and was stable for two months at 4°C. Compared to DocSEs and DocCSEs, RLT-DocCSEs caused significantly more PC-3 cell inhibition and cell apoptosis. RLT-DocCSEs also showed more cellular uptake and slower cellular elimination than that of DocSEs and DocCSEs. The present study indicated RLT-DocCSEs could be a potential formulation for injection of anti-cancer therapeutics with increased tumor targeting and anti-tumor efficacy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. Fetoprotein Derived Short Peptide Coated Nanostructured Amphiphilic Surfaces for Targeting Mouse Breast Cancer Cells

    Science.gov (United States)

    Brown, Alexandra M.; Miranda-Alarćon, Yoliem S.; Knoll, Grant A.; Santora, Anthony M.; Banerjee, Ipsita A.

    In this work, self-assembled tumor targeting nanostructured surfaces were developed from a newly designed amphiphile by conjugating boc protected isoleucine with 2,2‧ ethylenedioxy bis ethylamine (IED). To target mouse mammary tumor cells, a short peptide sequence derived from the human alpha-fetoprotein (AFP), LSEDKLLACGEG was attached to the self-assembled nanostructures. Tumor targeting and cell proliferation were examined in the presence of nanoscale assemblies. To further obliterate mouse breast tumor cells, the chemotherapeutic drug tamoxifen was then entrapped into the nanoassemblies. Our studies indicated that the targeting systems were able to efficiently encapsulate and release tamoxifen. Cell proliferation studies showed that IED-AFP peptide loaded with tamoxifen decreased the proliferation of breast cancer cells while in the presence of the IED-AFP peptide nanoassemblies alone, the growth was relatively slower. In the presence of human dermal fibroblasts however cell proliferation continued similar to controls. Furthermore, the nanoscale assemblies were found to induce apoptosis in mouse breast cancer cells. To examine live binding interactions, SPR analysis revealed that tamoxifen encapsulated IED-AFP peptide nanoassemblies bound to the breast cancer cells more efficiently compared to unencapsulated assemblies. Thus, we have developed nanoscale assemblies that can specifically bind to and target tumor cells, with increased toxicity in the presence of a chemotherapeutic drug.

  19. CT/FMT dual-model imaging of breast cancer based on peptide-lipid nanoparticles

    Science.gov (United States)

    Xu, Guoqiang; Lin, Qiaoya; Lian, Lichao; Qian, Yuan; Lu, Lisen; Zhang, Zhihong

    2016-03-01

    Breast cancer is one of the most harmful cancers in human. Its early diagnosis is expected to improve the patients' survival rate. X-ray computed tomography (CT) has been widely used in tumor detection for obtaining three-dimentional information. Fluorescence Molecular Tomography (FMT) imaging combined with near-infrared fluorescent dyes provides a powerful tool for the acquisition of molecular biodistribution information in deep tissues. Thus, the combination of CT and FMT imaging modalities allows us to better differentiate diseased tissues from normal tissues. Here we developed a tumor-targeting nanoparticle for dual-modality imaging based on a biocompatible HDL-mimicking peptide-phospholipid scaffold (HPPS) nanocarrier. By incorporation of CT contrast agents (iodinated oil) and far-infrared fluorescent dyes (DiR-BOA) into the hydrophobic core of HPPS, we obtained the FMT and CT signals simultaneously. Increased accumulation of the nanoparticles in the tumor lesions was achieved through the effect of the tumor-targeting peptide on the surface of nanoparticle. It resulted in excellent contrast between lesions and normal tissues. Together, the abilities to sensitively separate the lesions from adjacent normal tissues with the aid of a FMT/CT dual-model imaging approach make the targeting nanoparticles a useful tool for the diagnostics of breast cancer.

  20. Design, synthesis, and biological evaluation of theranostic vitamin-linker-taxoid conjugates.

    Science.gov (United States)

    Vineberg, Jacob G; Wang, Tao; Zuniga, Edison S; Ojima, Iwao

    2015-03-12

    Novel tumor-targeting theranostic conjugates 1 and 2, bearing either a fluorine-labeled prosthetic as a potential (18)F-PET radiotracer (1) or a fluorescence probe (2) for internalization studies in vitro, were designed and synthesized. We confirmed efficient internalization of 2 in biotin-receptor positive (BR+) cancer cells via receptor-mediated endocytosis (RME) based on flow cytometry and confocal fluorescence microscopy (CFM) analyses, which exhibited very high specificity to BR+ cancer cells. The potency and cancer-cell selectivity of 1 were evaluated against MX-1, L1210FR and ID8 cancer cells (BR+) as well as L1210 cells and WI38 normal human lung fibroblast cells (biotin-receptor negative: BR-). In particular, we designed and performed an assay in the presence of glutathione ethyl ester (GSH-OEt) wherein only 1 molecules internalized into cells via RME in the first 24 h period exert cytotoxic effect. The observed selectivity of 1 was remarkable, with 2 orders of magnitude difference in IC50 values between BR+ cancer cells and WI38 cells, demonstrating a salient feature of this tumor-targeted drug delivery system.

  1. Biodegradable polymers for targeted delivery of anti-cancer drugs.

    Science.gov (United States)

    Doppalapudi, Sindhu; Jain, Anjali; Domb, Abraham J; Khan, Wahid

    2016-06-01

    Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

  2. Rhenium and Technetium-oxo Complexes with Thioamide Derivatives of Pyridylhydrazine Bifunctional Chelators Conjugated to the Tumour Targeting Peptides Octreotate and Cyclic-RGDfK.

    Science.gov (United States)

    North, Andrea J; Karas, John A; Ma, Michelle T; Blower, Philip J; Ackermann, Uwe; White, Jonathan M; Donnelly, Paul S

    2017-08-21

    This research aimed to develop new tumor targeted theranostic agents taking advantage of the similarities in coordination chemistry between technetium and rhenium. A γ-emitting radioactive isotope of technetium is commonly used in diagnostic imaging, and there are two β(-) emitting radioactive isotopes of rhenium that have the potential to be of use in radiotherapy. Variants of the 6-hydrazinonicotinamide (HYNIC) bifunctional ligands have been prepared by appending thioamide functional groups to 6-hydrazinonicotinamide to form pyridylthiosemicarbazide ligands (SHYNIC). The new bidentate ligands were conjugated to the tumor targeting peptides Tyr(3)-octreotate and cyclic-RGD. The new ligands and conjugates were used to prepare well-defined {M═O}(3+) complexes (where M = (99m)Tc or (nat)Re or (188)Re) that feature two targeting peptides attached to the single metal ion. These new SHYNIC ligands are capable of forming well-defined rhenium and technetium complexes and offer the possibility of using the (99m)Tc imaging and (188/186)Re therapeutic matched pairs.

  3. Riboflavin-containing telodendrimer nanocarriers for efficient doxorubicin delivery: High loading capacity, increased stability, and improved anticancer efficacy.

    Science.gov (United States)

    Guo, Dandan; Shi, Changying; Wang, Xu; Wang, Lili; Zhang, Shengle; Luo, Juntao

    2017-10-01

    We have developed two linear-dendritic telodendrimers (TDs) with rational design using amphiphilic riboflavin (Rf) as building blocks for efficient doxorubicin (DOX) delivery. Micellar TD nanoparticles (NPs) are composed of a hydrophilic polyethylene glycol (PEG) shell and a Rf-containing affinitive core for DOX encapsulation. Strong DOX-Rf interactions and amphiphilic Rf structure render these nanocarriers with an ultra-high DOX loading capacity (>1/1, DOX/TD, w/w), ∼100% loading efficiency, the sustained drug release and the optimal particle sizes (20-40 nm) for efficient tumor-targeted drug delivery. These nanoformulations significantly prolonged DOX circulation time in the blood without the accelerated clearance observed after multiple injections. DOX-TDs target several types of tumors efficiently in vivo, e.g. Raji lymphoma, MDA-MB-231 breast cancer, and SKOV-3 ovarian cancer. In vivo maximum tolerated dose (MTD) of DOX was increased by 2-2.5 folds for the nanoformulations in mice relative to those of free DOX and Doxil(®). These nanoformulations significantly inhibited tumor growth and prolonged survival of mice bearing SKOV-3 ovarian cancer xenografts. In summary, Rf-containing nanoformulations with high DOX loading capacity, improved stability and efficient tumor targeting lead to superior antitumor efficacy, which merit the further development for clinical application. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Multi-functional liposomes showing radiofrequency-triggered release and magnetic resonance imaging for tumor multi-mechanism therapy

    Science.gov (United States)

    Du, Bin; Han, Shuping; Li, Hongyan; Zhao, Feifei; Su, Xiangjie; Cao, Xiaohui; Zhang, Zhenzhong

    2015-03-01

    Recently, nanoplatforms with multiple functions, such as tumor-targeting drug carriers, MRI, optical imaging, thermal therapy etc., have become popular in the field of cancer research. The present study reports a novel multi-functional liposome for cancer theranostics. A dual targeted drug delivery with radiofrequency-triggered drug release and imaging based on the magnetic field influence was used advantageously for tumor multi-mechanism therapy. In this system, the surface of fullerene (C60) was decorated with iron oxide nanoparticles, and PEGylation formed a hybrid nanosystem (C60-Fe3O4-PEG2000). Thermosensitive liposomes (dipalmitoylphosphatidylcholine, DPPC) with DSPE-PEG2000-folate wrapped up the hybrid nanosystem and docetaxel (DTX), which were designed to combine features of biological and physical (magnetic) drug targeting for fullerene radiofrequency-triggered drug release. The magnetic liposomes not only served as powerful tumor diagnostic magnetic resonance imaging (MRI) contrast agents, but also as powerful agents for photothermal ablation of tumors. Furthermore, a remarkable thermal therapy combined chemotherapy multi-functional liposome nanoplatform converted radiofrequency energy into thermal energy to release drugs from thermosensitive liposomes, which was also observed during both in vitro and in vivo treatment. The multi-functional liposomes also could selectively kill cancer cells in highly localized regions via their excellent active tumor targeting and magnetic targeted abilities.

  5. Synthesis of dimeric cyclic RGD based near-infrared probe for in vivo tumor diagnosis

    Science.gov (United States)

    Cao, Jie; Wan, Shunan; Tian, Junmei; Chi, Xuemei; Du, Changli; Deng, Dawei; Chen, Wei R.; Gu, Yueqing

    2012-03-01

    Cell adhesion molecule integrin αvβ3 is an excellent target for tumor interventions because of its unique expression on the surface of several types of solid tumor cells and on almost all sprouting tumor vasculatures. In this manuscript, we describe the synthesis of near-infrared (NIR) fluorochrome ICG-Der-02-labeled dimeric cyclic RGD peptides (ICG-Der-02-c(RGDyK)2) for in vivo tumor integrin targeting. The optical properties and structure of the probe were intensively characterized. Afterwards, the integrin specificity of the fluorescent probe was tested in vitro for receptor binding assay and fluorescence microscopy and in vivo for subcutaneous MDA-MB-231 and U87MG tumor targeting. The results indicated that after labeling RGD peptide, the optical properties of ICG-Der-02 showed no obvious change. Besides, in vitro and in vivo tumor targeting experiment indicated that the ICG-Der-02-c(RGDyK)2 probe with high integrin affinity showed excellent tumor activity accumulation. Noninvasive NIR fluorescence imaging is able to detect tumor integrin expression based upon the highly potent RGD peptide probe.

  6. Synthesis and characterization of near IR fluorescent albumin nanoparticles for optical detection of colon cancer

    Energy Technology Data Exchange (ETDEWEB)

    Cohen, Sarit; Pellach, Michal [Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 52900 (Israel); Kam, Yossi [Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120 (Israel); Grinberg, Igor; Corem-Salkmon, Enav [Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 52900 (Israel); Rubinstein, Abraham [Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120 (Israel); Margel, Shlomo, E-mail: shlomo.margel@mail.biu.ac.il [Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 52900 (Israel)

    2013-03-01

    Near IR (NIR) fluorescent human serum albumin (HSA) nanoparticles hold great promise as contrast agents for tumor diagnosis. HSA nanoparticles are considered to be biocompatible, non-toxic and non-immunogenic. In addition, NIR fluorescence properties of these nanoparticles are important for in vivo tumor diagnostics, with low autofluorescence and relatively deep penetration of NIR irradiation due to low absorption of biomatrices. The present study describes the synthesis of new NIR fluorescent HSA nanoparticles, by entrapment of a NIR fluorescent dye within the HSA nanoparticles, which also significantly increases the photostability of the dye. Tumor-targeting ligands such as peanut agglutinin (PNA) and anti-carcinoembryonic antigen antibodies (anti-CEA) were covalently conjugated to the NIR fluorescent albumin nanoparticles, increasing the potential fluorescent signal in tumors with upregulated corresponding receptors. Specific colon tumor detection by the NIR fluorescent HSA nanoparticles was demonstrated in a chicken embryo model and a rat model. In future work we also plan to encapsulate cancer drugs such as doxorubicin within the NIR fluorescent HSA nanoparticles for both colon cancer imaging and therapy. - Highlights: Black-Right-Pointing-Pointer Near IR human serum albumin nanoparticles were synthesized and characterized. Black-Right-Pointing-Pointer Nanoparticles were shown to be physically and chemically stable and photostable. Black-Right-Pointing-Pointer Tumor-targeting ligands were covalently conjugated to the nanoparticles. Black-Right-Pointing-Pointer Specific colon cancer tumor detection was demonstrated in chicken-embryo and rat models.

  7. An IL12-IL2-antibody fusion protein targeting Hodgkin's lymphoma cells potentiates activation of NK and T cells for an anti-tumor attack.

    Science.gov (United States)

    Jahn, Tobias; Zuther, Martin; Friedrichs, Björn; Heuser, Claudia; Guhlke, Stefan; Abken, Hinrich; Hombach, Andreas A

    2012-01-01

    Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30(+) Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer.

  8. An IL12-IL2-antibody fusion protein targeting Hodgkin's lymphoma cells potentiates activation of NK and T cells for an anti-tumor attack.

    Directory of Open Access Journals (Sweden)

    Tobias Jahn

    Full Text Available Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30(+ Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer.

  9. Glypican-3 Targeting of Liver Cancer Cells Using Multifunctional Nanoparticles

    Directory of Open Access Journals (Sweden)

    James O. Park

    2011-01-01

    Full Text Available Imaging is essential in accurately detecting, staging, and treating primary liver cancer (hepatocellular carcinoma [HCC], one of the most prevalent and lethal malignancies. We developed a novel multifunctional nanoparticle (NP specifically targeting glypican-3 (GPC3, a proteoglycan implicated in promotion of cell growth that is overexpressed in most HCCs. Quantitative real-time polymerase chain reaction was performed to confirm the differential GPC3 expression in two human HCC cells, Hep G2 (high and HLF (negligible. These cells were treated with biotin-conjugated GPC3 monoclonal antibody (αGPC3 and subsequently targeted using superparamagnetic iron oxide NPs conjugated to streptavidin and Alexa Fluor 647. Flow cytometry demonstrated that only GPC3-expressing Hep G2 cells were specifically targeted using this αGPC3-NP conjugate (fourfold mean fluorescence over nontargeted NP, and magnetic resonance imaging (MRI experiments showed similar findings (threefold R2 relaxivity. Confocal fluorescence microscopy localized the αGPC3 NPs only to the cell surface of GPC3-expressing Hep G2 cells. Further characterization of this construct demonstrated a negatively charged, monodisperse, 50 nm NP, ideally suited for tumor targeting. This GPC3-specific NP system, with dual-modality imaging capability, may enhance pretreatment MRI, enable refined intraoperative HCC visualization by near-infrared fluorescence, and be potentially used as a carrier for delivery of tumor-targeted therapies, improving patient outcomes.

  10. Macromolecular nanotheranostics for multimodal anticancer therapy

    Science.gov (United States)

    Huis in't Veld, Ruben; Storm, Gert; Hennink, Wim E.; Kiessling, Fabian; Lammers, Twan

    2011-10-01

    Macromolecular carrier materials based on N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized drug delivery systems that have been extensively evaluated in the past two decades, both at the preclinical and at the clinical level. Using several different imaging agents and techniques, HPMA copolymers have been shown to circulate for prolonged periods of time, and to accumulate in tumors both effectively and selectively by means of the Enhanced Permeability and Retention (EPR) effect. Because of this, HPMA-based macromolecular nanotheranostics, i.e. formulations containing both drug and imaging agents within a single formulation, have been shown to be highly effective in inducing tumor growth inhibition in animal models. In patients, however, as essentially all other tumor-targeted nanomedicines, they are generally only able to improve the therapeutic index of the attached active agent by lowering its toxicity, and they fail to improve the efficacy of the intervention. Bearing this in mind, we have recently reasoned that because of their biocompatibility and their beneficial biodistribution, nanomedicine formulations might be highly suitable systems for combination therapies. In the present manuscript, we briefly summarize several exemplary efforts undertaken in this regard in our labs in the past couple of years, and we show that long-circulating and passively tumor-targeted macromolecular nanotheranostics can be used to improve the efficacy of radiochemotherapy and of chemotherapy combinations.

  11. Normalizing Tumor Vessels To Increase the Enzyme-Induced Retention and Targeting of Gold Nanoparticle for Breast Cancer Imaging and Treatment.

    Science.gov (United States)

    Xiao, Wei; Ruan, Shaobo; Yu, Wenqi; Wang, Ranran; Hu, Chuan; Liu, Rui; Gao, Huile

    2017-10-02

    Abnormal tumor vessels impede the transport and distribution of chemotherapeutics, resulting in low drug concentration at tumor sites and compromised drug efficacy. Normalizing tumor vessels can modulate tumor vascular permeability, alleviate tumor hypoxia, increase blood perfusion, attenuate interstitial fluid pressure, and improve drug delivery. Herein, a novel strategy combining cediranib, a tumor vessel normalizing agent, with an enzyme responsive size-changeable gold nanoparticle (AuNPs-A&C) was developed. In vivo photoacoustic and fluorescence imaging showed that oral pretreatment with 6 mg/kg/day of cediranib for two consecutive days significantly enhanced the retention of AuNPs-A&C in 4T1 tumor. In vivo photoacoustic imaging for hemoglobin (Hb) and oxyhemoglobin (HbO2), Evans blue assay, and immunofluorescence assay showed that cediranib pretreatment markedly increased tumor vascular permeability and tumor oxygenation, while distinctly decreased the tumor microvessel density, demonstrating normalized tumor vessels and favorably altered microenvironment. Additionally, the combination strategy considerably elevated the tumor targeting capacity of different nanoparticle formulations (AuNPs-PEG, AuNPs-A&C), while coadministration of cediranib and AuNPs-A&C achieved prevailing tumor targeting and antitumor efficacy in 4T1 tumor bearing mouse model. In conclusion, we report a novel combined administration strategy to further improve tumor diagnosis and treatment.

  12. MO-D-BRC-01: Memorial Lecture

    Energy Technology Data Exchange (ETDEWEB)

    Fraass, B. [Cedars Sinai Medical Center (United States)

    2016-06-15

    Treatment planning is a central part of radiation therapy, including delineation in tumor volumes and critical organs, setting treatment goals of prescription doses to the tumor targets and tolerance doses to the critical organs, and finally generation of treatment plans to meet the treatment goals. National groups like RTOG have led the effort to standardize treatment goals of the prescription doses to the tumor targets and tolerance doses to the critical organs based on accumulated knowledge from decades of abundant clinical trial experience. The challenge for each clinical department is how to achieve or surpass these set goals within the time constraints of clinical practice. Using fifteen testing cases from different treatment sites such as head and neck, prostate with and without pelvic lymph nodes, SBRT spine, we will present clinically utility of advanced planning tools, including knowledge based, automatic based, and multiple criteria based tools that are clinically implemented. The objectives of this session are: Understand differences among these three advanced planning tools Provide clinical assessments on the utility of the advanced planning tools Discuss clinical challenges of treatment planning with large variations in tumor volumes and their relationships with adjacent critical organs. Ping Xia received research grant from Philips. Jackie Wu received research grant from Varian; P. Xia, Research support by Philips and Varian; Q. Wu, NIH, Varian Medical.

  13. Circulation time estimates of optically active nanoparticles using a pulse photometer

    Science.gov (United States)

    Michalak, Gregory J.; Schwartz, Jon A.; O'Neal, D. Patrick

    2009-02-01

    Researchers employ increasingly complex sub-micron particles for oncological applications to deliver bioactive therapeutic or imaging compounds to known and unknown in vivo tumor targets. In practice, experimental homogeneity using nanoparticles can be difficult to achieve. While several imaging techniques have been previously shown to follow the accumulation of nanoparticles into tumor targets, a more rapid sensor that provides a quantifiable estimate of dose delivery and short-term systemic response could increase the clinical efficacy and greatly reduce the variability of these treatments. We have developed a pulse photometer that when placed on an optically accessible location will estimate the concentration of near-infrared absorbing nanoparticles. The goal is to monitor the accuracy of the delivered dose and the effective circulation time of nanoparticles immediately after intravenous delivery but prior to therapeutic intervention. We present initial tests of our prototype using murine models to assess its ability to quantify circulation half-life and nanoparticle concentration. Four mice were injected with nanoparticles and circulation half-life estimates ranged from 3- 43 minutes. UV-Vis spectrophotometry was used to independently verify these measurements using 5μL blood samples. Linear models relating the two methods produced R2 values of 0.91, 0.99, 0.88, and 0.24.

  14. An optical device employing multiwavelength photoplethysmography for non-invasive in-vivo monitoring of optically active nanoparticles

    Science.gov (United States)

    Michalak, Gregory J.; Adhikari, Pratik; Schwartz, Jon A.; Goodrich, Glenn P.; O'Neal, D. Patrick

    2011-03-01

    Researchers employ increasingly complex sub-micron particles for oncological applications to deliver bioactive therapeutic or imaging compounds to known and unknown in vivo tumor targets. These particles are often manufactured using a vast array of compounds and techniques resulting in a complex architecture, which can be quantified ex vivo by conventional metrology and chemical assays. In practice however, experimental homogeneity using nanoparticles can be difficult to achieve. While several imaging techniques have been previously shown to follow the accumulation of nanoparticles into tumor targets, a more rapid sensor that provides a quantifiable estimate of dose delivery and short-term systemic response could increase the clinical efficacy and greatly reduce the variability of these treatments. We have developed an optical device, the pulse photometer, that when placed on an accessible location will estimate the vascular concentration of near-infrared extinguishing nanoparticles in murine subjects. Using a technique called multi-wavelength photoplethysmography, the same technique used in pulse oximetry, our pulse photometer requires no baseline for each estimate allowing it to be taken on and off of the subject several times during experiments employing long circulating nanoparticles. We present a formal study of our prototype instrument in which circulation half-life and nanoparticle concentration of gold nanorods is determined in murine subjects with the aid of light anesthesia. In this study, we show good agreement between vascular nanorod concentrations (given in optical density) as determined by our device and with UV-VIS spectrophotometry using low volume blood samples.

  15. ANTIBODY-CYTOKINE FUSION PROTEINS FOR TREATMENT OF CANCER: ENGINEERING CYTOKINES FOR IMPROVED EFFICACY AND SAFETY

    Science.gov (United States)

    Young, Patricia A.; Morrison, Sherie L.; Timmerman, John M.

    2014-01-01

    The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing IL-2, IL-12, IL-21, TNFα, and interferons α, β and γ have been constructed and have shown anti-tumor activity in pre-clinical and early phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody-cytokine fusion protein, focusing on previously developed constructs and their clinical trial results. PMID:25440607

  16. Immunoscintigraphy of patients with head and neck carcinomas, with an anti-angiogenetic antibody fragment.

    Science.gov (United States)

    Birchler, Manfred T; Thuerl, Christina; Schmid, Daniel; Neri, Dario; Waibel, Robert; Schubiger, August; Stoeckli, Sandro J; Schmid, Stephen; Goerres, Gerrhard W

    2007-04-01

    In a phase I/II clinical study, we investigated tumor targeting in patients with head and neck squamous cell carcinomas (SCC), using an antibody directed against the extra-domain-B of fibronectin (EDB), a marker of angiogenesis and tissue remodeling. Five patients with SCC were injected with the 123-iodine-radiolabeled L19(scFv)2 antibody and underwent scintigraphic detection with single photon emission tomography with computerized tomography (SPECT/CT). In addition, 18F-fluorodeoxyglucose (18FDG) positron emission tomography with computerized tomography (PET/CT) was performed. Successful targeting of the primary tumor could be achieved in 4 of 5 patients and was comparable to PET imaging. No side effects were observed. Tumor targeting with the L19(scFv)2 antibody is also feasible for head and neck SCC. These results may serve as a base for future therapeutical applications in human beings, with modified versions of the L19(scFv)2 antibody, designed to selectively deliver bioactive molecules into malignant tumors.

  17. Mannosylated Lipid Nano-emulsions Loaded with Lycorine-oleic Acid Ionic Complex for Tumor Cell-specific Delivery

    Science.gov (United States)

    Guo, Yangming; Liu, Xing; Sun, Xun; Zhang, Qiang; Gong, Tao; Zhang, Zhirong

    2012-01-01

    This study was to prepare a mannosylated lycorine lipid nano-emulsion formulation (M-LYC-OA-LNEs) for the aim of achieving tumor targeting delivery of lycorine (LYC) . The low lipophilicity of LYC made it hard to be dispersed into lipid nano-emulsions (LNEs). In order to increase its lipophilicity, lycorine-oleic acid ionic complex (LYC-OA) was made. M-LYC-OA-LNEs and uncoated lycorine-oleic acid loaded lipid nano-emulsions (LYC-OA-LNEs) were prepared by solvent injection method and characterized by transmission electron microscopy (TEM), particle size, polydispersity index, zeta-potential and entrapment efficiency analysis. The in vitro cellular uptake and growth inhibition activity studies were performed on A549 cell lines. The entrapment efficiency of M-LYC-OA-LNEs was 82.7 ± 1.6 %. The cellular uptake study showed that coated LNEs were preferably taken up by A549 cells than uncoated LNEs. The effective test by MTT assay showed better growth inhibition activity of M-LYC-OA-LNEs on A549 cell lines when compared with LYC-OA-LNEs and blank LNEs. These results demonstrated that M-LYC-OA-LNEs could be a promising formulation for tumor targeting delivery of LYC with the potential of being applied in the diagnosis and treatment of cancer. PMID:23227126

  18. Quantitative analysis of proton boron fusion therapy (PBFT) in various conditions

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Joo-Young; Yoon, Do-Kun; Suh, Tae Suk [College of Medicine, Catholic University of Korea, Seoul (Korea, Republic of)

    2015-05-15

    From the theoretical point of view, the PBFT has some strong advantages over currently existing radiotherapy methods. First, boron-based tumor targeting is required prior to performing the treatments such as boron-neutron capture therapy (BNCT). Tumor targeting should be performed before the BNCT by injecting the boronate compound. If boron is not taken up by the normal tissue, the normal tissue can be spared the irradiation by alpha particles. When boron uptake occurs in the target region, selective therapy is possible by neutron capture reaction of labeled boron particles in the target region. Likewise, when boron is distributed in the tumor region for the PBFT, the proposed method can represent a more critical discriminative therapy than either the BNCT or conventional particle therapy. In the conventional proton therapy, in order to deliver a dose to a tumor, the proton beam energy has to be adjusted along the tumor region (e.g., shape and depth). The proton therapy aims at delivering the maximal dose to the tumor by using protons only. In this study, the effectiveness of the PBFT with respect to several physical parameters was evaluated quantitatively by using Monte Carlo simulations. We confirmed that the PBFT can be used to perform critical discriminative therapy. Also, the results of our studies can be used for constructing the PFBT dose database that can be utilized in treatment planning systems (TPSs)

  19. Nucleolin-targeting liposomes guided by aptamer AS1411 for the delivery of siRNA for the treatment of malignant melanomas.

    Science.gov (United States)

    Li, Liyu; Hou, Jianjun; Liu, Xinjie; Guo, Yujia; Wu, Yun; Zhang, Lihe; Yang, Zhenjun

    2014-04-01

    BRAF gene mutation is found in more than 60% of malignant melanomas, which are difficult to treat. In this study, a new tumor-targeting liposome was developed to deliver anti-BRAF siRNA (siBraf) for the treatment of melanomas. Nucleolin is overexpressed on the surface of cancer cells. AS1411, an aptamer showing specific binding to nucleolin, was conjugated to PEGylated cationic liposome as the targeting probe ASLP (AS1411-PEG-liposome). The ASLP/siRNA complex was formed through electrostatic interaction between ASLP and siRNA. The binding of AS1411 to the surface of PEGylated liposomes was confirmed by gel electrophoresis and capillary electrophoresis. Real-time PCR and Western blot analysis showed that ASLP/siBraf exhibited strong silencing activity of BRAF gene. The much higher accumulation of the siRNA in tumor cells comparing with normal cells indicated that ASLP displayed excellent tumor-targeting capability. Notably, ASLP/siBraf showed significant silencing activity in A375 tumor xenograft mice and inhibited the melanoma growth. These results suggested that the new nucleolin-targeted siRNA delivery system by AS1411 may have the potential for the treatment of melanoma. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Thermal Characteristics of ThermoBrachytherapy Surface Applicators (TBSA) for Treating Chestwall Recurrence

    Science.gov (United States)

    Arunachalam, K.; Maccarini, P. F.; Craciunescu, O. I.; Schlorff, J. L.; Stauffer, P. R.

    2010-01-01

    Purpose To study temperature and thermal dose distributions of ThermoBrachytherapy Surface Applicators (TBSA) developed for concurrent or sequential high dose rate (HDR) brachytherapy and microwave hyperthermia treatment of chest wall recurrence and other superficial disease. Methods A steady state thermodynamics model coupled with the fluid dynamics of water bolus and electromagnetic radiation of hyperthermia applicator is used to characterize the temperature distributions achievable with TBSA applicators in an elliptical phantom model of the human torso. Power deposited by 915 MHz conformal microwave array (CMA) applicators is used to assess the specific absorption rate (SAR) distributions of rectangular (500 cm2) and L-shaped (875 cm2) TBSA. The SAR distribution in tissue and fluid flow distribution inside the Dual-Input Dual-Output (DIDO) water bolus are coupled to solve the steady state temperature and thermal dose distributions of rectangular TBSA (R-TBSA) for superficial tumor targets extending 10–15 mm beneath the skin surface. Thermal simulations are carried out for a range of bolus inlet temperature (Tb=38–43°C), water flow rate (Qb=2–4 L/min) and tumor blood perfusion (ωb=2–5 kg/m3/s) to characterize their influence on thermal dosimetry. Results Steady state SAR patterns of R- and L-TBSA demonstrate the ability to produce conformal and localized power deposition inside tumor target sparing surrounding normal tissues and nearby critical organs. Acceptably low variation in tissue surface cooling and surface temperature homogeneity was observed for the new DIDO bolus at 2 L/min water flow rate. Temperature depth profiles and thermal dose volume histograms indicate bolus inlet temperature (Tb) to be the most influential factor on thermal dosimetry. A 42 °C water bolus was observed to be the optimal choice for superficial tumors extending 10–15 mm from the surface even under significant blood perfusion. Lower bolus temperature may be chosen to

  1. Positron emission tomography (PET) guided glioblastoma targeting by a fullerene-based nanoplatform with fast renal clearance.

    Science.gov (United States)

    Peng, Yayun; Yang, Dongzhi; Lu, Weifei; Hu, Xiongwei; Hong, Hao; Cai, Ting

    2017-10-01

    Various carbonaceous nanomaterials, including fullerene, carbon nanotube, graphene, and carbon dots, have attracted increasing attention during past decades for their potential applications in biological imaging and therapy. In this study, we have developed a fullerene-based tumor-targeted positron emission tomography (PET) imaging probe. Water-soluble functionalized C60 conjugates were radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for targeting of integrin αvβ3 in glioblastoma. The specificity of fluorescein-labeled C60 conjugates against cellular integrin αvβ3 was evaluated in U87MG (integrin αvβ3 positive) and MCF-7 cells (integrin αvβ3 negative) by confocal fluorescence microscopy and flow cytometry. Our results indicated that cRGD-conjugated C60 derivatives showed better cellular internalization compared with C60 derivatives without the cRGD attachment. Moreover, an interesting finding on intra-nuclei transportation of cRGD-conjugated C60 derivatives was observed in U87MG cells. In vivo serial PET studies showed preferential accumulation of cRGD-conjugated C60 derivatives at in U87MG tumors. In addition, the pharmacokinetic profiles of these fullerene-based nanoparticles conjugated with cRGD and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) fit well with the three compartment model. The renal clearance of C60-based nanoparticles is remarkably fast, which makes this material very promising for safer cancer theranostic applications. Safety is one of the major concerns for nanomedicine and nanomaterials with fast clearance profile are highly desirable. Fullerene is a distinct type of zero-dimensional carbon nanomaterial with ultrasmall size, uniform dispersity, and versatile reactivity. Here we have developed a fullerene-based tumor-targeted positron emission tomography imaging probe using water-soluble functionalized C60 conjugates radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for

  2. Thermal characteristics of thermobrachytherapy surface applicators for treating chest wall recurrence

    Science.gov (United States)

    Arunachalam, K.; Maccarini, P. F.; Craciunescu, O. I.; Schlorff, J. L.; Stauffer, P. R.

    2010-04-01

    The aim of this study was to investigate temperature and thermal dose distributions of thermobrachytherapy surface applicators (TBSAs) developed for concurrent or sequential high dose rate (HDR) brachytherapy and microwave hyperthermia treatment of chest wall recurrence and other superficial diseases. A steady-state thermodynamics model coupled with the fluid dynamics of a water bolus and electromagnetic radiation of the hyperthermia applicator is used to characterize the temperature distributions achievable with TBSAs in an elliptical phantom model of the human torso. Power deposited by 915 MHz conformal microwave array (CMA) applicators is used to assess the specific absorption rate (SAR) distributions of rectangular (500 cm2) and L-shaped (875 cm2) TBSAs. The SAR distribution in tissue and fluid flow distribution inside the dual-input dual-output (DIDO) water bolus are coupled to solve the steady-state temperature and thermal dose distributions of the rectangular TBSA (R-TBSA) for superficial tumor targets extending 10-15 mm beneath the skin surface. Thermal simulations are carried out for a range of bolus inlet temperature (Tb = 38-43 °C), water flow rate (Qb = 2-4 L min-1) and tumor blood perfusion (ωb = 2-5 kg m-3 s-1) to characterize their influence on thermal dosimetry. Steady-state SAR patterns of the R- and L-TBSA demonstrate the ability to produce conformal and localized power deposition inside the tumor target sparing surrounding normal tissues and nearby critical organs. Acceptably low variation in tissue surface cooling and surface temperature homogeneity was observed for the new DIDO bolus at a 2 L min-1 water flow rate. Temperature depth profiles and thermal dose volume histograms indicate bolus inlet temperature (Tb) to be the most influential factor on thermal dosimetry. A 42 °C water bolus was observed to be the optimal choice for superficial tumors extending 10-15 mm from the surface even under significant blood perfusion. Lower bolus

  3. Clinically Applicable Monte Carlo–based Biological Dose Optimization for the Treatment of Head and Neck Cancers With Spot-Scanning Proton Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Wan Chan Tseung, Hok Seum, E-mail: wanchantseung.hok@mayo.edu; Ma, Jiasen; Kreofsky, Cole R.; Ma, Daniel J.; Beltran, Chris

    2016-08-01

    Purpose: Our aim is to demonstrate the feasibility of fast Monte Carlo (MC)–based inverse biological planning for the treatment of head and neck tumors in spot-scanning proton therapy. Methods and Materials: Recently, a fast and accurate graphics processor unit (GPU)–based MC simulation of proton transport was developed and used as the dose-calculation engine in a GPU-accelerated intensity modulated proton therapy (IMPT) optimizer. Besides dose, the MC can simultaneously score the dose-averaged linear energy transfer (LET{sub d}), which makes biological dose (BD) optimization possible. To convert from LET{sub d} to BD, a simple linear relation was assumed. By use of this novel optimizer, inverse biological planning was applied to 4 patients, including 2 small and 1 large thyroid tumor targets, as well as 1 glioma case. To create these plans, constraints were placed to maintain the physical dose (PD) within 1.25 times the prescription while maximizing target BD. For comparison, conventional intensity modulated radiation therapy (IMRT) and IMPT plans were also created using Eclipse (Varian Medical Systems) in each case. The same critical-structure PD constraints were used for the IMRT, IMPT, and biologically optimized plans. The BD distributions for the IMPT plans were obtained through MC recalculations. Results: Compared with standard IMPT, the biologically optimal plans for patients with small tumor targets displayed a BD escalation that was around twice the PD increase. Dose sparing to critical structures was improved compared with both IMRT and IMPT. No significant BD increase could be achieved for the large thyroid tumor case and when the presence of critical structures mitigated the contribution of additional fields. The calculation of the biologically optimized plans can be completed in a clinically viable time (<30 minutes) on a small 24-GPU system. Conclusions: By exploiting GPU acceleration, MC-based, biologically optimized plans were created for

  4. Gold nanoparticles for cancer theranostics — A brief update

    Directory of Open Access Journals (Sweden)

    Ning Zhao

    2016-07-01

    Full Text Available Gold nanoparticles (AuNPs exhibit superior optical and physical properties for more effective treatment of cancer through incorporating both diagnostic and therapeutic functions into one single platform. The ability to passively accumulate on tumor cells provides AuNPs the opportunity to become an attractive contrast agent for X-ray based computed tomography (CT imaging in vivo. Because of facile surface modification, various size and shape of AuNPs have been extensively functionalized and applied as active nanoprobes and drug carriers for cancer targeted theranostics. Moreover, their capabilities on producing photoacoustic (PA signals and photothermal effects have been used to image and treat tumor progression, respectively. Herein, we review the developments of AuNPs as cancer diagnostics and chemotherapeutic drug vector, summarizing strategies for tumor targeting and their applications in vitro and in vivo.

  5. OXavidin for Tissue Targeting Biotinylated Therapeutics

    Directory of Open Access Journals (Sweden)

    Rita De Santis

    2009-01-01

    Full Text Available Avidin is a glycoprotein from hen egg white that binds biotin with very high affinity. Here we describe OXavidin, a product containing aldehyde groups, obtained by ligand-assisted sugar oxidation of avidin by sodium periodate. OXavidin chemically reacts with cellular and tissue proteins through Schiff's base formation thus residing in tissues for weeks while preserving the biotin binding capacity. The long tissue residence of OXavidin as well as that of OXavidin/biotinylated agent complex occurs in normal and neoplastic tissues and immunohistochemistry shows a strong and homogenous stromal localization. Once localized in tissue/tumor, OXavidin becomes an “artificial receptor” for intravenous injected biotin allowing tumor targeting with biotinylated therapeutics like radioisotopes or toxins. Moreover, present data also suggest that OXavidin might be useful for the homing of biotinylated cells. Overall, OXavidin exhibits a remarkable potential for many different therapeutic applications.

  6. New Advances in Nanotechnology-Based Diagnosis and Therapeutics for Breast Cancer: An Assessment of Active-Targeting Inorganic Nanoplatforms.

    Science.gov (United States)

    Falagan-Lotsch, Priscila; Grzincic, Elissa M; Murphy, Catherine J

    2017-01-18

    Breast cancer is a major cause of suffering and mortality among women. Limitations in the current diagnostic methods and treatment approaches have led to new strategies to positively impact the survival rates and quality of life of breast cancer patients. Nanotechnology offers a real possibility of mitigating breast cancer mortality by early-stage cancer detection and more precise diagnosis as well as more effective treatments with minimal side effects. The current nanoplatforms approved for breast cancer therapeutics are based on passive tumor targeting using organic nanoparticles and have not provided the expected significant improvements in the clinic. In this review, we present the emerging approaches in breast cancer nanomedicine based on active targeting using versatile inorganic nanoplatforms with biomedical relevance, such as gold, silica, and iron oxide nanoparticles, as well as their efficacy in breast cancer imaging, drug and gene delivery, thermal therapy, combinational therapy, and theranostics in preclinical studies. The main challenges for clinical translation and perspectives are discussed.

  7. Glucose-functionalized gold nanoparticles as a metabolically targeted CT contrast agent for distinguishing tumors from non-malignant metabolically active processes

    Science.gov (United States)

    Dreifuss, Tamar; Motiei, Menachem; Betzer, Oshra; Popovtzer, Aron; Abourbeh, Galith; Mishani, Eyal; Popovtzer, Rachela

    2017-02-01

    The highly used cancer imaging technique, [18F]FDG-PET, is based on the increased glucose metabolic activity in tumors. However, since there are other biological processes that exhibit increased metabolic activity, in particular inflammation, this methodology is prone to non-specificity for cancer. Herein we describe the development of a novel nanoparticle-based approach, utilizes Glucose-Functionalized Gold Nanoparticles (GF-GNPs) as a metabolically targeted CT contrast agent. Our method has demonstrated specific tumor targeting and has successfully differentiated between cancer and inflammation in a combined tumor-inflammation mouse model, due to dissimilarities in vasculatures in different pathologic conditions. This novel approach provides new capabilities in cancer imaging, and can be applicable to a wide range of cancers.

  8. New concepts in monoclonal antibody based radioimmunodiagnosis and radioimmunotherapy of carcinoma.

    Science.gov (United States)

    Schlom, J; Milenic, D E; Roselli, M; Colcher, D; Bird, R; Johnson, S; Hardman, K D; Guadagni, F; Greiner, J W

    1991-01-01

    It is now generally agreed that while numerous monoclonal antibodies (MAbs) have been shown to efficiently target tumors in patients, much still needs to be accomplished to optimize MAb based tumor targeting and the use of MAbs in the therapy of human carcinoma. This article will review some recent studies undertaken in our laboratory in an attempt to generate novel recombinant constructs and test new principles to aid in optimizing MAb based diagnosis and therapy. Three areas will be covered: (a) the analysis of dose fractionation protocols; (b) the generation of recombinant/chimeric (rec/chi) MAbs including the generation of a single chain antigen binding protein (SCA); and (c) the use of recombinant interferons (rec IFNs) to selectively up-regulate tumor antigen expression. Each of these topics has been previously described in detail and appropriate references to these articles are included.

  9. The impact of nuclear science on medicine

    CERN Document Server

    Kraft, G

    1999-01-01

    From the very beginning, i.e. from the discovery of the natural radioactivity by H. Becquerel and the production of radium by M. Curie, nuclear physics had a strong impact on medicine: Radioactive sources were immediately made use of in tumor therapy long before the action mechanisms of ionizing radiation were understood. The invention of the tracer technique by G. Hevesy opened a new field for the study of chemokinetics as well as for the in-vivo measurement of various organ functions. In the percutane tumor therapy hadrons like neutrons, pions, protons and heavier ions were tested. Presently, proton therapy is a great success and is spreading all over the world. The new techniques of target-conform treatment using heavy ions for an improved tumor targeting and control represent the latest great improvement of radiation tumor therapy.

  10. Biological Effects of Nonionizing Electromagnetic Radiation. Volume 8, Number 1. A Digest of Current Literature.

    Science.gov (United States)

    1983-10-01

    electrodes ind disappeared 11)-i5 rrn Itil t, t i ’h 0 ati SO degree arc were submerged i-suire . uodenal sot ion not n i - I i al ine water bath to 22 .1 C...immed latel 1A,-e :1 Dept. Genie Electrique , Kcole Plyt o: ., , B C,, , i not i nsi de the tumor. Target terp;.-ratures 6079, station A"", Montrea...G 7 C TC’I’.j 0 % I H L f-if i 0j AS OF ’k I. _u:?TL - JNSEOLENCES OF EXPOSURE TO WEAK -,"’r MIENDwAVE FIELDS: ARC THEKk B,LL P.L CTS CF THE EFFECT

  11. In Vivo Tumor Vasculature Targeting of CuS@MSN Based Theranostic Nanomedicine.

    Science.gov (United States)

    Chen, Feng; Hong, Hao; Goel, Shreya; Graves, Stephen A; Orbay, Hakan; Ehlerding, Emily B; Shi, Sixiang; Theuer, Charles P; Nickles, Robert J; Cai, Weibo

    2015-01-01

    Actively targeted theranostic nanomedicine may be the key for future personalized cancer management. Although numerous types of theranostic nanoparticles have been developed in the past decade for cancer treatment, challenges still exist in the engineering of biocompatible theranostic nanoparticles with highly specific in vivo tumor targeting capabilities. Here, we report the design, synthesis, surface engineering, and in vivo active vasculature targeting of a new category of theranostic nanoparticle for future cancer management. Water-soluble photothermally sensitive copper sulfide nanoparticles were encapsulated in biocompatible mesoporous silica shells, followed by multistep surface engineering to form the final theranostic nanoparticles. Systematic in vitro targeting, an in vivo long-term toxicity study, photothermal ablation evaluation, in vivo vasculature targeted imaging, biodistribution and histology studies were performed to fully explore the potential of as-developed new theranostic nanoparticles.

  12. Polyester micelles for drug delivery and cancer theranostics: Current achievements, progresses and future perspectives.

    Science.gov (United States)

    Yi, Yu; Lin, Gan; Chen, Shaoyi; Liu, Jing; Zhang, Huaping; Mi, Peng

    2018-02-01

    The development of tumor-targeting nanocarriers is critical important for effective treatment. The synthetic polyesters have demonstrated high potential for developing nanocarriers for cancer theranostics. Especially, the biocompatible and biodegradable polyester micelles have held great promise for cancer therapy and diagnosis, while some candidates have been translated into clinical applications or under clinical trial. In this review, we have provided the state-of-the-art of polyester micelles for drug delivery and cancer theranostics. In addition, we have summarized several major types of polyesters used in the biomedical fields, the current clinical achievements of polyester micelles and recent progresses of multi-functional polyester micelles for tumor molecular imaging and therapeutic applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. General strategy for the protection of organs at risk in IMRT therapy of a moving body

    Energy Technology Data Exchange (ETDEWEB)

    Abolfath, Ramin M.; Papiez, Lech [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 (United States)

    2009-07-15

    We investigated protection strategies of organs at risk (OARs) in intensity modulated radiation therapy (IMRT). These strategies apply to delivery of IMRT to moving body anatomies that show relative displacement of OAR in close proximity to a tumor target. We formulated an efficient genetic algorithm which makes it possible to search for global minima in a complex landscape of multiple irradiation strategies delivering a given, predetermined intensity map to a target. The optimal strategy was investigated with respect to minimizing the dose delivered to the OAR. The optimization procedure developed relies on variability of all parameters available for control of radiation delivery in modern linear accelerators, including adaptation of leaf trajectories and simultaneous modification of beam dose rate during irradiation. We showed that the optimization algorithms lead to a significant reduction in the dose delivered to OAR in cases where organs at risk move relative to a treatment target.

  14. Hyaluronic acid grafted PLGA copolymer nanoparticles enhance the targeted delivery of Bromelain in Ehrlich's Ascites Carcinoma.

    Science.gov (United States)

    Bhatnagar, Priyanka; Pant, Aditya Bhushan; Shukla, Yogeshwer; Panda, Amulya; Gupta, Kailash Chand

    2016-08-01

    Rapidly increasing malignant neoplastic disease demands immediate attention. Several dietary compounds have recently emerged as strong anti-cancerous agents. Among, Bromelain (BL), a protease from pineapple plant, was used to enhance its anti-cancerous efficacy using nanotechnology. In lieu of this, hyaluronic acid (HA) grafted PLGA copolymer, having tumor targeting ability, was developed. BL was encapsulated in copolymer to obtain BL-copolymer nanoparticles (NPs) that ranged between 140 to 281nm in size. NPs exhibited higher cellular uptake and cytotoxicity in cells with high CD44 expression as compared with non-targeted NPs. In vivo results on tumor bearing mice showed that NPs were efficient in suppressing the tumor growth. Hence, the formulation could be used as a self-targeting drug delivery cargo for the remission of cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. CSF-1R Inhibitor Development: Current Clinical Status.

    Science.gov (United States)

    Peyraud, Florent; Cousin, Sophie; Italiano, Antoine

    2017-09-05

    Colony-stimulating factor 1 receptor (CSF-1R) and its ligands, CSF-1 and interleukin 34 (IL-34), regulate the function and survival of tumor-associated macrophages, which are involved in tumorigenesis and in the suppression of antitumor immunity. Moreover, the CSF-1R/CSF-1 axis has been implicated in the pathogenesis of pigmented villonodular synovitis (PVNS), a benign tumor of the synovium. As advanced or metastatic malignant solid tumors and relapsed/refractory PVNS remain unresolved therapeutic problems, new approaches are needed to improve the outcome of patients with these conditions. In solid tumors, targeting CSF-1R via either small molecules or antibodies has shown interesting results in vitro but limited antitumor activity in vivo. Concerning PVNS, clinical trials assessing CSF-1R inhibitors have revealed promising initial outcomes. Blocking CSF-1/CSF-1R signaling represents a promising immunotherapy approach and several new potential combination therapies for future clinical testing.

  16. Delivery of paclitaxel using nanoparticles composed of poly(ethylene oxide)-b-poly(butylene oxide) (PEO-PBO).

    Science.gov (United States)

    Wang, Lijiang; Yao, Ju; Zhang, Xiaomin; Zhang, Yingxin; Xu, Chang; Lee, Robert J; Yu, Gary; Yu, Bo; Teng, Lesheng

    2017-11-07

    An amphiphilic block copolymer poly(ethylene oxide)-b-poly(butylene oxide) (PEO-PBO) was evaluated as a carrier for therapeutic delivery of paclitaxel (PTX). PEO-PBO and PTX form nanoparticles (NPs) by self-assembly upon hydration. The size of these NPs was about 92.71nm and the zeta potential was -5.06mV, which met the requirements for passive tumor targeting through the enhanced permeability and retention effect. Compared with a commonly used block copolymer poly(ethylene glycol)-b-poly-D,L-(lactic acid) (PEG-PDLLA), PEO-PBO forms nanoparticles with superior pharmacokinetic, biodistribution, and tumor inhibitory properties. Meanwhile, results of hemolysis study and CMC determination showed that PEO-PBO had better biocompatibility and stability than PEG-PDLLA. These data suggest that PEO-PBO has potential for application in drug delivery and warrant further evaluation. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Viruses in cancer treatment.

    Science.gov (United States)

    Alemany, R

    2013-03-01

    Soon after the discovery that viruses cause human disease, started the idea of using viruses to treat cancer. After the initial indiscriminate use, crude preparations of each novel virus in the early twentieth century, a second wave of virotherapy blossomed in the 60s with purified and selected viruses. Responses were rare and short-lived. Immune rejection of the oncolytic viruses was identified as the major problem and virotherapy was abandoned. During the past two decades virotherapy has re-emerged with engineered viruses, with a trend towards using them as tumor-debulking immunostimulatory agents combined with radio or chemotherapy. Currently, oncolytic Reovirus, Herpes, and Vaccinia virus are in late phase clinical trials. Despite the renewed hope, efficacy will require improving systemic tumor targeting, overcoming stroma barriers for virus spread, and selectively stimulating immune responses against tumor antigens but not against the virus. Virotherapy history, viruses, considerations for clinical trials, and hurdles are briefly overviewed.

  18. Intratumoral administration of IL2- and TNF-based fusion proteins cures cancer without establishing protective immunity.

    Science.gov (United States)

    Ziffels, Barbara; Pretto, Francesca; Neri, Dario

    2018-03-01

    The combination of tumor-targeting IL2- and TNF-based antibody-cytokine fusions has exhibited encouraging results in mouse and men. Here, we studied their combination to assess efficacy and mechanism of action in four different immunocompetent mouse models of cancer. Mice receiving a single intratumoral injection of F8-IL2, F8-TNF or the combination were investigated for tumor-infiltrating leukocytes and rechallenged when cured. In three models, a proportion of treated animals could be cured, most probably by infiltrating NK and CD8 + T cells. Most of the cured mice did not acquire protective immunity when rechallenged with the same tumor cell line. Immunocompetent mouse tumor models may not be adequate enough to predict the search for more efficacious therapy regimens.

  19. Targeted Shiga toxin-drug conjugates prepared via Cu-free click chemistry.

    Science.gov (United States)

    Kostova, Vesela; Dransart, Estelle; Azoulay, Michel; Brulle, Laura; Bai, Siau-Kun; Florent, Jean-Claude; Johannes, Ludger; Schmidt, Frédéric

    2015-11-15

    The main drawback of the anticancer chemotherapy consists in the lack of drug selectivity causing severe side effects. The targeted drug delivery appears to be a very promising strategy for controlling the biodistribution of the cytotoxic agent only on malignant tissues by linking it to tumor-targeting moiety. Here we exploit the natural characteristics of Shiga toxin B sub-unit (STxB) as targeting carrier on Gb3-positive cancer cells. Two cytotoxic conjugates STxB-doxorubicin (STxB-Doxo) and STxB-monomethyl auristatin F (STxB-MMAF) were synthesised using copper-free 'click' chemistry. Both conjugates were obtained in very high yield and demonstrated strong tumor inhibition activity in a nanomolar range on Gb3-positive cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Surface Engineering of Graphene-Based Nanomaterials for Biomedical Applications

    Science.gov (United States)

    2015-01-01

    Graphene-based nanomaterials have attracted tremendous interest over the past decade due to their unique electronic, optical, mechanical, and chemical properties. However, the biomedical applications of these intriguing nanomaterials are still limited due to their suboptimal solubility/biocompatibility, potential toxicity, and difficulties in achieving active tumor targeting, just to name a few. In this Topical Review, we will discuss in detail the important role of surface engineering (i.e., bioconjugation) in improving the in vitro/in vivo stability and enriching the functionality of graphene-based nanomaterials, which can enable single/multimodality imaging (e.g., optical imaging, positron emission tomography, magnetic resonance imaging) and therapy (e.g., photothermal therapy, photodynamic therapy, and drug/gene delivery) of cancer. Current challenges and future research directions are also discussed and we believe that graphene-based nanomaterials are attractive nanoplatforms for a broad array of future biomedical applications. PMID:25117569

  1. New Protein Vector ApE1 for Targeted Delivery of Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    N. V. Pozdniakova

    2012-01-01

    Full Text Available A new chimeric gene ApE1 encoding the receptor-binding domain of the human alpha-fetoprotein fused to a sequence of 22 glutamic acid residues was constructed. A new bacterial producer strain E. coli SHExT7 ApE1 was selected for ApE1 production in a soluble state. A simplified method was developed to purify ApE1 from bacterial biomass. It was shown that the new vector protein selectively interacts with AFP receptors on the tumor cell surface and can be efficiently accumulated in tumor cells. In addition, ApE1 was shown to be stable in storage and during its chemical modification. An increased number of carboxyl groups in the molecule allows the production of cytotoxic compound conjugates with higher drug-loading capacity and enhanced tumor targeting potential.

  2. Targeted Cancer Diagnostic and Therapeutic Agents: Delivery by Carriers or Conjugation

    Directory of Open Access Journals (Sweden)

    Mohsen Mohammadgholi

    2016-07-01

    Full Text Available Receptors and proteins are overexpressed in many human cancer cell membranes rather than normal tissues and are considered as the main molecular targets. Specific tumor- targeting molecules which have high affinity for these receptors can be valuable tools as carrier molecules for targeted cancer therapy and imaging. Pharmacokinetics and bioavailability of diagnostic and therapeutic agents are very important. Poor selectivity of cancer therapeutic agents causes toxicity on normal cells that limits maximum effective dose. The Attachment of these agents to macromolecules or their installation on carriers is currently under investigation. This article presents recent developments in the field of targeting agents and introduces different carriers and their applications in the diagnosis and treatment of cancer.

  3. Dual targeting of a thermosensitive nanogel conjugated with transferrin and RGD-containing peptide for effective cell uptake and drug release

    Energy Technology Data Exchange (ETDEWEB)

    Quan Changyun; Chang Cong; Wei Hua; Chen Changsheng; Xu Xiaoding; Cheng Sixue; Zhang Xianzheng; Zhuo Renxi, E-mail: xz-zhang@whu.edu.c [Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072 (China)

    2009-08-19

    In this paper, both arginine-glycine-aspartic acid (RGD)-containing peptide and transferrin (Tf) were conjugated to the thermosensitive poly(N-isopropylacrylamide-co-propyl acrylic acid) (poly(NIPAAm-co-PAAc)) nanogel to prepare a dual-targeting drug carrier. The obtained nanogel was characterized in terms of fluorescence spectroscopy, UV-vis spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). In order to track the dual-ligand conjugated nanogel, fluorescein isothiocyanate (FITC) was further conjugated to the nanogel. A cell internalization experiment showed that the dual-ligand conjugated nanogel exhibited obviously enhanced endocytosis by HeLa cells as compared with non-tumorous cells (COS-7 cells). The drug-loaded dual-ligand conjugated nanogel could be transported efficiently into the target tumor cells and the anti-tumor effect was enhanced significantly, suggesting that the dual-ligand conjugated nanogel has great potential as a tumor targeting drug carrier.

  4. Dual targeting of a thermosensitive nanogel conjugated with transferrin and RGD-containing peptide for effective cell uptake and drug release

    Science.gov (United States)

    Quan, Chang-Yun; Chang, Cong; Wei, Hua; Chen, Chang-Sheng; Xu, Xiao-Ding; Cheng, Si-Xue; Zhang, Xian-Zheng; Zhuo, Ren-Xi

    2009-08-01

    In this paper, both arginine-glycine-aspartic acid (RGD)-containing peptide and transferrin (Tf) were conjugated to the thermosensitive poly(N-isopropylacrylamide-co-propyl acrylic acid) (poly(NIPAAm-co-PAAc)) nanogel to prepare a dual-targeting drug carrier. The obtained nanogel was characterized in terms of fluorescence spectroscopy, UV-vis spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). In order to track the dual-ligand conjugated nanogel, fluorescein isothiocyanate (FITC) was further conjugated to the nanogel. A cell internalization experiment showed that the dual-ligand conjugated nanogel exhibited obviously enhanced endocytosis by HeLa cells as compared with non-tumorous cells (COS-7 cells). The drug-loaded dual-ligand conjugated nanogel could be transported efficiently into the target tumor cells and the anti-tumor effect was enhanced significantly, suggesting that the dual-ligand conjugated nanogel has great potential as a tumor targeting drug carrier.

  5. Trojan horse lymphocytes: a vesicular stomatitis virus-specific T-cell clone lyses target cells by carrying virus.

    Science.gov (United States)

    Hom, R C; Soman, G; Finberg, R

    1989-10-01

    We have isolated a vesicular stomatitis virus (VSV)-specific CD4+ CD8- murine T-cell clone. This clone proliferates only in response to VSV and lyses infected tumor cells bearing class II major histocompatibility antigens in short-term chromium release assays. In addition, the cell has VSV antigens on its surface and is capable of killing uninfected tumor cells without major histocompatibility antigen restriction in a 2-day assay. This latter cytolytic activity is eliminated by anti-VSV antibody, indicating that its lytic activity is provided by the virus. [35S]methionine labeling and immunoprecipitation experiments demonstrated that viral protein translation is initiated after incubation of the clone with a tumor target cell, defining this as the mechanism of its cytolytic activity.

  6. Engineering CAR-T cells: Design concepts.

    Science.gov (United States)

    Srivastava, Shivani; Riddell, Stanley R

    2015-08-01

    Despite being empirically designed based on a simple understanding of TCR signaling, T cells engineered with chimeric antigen receptors (CARs) have been remarkably successful in treating patients with advanced refractory B cell malignancies. However, many challenges remain in improving the safety and efficacy of this therapy and extending it toward the treatment of epithelial cancers. Other aspects of TCR signaling beyond those directly provided by CD3ζ and CD28 phosphorylation strongly influence a T cell's ability to differentiate and acquire full effector functions. Here, we discuss how the principles of TCR recognition, including spatial constraints, Kon/Koff rates, and synapse formation, along with in-depth analysis of CAR signaling might be applied to develop safer and more effective synthetic tumor targeting receptors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Cell-penetrating peptides: strategies for anticancer treatment.

    Science.gov (United States)

    Raucher, Drazen; Ryu, Jung Su

    2015-09-01

    Cell-penetrating peptides (CPP) provide an efficient strategy for the intracellular delivery of bioactive molecules in various biomedical applications. This review focuses on recent advances in the use of CPPs to deliver anticancer therapeutics and imaging reagents to cancer cells, along with CPP contributions to novel tumor-targeting techniques. CPPs are now used extensively to deliver a variety of therapeutics, despite lacking cell specificity and having a short duration of action. Resolution of these shortcomings to enable increased cancer cell and/or tumor specificity could improve CPP-based drug delivery strategies, expand combined drug delivery possibilities, and strengthen future clinical applications of these peptides. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Accumulation of arginine-rich cell-penetrating peptides in tumors and the potential for anticancer drug delivery in vivo.

    Science.gov (United States)

    Nakase, Ikuhiko; Konishi, Yusuke; Ueda, Masashi; Saji, Hideo; Futaki, Shiroh

    2012-04-30

    We investigated the biodistribution of arginine-rich cell-penetrating peptides (CPPs) in tumor-xenografted nude mice after intravenous injection of fluorescently labeled CPPs using in vivo imaging. The CPPs used included HIV-1 Tat (48-60), penetratin, and the L- and D-enantiomers of oligoarginines (8, 12, and 16 residues), all of which are reported to have high cell penetration. Among the tested peptides, high accumulation in tumors was observed for the D-form of octaarginine (r8), and glycosaminoglycans played a key role. Injection of an r8-doxorubicin conjugate (4mg doxorubicin/kg) effectively suppressed tumor proliferation, with no significant decrease in mouse weight, whereas administration of doxorubicin itself (6mg/kg), yielding a similar degree of tumor-growth suppression, resulted in significant weight loss. These results suggest the potential of r8 as a prototypic tumor-targeting vector. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Real-time, continuous, fluorescence sensing in a freely-moving subject with an implanted hybrid VCSEL/CMOS biosensor.

    Science.gov (United States)

    O'Sullivan, Thomas D; Heitz, Roxana T; Parashurama, Natesh; Barkin, David B; Wooley, Bruce A; Gambhir, Sanjiv S; Harris, James S; Levi, Ofer

    2013-01-01

    Performance improvements in instrumentation for optical imaging have contributed greatly to molecular imaging in living subjects. In order to advance molecular imaging in freely moving, untethered subjects, we designed a miniature vertical-cavity surface-emitting laser (VCSEL)-based biosensor measuring 1cm(3) and weighing 0.7g that accurately detects both fluorophore and tumor-targeted molecular probes in small animals. We integrated a critical enabling component, a complementary metal-oxide semiconductor (CMOS) read-out integrated circuit, which digitized the fluorescence signal to achieve autofluorescence-limited sensitivity. After surgical implantation of the lightweight sensor for two weeks, we obtained continuous and dynamic fluorophore measurements while the subject was un-anesthetized and mobile. The technology demonstrated here represents a critical step in the path toward untethered optical sensing using an integrated optoelectronic implant.

  10. Growth factor transduction pathways: paradigm of anti-neoplastic targeted therapy.

    Science.gov (United States)

    Carlomagno, Francesca; Chiariello, Mario

    2014-07-01

    Molecularly targeted cancer treatment has become an achievable goal thanks to systematic analysis of cancer genome as well as development of highly selective tumor targeted drugs. In many human cancers, deregulation of the RTK/RAS/MAPK pathway is the driving force of the disease. Indeed, cancer cells become addicted to such signaling, rendering them susceptible to drugs that can intercept growth factor signaling cascade at different levels. Discovery of mutations or aberrant expression of components of this cascade in radio- and chemotherapy refractory human melanoma acted as an enormous stimulus for scientist to try to identify and clinically test new therapeutic approaches blocking the RTK/RAS/MAPK cascade. These efforts not only resulted in the identification of new drugs for melanoma treatment but also in a better understanding of molecular basis of primary and secondary resistance to targeted therapies.

  11. Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors.

    Science.gov (United States)

    Buckway, Brandon; Wang, Yongjian; Ray, Abhijit; Ghandehari, Hamidreza

    2013-11-01

    Delivery of macromolecules to pancreatic cancer is inhibited by a dense extracellular matrix composed of hyaluronic acid, smooth muscle actin and collagen fibers. Hyaluronic acid causes a high intratumoral fluidic pressure which prevents diffusion and penetration into the pancreatic tumor. This study involves the breaking down of hyaluronic acid by treating CAPAN-1 xenograft tumors in athymic nu/nu mice with targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers radiolabeled with (111)In for single photon emission computerized tomography (SPECT) imaging. Two targeting strategies were investigated including αvβ3 integrin and HER2 receptors. HPMA copolymers were targeted to these receptors by conjugating short peptide ligands cRGDfK and KCCYSL to the side chains of the copolymer. Results demonstrate that tumor targeting can be achieved in vivo after treatment with hyaluronidase. This approach shows promise for enhanced delivery of polymer-peptide conjugates to solid tumors. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Ribosome-Inactivating Proteins: From Plant Defense to Tumor Attack

    Directory of Open Access Journals (Sweden)

    Maria Serena Fabbrini

    2010-11-01

    Full Text Available Ribosome-inactivating proteins (RIPs are EC3.2.32.22 N-glycosidases that recognize a universally conserved stem-loop structure in 23S/25S/28S rRNA, depurinating a single adenine (A4324 in rat and irreversibly blocking protein translation, leading finally to cell death of intoxicated mammalian cells. Ricin, the plant RIP prototype that comprises a catalytic A subunit linked to a galactose-binding lectin B subunit to allow cell surface binding and toxin entry in most mammalian cells, shows a potency in the picomolar range. The most promising way to exploit plant RIPs as weapons against cancer cells is either by designing molecules in which the toxic domains are linked to selective tumor targeting domains or directly delivered as suicide genes for cancer gene therapy. Here, we will provide a comprehensive picture of plant RIPs and discuss successful designs and features of chimeric molecules having therapeutic potential.

  13. Current Perspectives on In Vivo Noninvasive Tracking of Extracellular Vesicles with Molecular Imaging

    Directory of Open Access Journals (Sweden)

    Prakash Gangadaran

    2017-01-01

    Full Text Available Clinical and preclinical in vivo tracking of extracellular vesicles (EVs are a crucial tool for the development and optimization of EV-based diagnosis and treatment. EVs have gained interest due to their unique properties that make them excellent candidates for biological applications. Noninvasive in vivo EV tracking has allowed marked progress towards elucidating the mechanisms and functions of EVs in real time in preclinical and clinical studies. In this review, we summarize several molecular imaging methods that deal with EVs derived from different cells, which have allowed investigations of EV biodistribution, as well as their tracking, delivery, and tumor targeting, to determine their physiological functions and to exploit imaging-derived information for EV-based theranostics.

  14. Therapeutic Cancer Vaccines in Prostate Cancer: The Quest for Intermediate Markers of Response

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Joseph W.; Bilusic, Marijo; Heery, Christopher J.; Madan, Ravi A., E-mail: madanr@mail.nih.gov [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2012-11-21

    Despite recent advances in cancer immunotherapy, no prospectively validated intermediate biomarkers exist to predict response. These biomarkers are highly desirable given modern immunotherapy’s paradoxical pattern of clinical benefit; that is, improvement in overall survival without short-term change in progression. Immunotherapy clinical trials have evaluated biomarkers that may correlate with clinical outcomes. Many of them are performed on peripheral blood to evaluate the systemic response, such as tumor-targeted humoral and cellular immunity, and cytokine responses. Accumulating evidence suggests that immune infiltrates in tumors may suggest evidence for the therapy’s mechanism of action, and have greater potential for providing prognostic and predictive information. In addition, a non-immunologic biomarker, such as tumor growth kinetics, may explain this paradoxical pattern of clinical benefit, and predict survival in patients treated with an immunotherapy. Prospective assessment and validation of these and other intermediate markers would be required to better understand their potential clinical role.

  15. Targeting the tumor microenvironment to enhance antitumor immune responses

    Science.gov (United States)

    Van der Jeught, Kevin; Bialkowski, Lukasz; Daszkiewicz, Lidia; Broos, Katrijn; Goyvaerts, Cleo; Renmans, Dries; Van Lint, Sandra; Heirman, Carlo; Thielemans, Kris; Breckpot, Karine

    2015-01-01

    The identification of tumor-specific antigens and the immune responses directed against them has instigated the development of therapies to enhance antitumor immune responses. Most of these cancer immunotherapies are administered systemically rather than directly to tumors. Nonetheless, numerous studies have demonstrated that intratumoral therapy is an attractive approach, both for immunization and immunomodulation purposes. Injection, recruitment and/or activation of antigen-presenting cells in the tumor nest have been extensively studied as strategies to cross-prime immune responses. Moreover, delivery of stimulatory cytokines, blockade of inhibitory cytokines and immune checkpoint blockade have been explored to restore immunological fitness at the tumor site. These tumor-targeted therapies have the potential to induce systemic immunity without the toxicity that is often associated with systemic treatments. We review the most promising intratumoral immunotherapies, how these affect systemic antitumor immunity such that disseminated tumor cells are eliminated, and which approaches have been proven successful in animal models and patients. PMID:25682197

  16. The Platin-X series: activation, targeting, and delivery.

    Science.gov (United States)

    Basu, Uttara; Banik, Bhabatosh; Wen, Ru; Pathak, Rakesh K; Dhar, Shanta

    2016-08-16

    Anticancer platinum (Pt) complexes have long been considered to be one of the biggest success stories in the history of medicinal inorganic chemistry. Yet there remains the hunt for the "magic bullet" which can satisfy the requirements of an effective chemotherapeutic drug formulation. Pt(iv) complexes are kinetically more inert than the Pt(ii) congeners and offer the opportunity to append additional functional groups/ligands for prodrug activation, tumor targeting, or drug delivery. The ultimate aim of functionalization is to enhance the tumor selective action and attenuate systemic toxicity of the drugs. Moreover, an increase in cellular accumulation to surmount the resistance of the tumor against the drugs is also of paramount importance in drug development and discovery. In this review, we will address the attempts made in our lab to develop Pt(iv) prodrugs that can be activated and delivered using targeted nanotechnology-based delivery platforms.

  17. Monte Carlo based dosimetry for neutron capture therapy of brain tumors

    Science.gov (United States)

    Zaidi, Lilia; Belgaid, Mohamed; Khelifi, Rachid

    2016-11-01

    Boron Neutron Capture Therapy (BNCT) is a biologically targeted, radiation therapy for cancer which combines neutron irradiation with a tumor targeting agent labeled with a boron10 having a high thermal neutron capture cross section. The tumor area is subjected to the neutron irradiation. After a thermal neutron capture, the excited 11B nucleus fissions into an alpha particle and lithium recoil nucleus. The high Linear Energy Transfer (LET) emitted particles deposit their energy in a range of about 10μm, which is of the same order of cell diameter [1], at the same time other reactions due to neutron activation with body component are produced. In-phantom measurement of physical dose distribution is very important for BNCT planning validation. Determination of total absorbed dose requires complex calculations which were carried out using the Monte Carlo MCNP code [2].

  18. Enzymatically triggered multifunctional delivery system based on hyaluronic acid micelles

    KAUST Repository

    Deng, Lin

    2012-01-01

    Tumor targetability and stimuli responsivity of drug delivery systems (DDS) are key factors in cancer therapy. Implementation of multifunctional DDS can afford targetability and responsivity at the same time. Herein, cholesterol molecules (Ch) were coupled to hyaluronic acid (HA) backbones to afford amphiphilic conjugates that can self-assemble into stable micelles. Doxorubicin (DOX), an anticancer drug, and superparamagnetic iron oxide (SPIO) nanoparticles (NPs), magnetic resonance imaging (MRI) contrast agents, were encapsulated by Ch-HA micelles and were selectively released in the presence of hyaluronidase (Hyals) enzyme. Cytotoxicity and cell uptake studies were done using three cancer cell lines (HeLa, HepG2 and MCF7) and one normal cell line (WI38). Higher Ch-HA micelles uptake was seen in cancer cells versus normal cells. Consequently, DOX release was elevated in cancer cells causing higher cytotoxicity and enhanced cell death. © 2012 The Royal Society of Chemistry.

  19. Antibody proteolysis: a common picture emerging from plants.

    Science.gov (United States)

    Donini, Marcello; Lombardi, Raffaele; Lonoce, Chiara; Di Carli, Mariasole; Marusic, Carla; Morea, Veronica; Di Micco, Patrizio

    2015-01-01

    We have recently characterized the degradation profiles of 2 human IgG1 monoclonal antibodies, the tumor-targeting mAb H10 and the anti-HIV mAb 2G12. Both mAbs were produced in plants either as stable transgenics or using a transient expression system based on leaf agroinfiltration. The purified antibodies were separated by 1DE and protein bands were characterized by N-terminal sequencing. The proteolytic cleavage sites identified in the heavy chain (HC) of both antibodies were localized in 3 inter-domain regions, suggesting that the number of proteolytic cleavage events taking place in plants is limited. One of the cleavage sites, close to the hinge region, was common to both antibodies.

  20. Preclinical Evaluation of Raman Nanoparticle Biodistribution for their Potential Use in Clinical Endoscopy Imaging

    DEFF Research Database (Denmark)

    Zavaleta, Cristina L; Hartman, Keith B; Miao, Zheng

    2011-01-01

    intestine (5 h = 10.37% ID g(-1) ; 24 h = 0.42% ID g(-1) ) with minimal uptake in other organs. Raman imaging of excised tissues correlate well with biodistribution data. These results suggest that the topical application of SERS nanoparticles in the mouse colon appears to minimize their systemic...... with endoscopy. The use of an accessory Raman endoscope in conjunction with topically administered tumor-targeting Raman nanoparticles during a routine colonoscopy could offer a new way to sensitively detect dysplastic lesions while circumventing Raman's limited depth of penetration and avoiding systemic...... toxicity. In this study, the natural biodistribution of gold surface-enhanced Raman scattering (SERS) nanoparticles is evaluated by radiolabeling them with (64) Cu and imaging their localization over time using micropositron emission tomography (PET). Mice are injected either intravenously (IV...

  1. Boron Drug Delivery via Encapsulated Magnetic Nanocomposites: A New Approach for BNCT in Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Yinghuai Zhu

    2010-01-01

    Full Text Available Ortho-carborane cages have been successfully attached to modified magnetic nanoparticles via catalytic azide-alkyne cycloadditions between 1-R-2-butyl-Ortho-C2B10H10(R=Me,3;Ph,4 and propargyl group-enriched magnetic nanoparticles. A loading amount of 9.83 mmol boron atom/g starch-matrixed magnetic nanoparticles has been reached. The resulting nanocomposites have been found to be highly tumor-targeted vehicles under the influence of an external magnetic field (1.14T, yielding a high boron concentration of 51.4 μg/g tumor and ratios of around 10 : 1 tumor to normal tissues.

  2. Monte Carlo based dosimetry for neutron capture therapy of brain tumors

    Directory of Open Access Journals (Sweden)

    Zaidi Lilia

    2016-01-01

    Full Text Available Boron Neutron Capture Therapy (BNCT is a biologically targeted, radiation therapy for cancer which combines neutron irradiation with a tumor targeting agent labeled with a boron10 having a high thermal neutron capture cross section. The tumor area is subjected to the neutron irradiation. After a thermal neutron capture, the excited 11B nucleus fissions into an alpha particle and lithium recoil nucleus. The high Linear Energy Transfer (LET emitted particles deposit their energy in a range of about 10μm, which is of the same order of cell diameter [1], at the same time other reactions due to neutron activation with body component are produced. In-phantom measurement of physical dose distribution is very important for BNCT planning validation. Determination of total absorbed dose requires complex calculations which were carried out using the Monte Carlo MCNP code [2].

  3. Synthesis and biological assessment of folate-accepted developer (99m)Tc-DTPA-folate-polymer.

    Science.gov (United States)

    Chen, Fei; Shao, Kejing; Zhu, Bao; Jiang, Mengjun

    2016-05-15

    A novel cancer-targetable folate-poly(2-hydroxyethyl methacrylate) (PFDH) copolymer containing DTPA segment was prepared by conventional chemical synthesis and labeled with (99m)Tc subsequently. The (99m)Tc-labled PFDH could be produced easily with high radiochemical yield of 91% and radiochemical purity of 95%. The LogP octanol-water value for the (99m)Tc-labled PFDH was -2.19 and the radiotracer was stable in phosphate-buffered saline and human serum for 2h (>95% in PBS or ∼90% in human serum). To investigate (99m)Tc-labled PFDH tumor targeting, the in vitro and in vivo stability, cell uptake, in vivo biodistribution, and SPECT imaging were evaluated, respectively. These preliminary results strongly suggest that the novel folate conjugated dendrimer maybe developed to be potential for delivery of therapeutic radionuclides. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Cellular uptake and antitumor activity of DOX-hyd-PEG-FA nanoparticles.

    Directory of Open Access Journals (Sweden)

    Wei-liang Ye

    Full Text Available A PEG-based, folate mediated, active tumor targeting drug delivery system using DOX-hyd-PEG-FA nanoparticles (NPs were prepared. DOX-hyd-PEG-FA NPs showed a significantly faster DOX release in pH 5.0 medium than in pH 7.4 medium. Compared with DOX-hyd-PEG NPs, DOX-hyd-PEG-FA NPs increased the intracellular accumulation of DOX and showed a DOX translocation from lysosomes to nucleus. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was much higher than that of free DOX, DOX-ami-PEG-FA NPs and DOX-hyd-PEG NPs. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was attenuated in the presence of exogenous folic acid. The IC50 of DOX-hyd-PEG-FA NPs and DOX-hyd-PEG NPs on A549 cells showed no significant difference. After DOX-hyd-PEG-FA NPs were intravenously administered, the amount of DOX distributed in tumor tissue was significantly increased, while the amount of DOX distributed in heart was greatly decreased as compared with free DOX. Compared with free DOX, NPs yielded improved survival rate, prolonged life span, delayed tumor growth and reduced the cardiotoxicity in tumor bearing mice model. These results indicated that the acid sensitivity, passive and active tumor targeting abilities were likely to act synergistically to enhance the drug delivery efficiency of DOX-hyd-PEG-FA NPs. Therefore, DOX-hyd-PEG-FA NPs are a promising drug delivery system for targeted cancer therapy.

  5. Production of a tumour-targeting antibody with a human-compatible glycosylation profile in N. benthamiana hairy root cultures.

    Science.gov (United States)

    Lonoce, Chiara; Salem, Reda; Marusic, Carla; Jutras, Philippe V; Scaloni, Andrea; Salzano, Anna Maria; Lucretti, Sergio; Steinkellner, Herta; Benvenuto, Eugenio; Donini, Marcello

    2016-09-01

    Hairy root (HR) cultures derived from Agrobacterium rhizogenes transformation of plant tissues are an advantageous biotechnological manufacturing platform due to the accumulation of recombinant proteins in an otherwise largely protein free culture medium. In this context, HRs descending from transgenic Nicotiana tabacum plants were successfully used for the production of several functional mAbs with plant-type glycans. Here, we expressed the tumor-targeting monoclonal antibody mAb H10 in HRs obtained either by infecting a transgenic N. tabacum line expressing H10 with A. rhizogenes or a glyco-engineered N. benthamiana line (ΔXTFT) with recombinant A. rhizogenes carrying mAb H10 heavy and light chain cDNAs. Selected HR clones derived from both plants accumulated mAb H10 in the culture medium with similar yields (2-3 mg/L). N-glycosylation profiles of antibodies purified from HR supernatant revealed the presence of plant-typical complex structures for N. tabacum-derived mAb H10 and of GnGn structures lacking xylose and fucose for the ΔXTFT-derived counterpart. Both antibody glyco-formats exhibited comparable antigen binding activities. Collectively, these data demonstrate that the co-infection of ΔXTFT Nicotiana benthamiana with recombinant A. rhizogenes is an efficient procedure for the generation of stable HR cultures expressing the tumor-targeting mAb H10 with a human-compatible glycosylation profile, thus representing an important step towards the exploitation of root cultures for the production of 'next generation' human therapeutic antibodies. Copyright © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Novel aspects of application of cadmium telluride quantum dots nanostructures in radiation oncology

    Energy Technology Data Exchange (ETDEWEB)

    Fazaeli, Yousef; Feizi, Shahzad [Nuclear Science and Technology Research Institute (NSTRI), Radiation Application Research School, Karaj (Iran, Islamic Republic of); Zare, Hakimeh; Karimi, Shokufeh [Yazd University, Department of Physics, Yazd (Iran, Islamic Republic of); Rahighi, Reza [Sharif University of Technology, Department of Physics, Tehran (Iran, Islamic Republic of)

    2017-08-15

    In the last two decades, quantum dots nanomaterials have garnered a great deal of scientific interest because of their unique properties. Quantum dots (QDs) are inorganic fluorescent nanocrystals in the size range between 1 and 20 nm. Due to their structural properties, they possess distinctive properties and behave in different way from crystals in macro scale, in many branches of human life. Cadmium telluride quantum dots (CdTe QDs) were labeled with {sup 68}Ga radio nuclide for fast in vivo targeting and coincidence imaging of tumors. Using instant paper chromatography, the physicochemical properties of the Cadmium telluride quantum dots labeled with {sup 68}Ga NPs ({sup 68}Ga rate at CdTe QDs) were found high enough stable in organic phases, e.g., a human serum, to be reliably used in bioapplications. In vivo biodistribution of the {sup 68}Ga rate at CdTe QDs nanoconposite was investigated in rats bearing fibro sarcoma tumor after various post-injection periods of time. The {sup 68}Ga NPs exhibited a rapid as well as high tumor uptake in a very short period of time (less than 10 min), resulting in an efficient tumor targeting/imaging agent. Meantime, the low lipophilicity of the {sup 68}Ga NPs caused to their fast excretion throughout the body by kidneys (as also confirmed by the urinary tract). Because of the short half-life of {sup 68}Ga radionuclide, the {sup 68}Ga rate at CdTe QDs with an excellent tumor targeting/imaging and fast washing out from the body can be suggested as one of the most effective and promising nanomaterials in nanotechnology-based cancer diagnosis and therapy. (orig.)

  7. A novel murine T-cell receptor targeting NY-ESO-1.

    Science.gov (United States)

    Rosati, Shannon F; Parkhurst, Maria R; Hong, Young; Zheng, Zhili; Feldman, Steven A; Rao, Mahadev; Abate-Daga, Daniel; Beard, Rachel E; Xu, Hui; Black, Mary A; Robbins, Paul F; Schrump, David A; Rosenberg, Steven A; Morgan, Richard A

    2014-04-01

    Cancer testis antigens, such as NY-ESO-1, are expressed in a variety of prevalent tumors and represent potential targets for T-cell receptor (TCR) gene therapy. DNA encoding a murine anti-NY-ESO-1 TCR gene (mTCR) was isolated from immunized HLA-A*0201 transgenic mice and inserted into a γ-retroviral vector. Two mTCR vectors were produced and used to transduce human PBL. Transduced cells were cocultured with tumor target cell lines and T2 cells pulsed with the NY-ESO-1 peptide, and assayed for cytokine release and cell lysis activity. The most active TCR construct was selected for production of a master cell bank for clinical use. mTCR-transduced PBL maintained TCR expression in short-term and long-term culture, ranging from 50% to 90% efficiency 7-11 days after stimulation and 46%-82% 10-20 days after restimulation. High levels of interferon-γ secretion were observed (1000-12000 pg/mL), in tumor coculture assays and recognition of peptide-pulsed cells was observed at 0.1 ng/mL, suggesting that the new mTCR had high avidity for antigen recognition. mTCR-transduced T cells also specifically lysed human tumor targets. In all assays, the mTCR was equivalent or better than the comparable human TCR. As the functional activity of TCR-transduced cells may be affected by the formation of mixed dimers, mTCRs, which are less likely to form mixed dimers with endogenous hTCRs, may be more effective in vivo. This new mTCR targeted to NY-ESO-1 represents a novel potential therapeutic option for adoptive cell-transfer therapy for a variety of malignancies.

  8. "Gold nanoparticles composite-folic acid conjugated graphene oxide nanohybrids" for targeted chemo-thermal cancer ablation: In vitro screening and in vivo studies.

    Science.gov (United States)

    Chauhan, Gaurav; Chopra, Vianni; Tyagi, Amit; Rath, Goutam; Sharma, Rakesh K; Goyal, Amit K

    2017-01-01

    Nano-graphene oxide (GO) nanometal composite (specifically nanogold and nanosilver) have shown to be a promising material for anticancer therapeutics. Owing to their high drug loading capacity, photothermal and synergizing effects, it is very important to exploit them for targeted chemo-thermal cancer therapeutics. In this work, gold nanoparticles (AuNPs) were selected as the composite metal, folic acid (FA) was taken as GO surface functionalization moiety for active tumor targeting of model anticancer drug Doxorubicin (Dox). AuNPs composite-folate conjugated graphene oxide (FA-GO@Au) nano-platforms were synthesized and characterized in detail. Near-infrared (NIR) sensitivity resulted in an aggravated release of both Dox and ionic gold from the nanohybrid surface. Simultaneous delivery of Dox and AuNPs in the cellular vicinity was further enhanced after localized NIR exposure which resulted in significantly improved cancer cell toxicity. Mechanistic evaluation revealed G0/G1 phase arrest due to increased DNA intercalation and provoked early apoptosis under NIR influence. Pharmacokinetics and organ distribution studies were carried out in healthy mice and rabbits to estimate the actual bio fate of these nanohybrids. In vivo studies showed substantial tumor regression in solid tumor model in Balb/c mice and NIR exposure induced photo-thermal effects further resulted in better tumor management. Study provides substantial evidences both at in vitro and in vivo level to support the fact that NIR induced local photo-thermal effects can solely be used as a tumor targeting tool. This NIR dependent nanohybrid approach presents a precise and flexible strategy for targeted chemotherapy and photo-thermal tumor ablation. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. [{sup 131}I]FIAU labeling of genetically transduced, tumor-reactive lymphocytes: cell-level dosimetry and dose-dependent toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Zanzonico, Pat [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Koehne, Guenther; Doubrovina, Ekaterina; O' Reilly, Richard J. [Memorial Sloan-Kettering Cancer Center, Allogeneic Transplantation Service, New York, NY (United States); Memorial Sloan-Kettering Cancer Center, Immunology Program, New York, NY (United States); Gallardo, Humilidad F. [Memorial Sloan-Kettering Cancer Center, Gene Transfer and Somatic Cell Engineering Facility, New York, NY (United States); Doubrovin, Mikhail; Blasberg, Ronald G. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York, NY (United States); Finn, Ronald [Memorial Sloan-Kettering Cancer Center, Radiochemistry and Cyclotron Core Facility, New York, NY (United States); Riviere, Isabelle; Sadelain, Michel [Memorial Sloan-Kettering Cancer Center, Immunology Program, New York, NY (United States); Memorial Sloan-Kettering Cancer Center, Gene Transfer and Somatic Cell Engineering Facility, New York, NY (United States); Larson, Steven M. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States)

    2006-09-15

    Donor T cells have been shown to be reactive against and effective in adoptive immunotherapy of Epstein-Barr virus (EBV) lymphomas which develop in some leukemia patients post marrow transplantation. These T cells may be genetically modified by incorporation of a replication-incompetent viral vector (NIT) encoding both an inactive mutant nerve growth factor receptor (LNGFR), as an immunoselectable surface marker, and a herpes simplex virus thymidine kinase (HSV-TK), rendering the cells sensitive to ganciclovir. The current studies are based on the selective HSV-TK-catalyzed trapping (phosphorylation) of the thymidine analog [{sup 131}I]-2'-fluoro-2'-deoxy-1-{beta}-D-arabinofuransyl-5-iodo-uracil (FIAU) as a means of stably labeling such T cells for in vivo trafficking (including tumor targeting) studies. Because of the radiosensitivity of lymphocytes and the potentially high absorbed dose to the nucleus from intracellular {sup 131}I (even at tracer levels), the nucleus absorbed dose (D{sub n}) and dose-dependent immune functionality were evaluated for NIT {sup +} T cells labeled ex vivo in [{sup 131}I ]FIAU-containing medium. Based on in vitro kinetic studies of [{sup 131}I ]FIAU uptake by NIT {sup +} T cells, D{sub n} was calculated using an adaptation of the MIRD formalism and the recently published MIRD cellular S factors. Immune cytotoxicity of [{sup 131}I ]FIAU-labeled cells was assayed against {sup 51}Cr-labeled target cells [B-lymphoblastoid cells (BLCLs) ] in a standard 4-h release assay. At median nuclear absorbed doses up to 830 cGy, a {sup 51}Cr-release assay against BLCLs showed no loss of immune cytotoxicity, thus demonstrating the functional integrity of genetically transduced, tumor-reactive T cells labeled at this dose level for in vivo cell trafficking and tumor targeting studies. (orig.)

  10. Facile Synthesis of Lipid-Perfluorocarbon Nanoemulsion Coated with Silica Shell as an Ultrasound Imaging Agent.

    Science.gov (United States)

    Yang, Qiang; Chen, Huali; Bai, Yan; Cao, Yang; Hu, Wenjing; Zhang, Liangke

    2017-12-21

    A novel organic/inorganic hybrid nanovesicle as an ultrasound imaging agent is synthesized via facile emulsion and silica deposition methods. This nanovesicle, hyaluronate (HA)-docetaxel (DTX)/perfluoro-n-pentane (PFP)@SNC, consists of an encapsulated liquid PFP core, loaded DTX, and an HA-decorated silica shell. The HA-DTX/PFP@SNC has a narrow size distribution of 274.5 ± 3.25 nm, a negative zeta potential of -11.6 ± 0.47 mV, and an entrapment efficiency of 86.70% ± 1.42%. HA-DTX/PFP@SNC possesses an ultrasound (US)-triggered drug release and a temperature-dependent size change behavior. Compared with DTX/PFP@soybean phosphatidylcholine (SPC), which has no silica shell, the HA-DTX/PFP@SNC is more stable under various conditions. The MTT assay indicates that the blank HA-PFP@SNC vehicle has no cytotoxicity to A549 cells. Furthermore, due to the HA-mediated tumor-targeting ability, the HA-DTX/PFP@SNC shows obvious cytotoxicity to A549 cells. In vitro and in vivo US imaging results indicate that HA-DTX/PFP@SNC has a stronger and more durable echo signal than DTX/PFP@SPC. Moreover, the in vivo echo signal of HA-DTX/PFP@SNC is stronger than that of DTX/PFP@SNC due to the HA-mediated tumor targeting. Therefore, this novel organic/inorganic hybrid vesicle is a US contrast agent candidate. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Inhibition of Histone Deacetylation and DNA Methylation Improves Gene Expression Mediated by the Adeno-Associated Virus/Phage in Cancer Cells

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    Amin Hajitou

    2013-10-01

    Full Text Available Bacteriophage (phage, viruses that infect bacteria only, have become promising vectors for targeted systemic delivery of genes to cancer, although, with poor efficiency. We previously designed an improved phage vector by incorporating cis genetic elements of adeno-associated virus (AAV. This novel AAV/phage hybrid (AAVP specifically targeted systemic delivery of therapeutic genes into tumors. To advance the AAVP vector, we recently introduced the stress-inducible Grp78 tumor specific promoter and found that this dual tumor-targeted AAVP provides persistent gene expression, over time, in cancer cells compared to silenced gene expression from the CMV promoter in the parental AAVP. Herein, we investigated the effect of histone deacetylation and DNA methylation on AAVP-mediated gene expression in cancer cells and explored the effect of cell confluence state on AAVP gene expression efficacy. Using a combination of AAVP expressing the GFP reporter gene, flow cytometry, inhibitors of histone deacetylation, and DNA methylation, we have demonstrated that histone deacetylation and DNA methylation are associated with silencing of gene expression from the CMV promoter in the parental AAVP. Importantly, inhibitors of histone deacetylases boost gene expression in cancer cells from the Grp78 promoter in the dual tumor-targeted AAVP. However, cell confluence had no effect on AAVP-guided gene expression. Our findings prove that combination of histone deacetylase inhibitor drugs with the Grp78 promoter is an effective approach to improve AAVP-mediated gene expression in cancer cells and should be considered for AAVP-based clinical cancer gene therapy.

  12. Imaging targeted at tumor with {sup 188}Re-labeled VEGF{sub 189} exon 6-encoded peptide and effects of the transfecting truncated KDR gene in tumor-bearing nude mice

    Energy Technology Data Exchange (ETDEWEB)

    Qin Zhexue; Li Qianwei; Liu Guangyuan; Luo Chaoxue; Xie Ganfeng; Zheng Lei [Department of Nuclear Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Huang Dingde [Department of Nuclear Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China)], E-mail: huangdde@tmmu.edu.cn

    2009-07-15

    Introduction: Planar imaging of {sup 188}Re-labeled vascular endothelial growth factor (VEGF){sub 189} exon 6-encoded peptide (QKRKRKKSRYKS) with single photon emission computed tomography (SPECT) in tumor-bearing nude mice and effects of the transfecting truncated KDR gene on its imaging were investigated, so as to provide a basis for further applying the peptide to tumor-targeted radionuclide treatment. Methods: QKRKRKKSRYKS, coupling with mercaptoacetyltriglycine (MAG{sub 3}) chelator was labeled with {sup 188}Re; then in vivo distribution, planar imaging with SPECT and blocking experiment in tumor-bearing nude mice were analyzed. Recombinant adenovirus vectors carrying the truncated KDR gene were constructed to transfect tumor tissues to evaluate the effects of truncated KDR on the in vivo distribution and tumor planar imaging of {sup 188}Re-MAG{sub 3}-QKRKRKKSRYKS in tumor-bearing nude mice. Results: The labeled peptide exhibited a sound receptor binding activity. Planar imaging with SPECT demonstrated significant radioactivity accumulation in tumor 1 h after injection of the labeled peptide and disappearance of radioactivity 3 h later. Significant radioactivity accumulation was also observed in the liver, intestines and kidneys but was not obvious in other tissues. An hour after injection of the labeled peptide, the percentage of the injected radioactive dose per gram (%ID/g) of tumor and tumor/contralateral muscle tissues ratio were 1.98{+-}0.38 and 2.53{+-}0.33, respectively, and increased to 3.08{+-}0.84 and 3.61{+-}0.59 in the group transfected with the truncated KDR gene, respectively, and radioactivity accumulation in tumor with planar imaging also increased significantly in the transfection group. Conclusion: {sup 188}Re-MAG{sub 3}-QKRKRKKSRYKS can accumulate in tumor tissues, which could be increased by the transfection of truncated KDR gene. This study provides a basis for further applying the peptide to tumor targeted radionuclide imaging and

  13. EXPERIENCE OF SUCCESSFUL ACNEFORM ERUPTIONS TREATMENT IN PATIENT WITH MULTIPLE MELANOMA

    Directory of Open Access Journals (Sweden)

    O. V. Minkina

    2016-01-01

    Full Text Available Objective: to describe the results of the joint monitoring and diversified treatment of oncologists and dermatologists those patient with multiple recurrent melanoma who received over a long period a targeted anti-cancer therapy, which was complicated by side-effect as widespread acneform rush, resistant to traditional treatment. Patient A., born in 1988, was followed up and got a treatment more than 2 years in oncology out-patient clinic diagnosed with “Melanoma of the front surface of the left leg T2bN0M0 IIA”. Subsequently, the patient was verified metastasis in the inginal lymph nodes, in the soft tissues of the hips, to liver. Acute adverse reaction has developed in a short time after getting the anti-tumor target therapy as generalized acneform rush and itching of the skin. Skin symptoms accompanied by pronounced psychological and emotional stress, therefore, dermatologists have been invited to provide additional medical assistance to this patient. Due to the fact that subsequent traditional anti-acne algorithms of topical and oral treatment was not such effective, there was made a decision to use an alternative supporting external therapy, which did not have similar examples of usage previously. Results. External application of tacrolimus ointment in combination with other drugs and then as a mono-therapy, allows us in a rather short period achieve a stable and pronounced regression of skin pathological lesions, to return to the previously cancelled initial drug dose of the anti-tumor target therapy, to change significantly components of the patient’s quality of life. Conclusion. The search for additional and alternative treatment approaches for similar patients, as in our case, remains relevant for specialists and patients themselves. This case is an example of alternative approach to the tacrolimus topical application in patient with drug-mediated acneform rush.

  14. Development of Lu-177-trastuzumab for radioimmunotherapy of HER2 expressing breast cancer and its feasibility assessment in breast cancer patients.

    Science.gov (United States)

    Bhusari, Priya; Vatsa, Rakhee; Singh, Gurpreet; Parmar, Madan; Bal, Amanjit; Dhawan, Devinder K; Mittal, Bhagwant R; Shukla, Jaya

    2017-02-15

    HER2/neu is over expressed in 20-25% of breast cancers. HER2 breast cancers are aggressive and are associated with poor prognosis. The aim of this study was to develop the clinical grade Lu-177-trastuzumab and its preliminary evaluation for specific tumor targeting in HER2 positive breast cancer patients. Trastuzumab was conjugated to bifunctional chelator, DOTA, and characterized for integrity and the number of molecules conjugated. Radiolabeling of DOTA-conjugated trastuzumab was optimized using Lu-177. Quality control parameters including radiochemical purity, stability, sterility, pyrogenicity and immunoreactivity were assessed. A preliminary pilot study was conducted on breast cancer patients (n = 6 HER2 positive and n = 4 HER2 negative) to evaluate the ability of Lu-177-trastuzumab for HER2 specific tumor targeting. The conjugates were efficiently labeled with Lu-177 with high radiochemical purity (up to 91%) and specific activity (6-13 µCi/µg). Lu-177-trastuzumab was stable up to 12 hr post labeling. The radioimmunoassay demonstrated good antigen binding ability and specificity for HER2 receptor protein. The patient studies showed the localization of Lu-177-trastuzumab at primary as well as metastatic sites (HER2 positive) in the planar and SPECT/CT images. No tracer uptake was observed in HER2 negative patients that indicated the specificity of Lu-177-trastuzumab. The study demonstrated that in-house developed Lu-177-trastuzumab has specific targeting ability for HER2 expressing lesions and may in future become a palliative treatment option in the form of targeted radionuclide therapy for disseminated HER2 positive breast cancer. © 2016 UICC.

  15. A Novel Platinum(II)-Based Bifunctional ADC Linker Benchmarked Using 89Zr-Desferal and Auristatin F-Conjugated Trastuzumab.

    Science.gov (United States)

    Sijbrandi, Niels J; Merkul, Eugen; Muns, Joey A; Waalboer, Dennis C J; Adamzek, Kevin; Bolijn, Marije; Montserrat, Veronica; Somsen, Govert W; Haselberg, Rob; Steverink, Paul J G M; Houthoff, Hendrik-Jan; van Dongen, Guus A M S

    2017-01-15

    Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADC). We have shown recently that a fluorescent dye can be stably conjugated to a mAb using a bifunctional platinum(II) linker. Here, we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs. The ethylenediamine platinum(II) moiety, herein called Lx, was coordinated to Desferal (DFO) or auristatin F (AF) to provide storable "semifinal" products, which were directly conjugated to unmodified mAbs. Conjugation resulted in ADCs with unimpaired mAb-binding characteristics, DAR in the range of 2.5 to 2.7 and approximately 85% payload bound to the Fc region, presumably to histidine residues. To evaluate the in vivo stability of Lx and its effect on pharmacokinetics and tumor targeting of an ADC, Lx-DFO was conjugated to the HER2 mAb trastuzumab, followed by radiolabeling with (89)Zr. Trastuzumab-Lx-DFO-(89)Zr was stable in vivo and exhibited pharmacokinetic and tumor-targeting properties similar to parental trastuzumab. In a xenograft mouse model of gastric cancer (NCI-N87) or an ado-trastuzumab emtansine-resistant breast cancer (JIMT-1), a single dose of trastuzumab-Lx-AF outperformed its maleimide benchmark trastuzumab-Mal-AF and FDA-approved ado-trastuzumab emtansine. Overall, our findings show the potential of the Lx technology as a robust conjugation platform for the preparation of anticancer ADCs. Cancer Res; 77(2); 257-67. ©2016 AACR. ©2016 American Association for Cancer Research.

  16. A Novel Method for Assessment of Natural Killer Cell Cytotoxicity Using Image Cytometry.

    Directory of Open Access Journals (Sweden)

    Srinivas S Somanchi

    Full Text Available Natural killer (NK cells belong to the innate arm of the immune system and though activated NK cells can modulate immune responses through the secretion of cytokines, their primary effector function is through target cell lysis. Accordingly, cytotoxicity assays are central to studying NK cell function. The 51Chromium release assay, is the "gold standard" for cytotoxicity assay, however, due to concerns over toxicity associated with the use and disposal of radioactive compounds there is a significant interest in non-radioactive methods. We have previously used the calcein release assay as a non-radioactive alternative for studying NK cell cytotoxicity. In this study, we show that the calcein release assay varies in its dynamic range for different tumor targets, and that the entrapped calcein could remain unreleased within apoptotic bodies of lysed tumor targets or incompletely released resulting in underestimation of percent specific lysis. To overcome these limitations, we developed a novel cytotoxicity assay using the Cellometer Vision Image Cytometer and compared this method to standard calcein release assay for measuring NK cell cytotoxicity. Using tumor lines K562, 721.221, and Jurkat, we demonstrate here that image cytometry shows significantly higher percent specific lysis of the target cells compared to the standard calcein release assay within the same experimental setup. Image cytometry is able to accurately analyze live target cells by excluding dimmer cells and smaller apoptotic bodies from viable target cell counts. The image cytometry-based cytotoxicity assay is a simple, direct and sensitive method and is an appealing option for routine cytotoxicity assay.

  17. Micro-CT Imaging of RGD-Conjugated Gold Nanorods Targeting Tumor In Vivo

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    Xiaochao Qu

    2016-01-01

    Full Text Available Gold nanomaterials as computed tomography (CT contrast agents at lower X-ray dosage to get a higher contrast have advantages of longer imaging time and lower toxic side effects compared to current contrast agents. As a receptor for Cyclo (Arg-Gly-Asp-D-Phe-Lys (RGD peptide, integrin αvβ3 is overexpressed on some tumor cells and tumor neovasculature. In this paper, we conjugated the RGD peptide on the surface of gold nanorods (AuNRs, designated as RGD-AuNRs, a promising candidate in applications such as tumor targeting and imaging capability for micro-CT imaging. Integrin αvβ3-positive U87 cells and integrin αvβ3-negative HT-29 cells were chosen to establish animal models relatedly and then texted the tumor targeting ability and imaging capability of RGD-AuNRs in vitro and in vivo. The MTT assay and stability measurement showed that RGD-conjugation eliminated their cytotoxicity and improved their biocompatibility and stability. Dark-field imaging of U87 cells and HT-29 cells testified the binding affinities and uptake abilities of RGD-AuNRs, and the results showed that RGD-AuNRs were more specifical to U87 cells. The enhanced micro-CT imaging contrast of intramuscular and subcutaneous injection illustrated the feasibility of RGD-AuNRs to be contrast agents. Furthermore, the micro-CT imaging of targeting U87 and HT-29 tumor models verified the targeting abilities of RGD-AuNRs.

  18. Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Qingwen [Shanghai Chest Hospital, Shanghai 200433 (China); State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Jiang, Songmin [State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Han, Baohui [Shanghai Chest Hospital, Shanghai 200433 (China); Sun, Tongwen [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China); Li, Zhengnan; Zhao, Lina; Gao, Qiang [College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457 (China); Sun, Jialin, E-mail: jialin_sun@126.com [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China)

    2012-11-02

    Highlights: Black-Right-Pointing-Pointer We construct and purify a fusion protein VEGF-SEA. Black-Right-Pointing-Pointer VEGF-SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. Black-Right-Pointing-Pointer T cells driven by VEGF-SEA were accumulated around tumor cells bearing VEGFR by mice image model. Black-Right-Pointing-Pointer VEGF-SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. Black-Right-Pointing-Pointer The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF-SEA treated with 15 {mu}g, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4{sup +} and CD8{sup +} T cells driven by VEGF-SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF-SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.

  19. Novel fluorescence nanobubbles for contrast-enhanced ultrasound imaging in rabbit VX2 hepatocellular carcinoma model

    Science.gov (United States)

    Yu, Houqiang; Wang, Wei; He, Xiaoling; Zhou, Qibing; Ding, Mingyue

    2017-03-01

    Ultrasound contrast agents (UCAs) such as SonoVue or Optison have been used widely in clinic for contrast-enhanced vascular imaging. However, microbubbles UCAs display limitations in tumor-targeted imaging due to the large sizes, nanoscaled UCAs has consequently attracted increasing attentions. In this work, we synthesized nanobubbles (NBs) by ultrasonic cavitation method, then a fluorescent marker of Alexa Fluor 680 was conjugated to the shell in order to observe the localization of NBs in tumor tissue. Measurement of fundamental characteristics showed that the NBs had homogeneous distribution of mean diameter of 267.9 +/- 19.2 nm and polydispersity index of 0.410 +/- 0.056. To assess in vivo tumor-selectivity of NBs, we established the rabbits VX2 hepatocellular carcinoma model though surgical implantation method. After the rabbits were intravenous administered of NBs, contrast-enhanced sonograms was observed in the surrounding of VX2 tumor, which showed there are rich capillaries in the tumor periphery. We additionally investigated the toxic of the NBs by hematoxylin-eosin staining. The results indicated that the NBs is a biocompatible non-toxic lipid system. Furthermore, the VX2 tumors and major organs were analyzed using ex vivo fluorescence imaging to confirm the targeted selectivity of NBs, and the results verified that the NBs were capable of targeting VX2 tumor. Confocal laser scanning microscopy examination showed that the NBs can traverse the VX2 tumor capillaries and target to the hepatocellular carcinoma tumor cells. All these results suggested that the newly prepared NBs have a potential application in molecular imaging and tumor-targeting therapy.

  20. Synthesis, characterization and theranostic evaluation of Indium-111 labeled multifunctional superparamagnetic iron oxide nanoparticles.

    Science.gov (United States)

    Zolata, Hamidreza; Abbasi Davani, Fereydoun; Afarideh, Hossein

    2015-02-01

    Indium-111 labeled, Trastuzumab-Doxorubicin Conjugated, and APTES-PEG coated magnetic nanoparticles were designed for tumor targeting, drug delivery, controlled drug release, and dual-modal tumor imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized by thermal decomposition method to obtain narrow size particles. To increase SPIONs circulation time in blood and decrease its cytotoxicity in healthy tissues, SPIONs surface was modified with 3-Aminopropyltriethoxy Silane (APTES) and then were functionalized with N-Hydroxysuccinimide (NHS) ester of Polyethylene Glycol Maleimide (NHS-PEG-Mal) to conjugate with thiolated 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA) bifunctional chelator (BFC) and Trastuzumab antibody. In order to tumor SPECT/MR imaging, SPIONs were labeled with Indium-111 (T1/2=2.80d). NHS ester of monoethyl malonate (MEM-NHS) was used for conjugation of Doxorubicin (DOX) chemotherapeutic agent onto SPIONs surface. Mono-Ethyl Malonate allows DOX molecules to be attached to SPIONs via pH-sensitive hydrazone bonds which lead to controlled drug release in tumor region. Active and passive tumor targeting were achieved through incorporated anti-HER2 (Trastuzumab) antibody and EPR effect of solid tumors for nanoparticles respectively. In addition to in vitro assessments of modified SPIONs in SKBR3 cell lines, their theranostic effects were evaluated in HER2 + breast tumor bearing BALB/c mice via biodistribution study, dual-modal molecular imaging and tumor diameter measurements. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine

    Directory of Open Access Journals (Sweden)

    Ahnert-Hilger Gudrun

    2004-05-01

    Full Text Available Abstract Background Therapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG and interferon-γ (IFNγ cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNγ and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells. Methods and results IFNγ receptors were expressed in both models. IFNγ dose- and time-dependently inhibited the growth of both STC-1 and of BON tumor cells with IC50-values of 95 ± 15 U/ml and 135 ± 10 U/ml, respectively. Above 10 U/ml IFNγ induced apoptosis-specific caspase-3 activity in a time-dependent manner in either cell line and caused a dose-dependent arrest in the S-phase of the cell cycle. Furthermore, IFNγ induced cytotoxic effects in NE tumor cells. The NE tumor-targeted drug MIBG is selectively taken up via norepinephrine transporters, thereby specifically inhibiting growth in NE tumor cells. Intriguingly, IFNγ treatment induced an upregulation of norepinephrine transporter expression in neuroendocrine tumors cells, as determined by semi-quantitative RT-PCR. Co-application of sub-IC50 concentrations of IFNγ and MIBG led to additive growth inhibitory effects, which were mainly due to increased cytotoxicity and S-phase arrest of the cell cycle. Conclusion Our data show that IFNγ exerts antiproliferative effects on neuroendocrine gastrointestinal tumor cells by inducing cell cycle arrest, apoptosis and cytotoxicity. The combination of IFNγ with the NE tumor-targeted agent MIBG leads to effective growth control at reduced doses of either drug. Thus, the administration of IFNγ alone and more so, in combination with MIBG, is a promising novel approach in the treatment of neuroendocrine gastrointestinal tumors.

  2. Construction of magnetic-carbon-quantum-dots-probe-labeled apoferritin nanocages for bioimaging and targeted therapy.

    Science.gov (United States)

    Yao, Hanchun; Su, Li; Zeng, Man; Cao, Li; Zhao, Weiwei; Chen, Chengqun; Du, Bin; Zhou, Jie

    Carbon dots (CDs) are one of the most highlighted carbon-based materials for biological applications, such as optical imaging nanoprobes, which are used for labeling cells in cancer treatment mainly due to their biocompatibility and unique optical properties. In this study, gadolinium (Gd)-complex-containing CDs were obtained through a one-step microwave method to develop multimodal nanoprobes integrating the advantages of optical and magnetic imaging. The obtained Gd-CDs exhibited highly fluorescent properties with excellent water solubility and biological compatibility. Natural apoferritin (AFn) nanocages, an excellent drug delivery carrier, are hollow in structure, with their pH-dependent, unfolding-refolding process at pH 2.0 and 7.4. The chemotherapeutic drug doxorubicin (DOX) can be highly effective and encapsulated into AFn cavity. A widely used tumor-targeting molecule, folic acid (FA), functionalized the surface of AFn to obtain an active tumor targeting effect on MCF-7 cells and malignant tumors in mice models. In this study, an AFn nanocarrier encapsulating high concentration of DOX labeled with magnetic and fluorescent Gd-CDs probe was developed. Gd-CDs exhibited a unique green photoluminescence and almost no toxicity compared with free GdCl3. Furthermore, Gd-doped CDs significantly increased the circulation time and decreased the toxicity of Gd(3+) in in vitro and in vivo magnetic resonance imaging, which demonstrated that the AFn nanocages labeled with Gd-CD compounds could serve as an excellent T1 contrast agent for magnetic resonance imaging. The self-assembling multifunctional Gd-CDs/AFn (DOX)/FA nanoparticles have a great potential for cancer theranostic applications.

  3. Novel aspects of application of cadmium telluride quantum dots nanostructures in radiation oncology

    Science.gov (United States)

    Fazaeli, Yousef; Zare, Hakimeh; Karimi, Shokufeh; Rahighi, Reza; Feizi, Shahzad

    2017-08-01

    In the last two decades, quantum dots nanomaterials have garnered a great deal of scientific interest because of their unique properties. Quantum dots (QDs) are inorganic fluorescent nanocrystals in the size range between 1 and 20 nm. Due to their structural properties, they possess distinctive properties and behave in different way from crystals in macro scale, in many branches of human life. Cadmium telluride quantum dots (CdTe QDs) were labeled with 68Ga radio nuclide for fast in vivo targeting and coincidence imaging of tumors. Using instant paper chromatography, the physicochemical properties of the Cadmium telluride quantum dots labeled with 68Ga NPs (68Ga@ CdTe QDs) were found high enough stable in organic phases, e.g., a human serum, to be reliably used in bioapplications. In vivo biodistribution of the 68Ga@ CdTe QDs nanoconposite was investigated in rats bearing fibro sarcoma tumor after various post-injection periods of time. The 68Ga NPs exhibited a rapid as well as high tumor uptake in a very short period of time (less than 10 min), resulting in an efficient tumor targeting/imaging agent. Meantime, the low lipophilicity of the 68Ga NPs caused to their fast excretion throughout the body by kidneys (as also confirmed by the urinary tract). Because of the short half-life of 68Ga radionuclide, the 68Ga@ CdTe QDs with an excellent tumor targeting/imaging and fast washing out from the body can be suggested as one of the most effective and promising nanomaterials in nanotechnology-based cancer diagnosis and therapy.

  4. Preparation and In Vitro Evaluation of Antitumor Activity of TGFαL3-SEB as a Ligand-Targeted Superantigen.

    Science.gov (United States)

    Yousefi, Forough; Mousavi, Seyed Fazlollah; Siadat, Seyed Davar; Aslani, Mohammad Mehdi; Amani, Jafar; Rad, Hamid Sedighian; Fooladi, Abbas Ali Imani

    2016-04-01

    Tumor-targeted superantigens (TTSs) have been used to treat a variety of tumors in preclinical studies. The TTS utilizes the powerful T-cell activation strategy by means of staphylococcal enterotoxins (SEs) as superantigens (Sags) to target tumor cells. Monoclonal antibodies and tumor-related ligands have been used as targeting molecules of Sag. In this study, we assessed the antitumor potency of tumor-targeted superantigen (TTS) strategy to design and produce fusion protein as a new antitumor candidate. The third loop (L3) of transforming growth factor α (TGF-α) was genetically conjugated to staphylococcal enterotoxin type B (TGFαL3-SEB), and its in vitro antitumor activity against murine breast cancer cells (A431 cell line) was evaluated. We designed and prepared TGFαL3-SEB chimeric protein and evaluated superantigenic activity, binding property to cancer cells, overexpression of epidermal growth factor receptor (EGFR), and in vitro antitumor activities. Cloning of tgfαl3-seb was confirmed by colony-polymerase chain reaction, enzymatic digestion, and sequencing. The recombinant TGFαL3-SEB fusion protein with molecular weight of 31 kDa was expressed and confirmed by anti-His Western-blot analysis. The TGFαL3-SEB fusion protein attached to A431 cell line with proper affinity and induced dose-dependent cytotoxicity against EGFR-expressing cancer cells in vitro. The TGFαL3-SEB chimeric protein exhibited potent in vitro antitumor activity. Our findings indicated that TGFαL3-SEB may be a promising anticancer candidate in cancer immunotherapy, and further studies are required to explore its potential in vivo therapeutic applications. © The Author(s) 2015.

  5. Integrin-mediated targeting of protein polymer nanoparticles carrying a cytostatic macrolide

    Science.gov (United States)

    Shi, Pu

    chapter illustrates how to tune the ELP sequence and architecture for either coassembly or sorting of distinct proteins into microdomains within a living cell. Passive tumor targeting utilizing enhanced permeability and retention (EPR) effect has limited efficiency in targeting non-leaky tumors such as MDA-MB-468 breast tumor; however, an RGD tri-peptide decorated micelle nanoparticle can effectively accumulate in tumor site via integrin-mediated active tumor targeting. Different from inefficient and cytotoxic chemical linkage reactions, an elastin-based multi-functional nanocarrier can be assembled by genetic protein fusion and micelle co-assembly technology. The novel drug carrier contains the cognate Rapamycin (Rapa) receptor -- FK506 binding protein (FKBP) as the high-avidity drug binding domain and an RGD peptide as the active tumor targeting domain. Here we show that by co-assembling FKBP and RGD contained protein polymers into mixed micelle nanoparticles, they not only competently targeted endothelial and tumor cells in cell assays, but specifically delivered the drug with a slow release half-life of 38h. It was demonstrated that the active tumor targeting formulation of Rapa more effectively suppressed tumor growth compared to the passive tumor targeting formulation and free drug in tumor regression studies of mouse MDA-MB-468 xenografts. We believe that the exciting results will provide a new tool for the development of next-generation "smart" multi-functional drug carriers. (Abstract shortened by UMI.).

  6. Optical molecular imaging-guided radiation therapy part 2: Integrated x-ray and fluorescence molecular tomography.

    Science.gov (United States)

    Shi, Junwei; Udayakumar, Thirupandiyur S; Wang, Zhiqun; Dogan, Nesrin; Pollack, Alan; Yang, Yidong

    2017-09-01

    Differentiating tumor from its surrounding soft tissues is challenging for x-ray computed tomography (CT). Fluorescence molecular tomography (FMT) can directly localize the internal tumors targeted with specific fluorescent probes. A FMT system was developed and integrated onto a CT-guided irradiator to improve tumor localization for image-guided radiation. The FMT system was aligned orthogonal to the cone-beam CT onboard our previously developed image-guided small animal arc radiation treatment system (iSMAART). Through rigorous physical registration, the onboard CT provides accurate surface contour which is used to generate three-dimensional mesh for FMT reconstruction. During FMT experiments, a point laser source perpendicular to the rotating axis was used to excite the internal fluorophores. The normalized optical images from multiple projection angles were adopted for tomographic reconstruction. To investigate the accuracy of the FMT in locating the tumor and recovering its volume, in vivo experiments were conducted on two breast cancer models: MDA-MB-231 cancer xenograft on nude mice and 4T1 cancer xenograft on white mice. Both cancer cell lines overexpress the epidermal growth factor receptor (EGFR). A novel fluorescent poly(lactic-co-glycolic) acid (PLGA) nanoparticle conjugated with anti-EGFR was intravenously injected to specifically target the breast cancer cells. Another ex vivo experiment on a mouse bearing a surgically implanted Indocyanine Green-containing glass tube was conducted, to additionally validate the precision of FMT-guided radiation therapy. The FMT can accurately localize the single-nodule breast tumors actively targeted with fluorescent nanoparticles with localization error FMT and CT. The reconstructed tumor volume in FMT was significantly correlated with that in the iodinated contrast-enhanced CT (R2 = 0.94, P FMT was able to guide focal radiation delivery with submillimeter accuracy. Using the tumor-targeting fluorescent probes, the i

  7. Ligand-targeted theranostic nanomedicines against cancer.

    Science.gov (United States)

    Yao, Virginia J; D'Angelo, Sara; Butler, Kimberly S; Theron, Christophe; Smith, Tracey L; Marchiò, Serena; Gelovani, Juri G; Sidman, Richard L; Dobroff, Andrey S; Brinker, C Jeffrey; Bradbury, Andrew R M; Arap, Wadih; Pasqualini, Renata

    2016-10-28

    Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human sc

  8. Near infrared light-actuated gold nanorods with cisplatin-polypeptide wrapping for targeted therapy of triple negative breast cancer

    Science.gov (United States)

    Feng, Bing; Xu, Zhiai; Zhou, Fangyuan; Yu, Haijun; Sun, Qianqian; Wang, Dangge; Tang, Zhaohui; Yu, Haiyang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2015-09-01

    Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR) laser illumination, the resulting FA-GNR@Pt hybrid nanoparticles are able to significantly inhibit the growth of the TNBC tumor when administered systemically. In particular, they can extensively suppress the dissemination of TNBC cells from the primary tumor to the lung by eliminating the peripheral tumor blood vessels. Collectively, our studies demonstrate that the combined PT therapy and chemotherapy using cisplatin-loaded GNRs with FA conjugation might imply a promising strategy for targeted treatment of TNBC.Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR

  9. Imaging cancer using PET--the effect of the bifunctional chelator on the biodistribution of a (64)Cu-labeled antibody.

    Science.gov (United States)

    Dearling, Jason L J; Voss, Stephan D; Dunning, Patricia; Snay, Erin; Fahey, Frederic; Smith, Suzanne V; Huston, James S; Meares, Claude F; Treves, S Ted; Packard, Alan B

    2011-01-01

    Use of copper radioisotopes in antibody radiolabeling is challenged by reported loss of the radionuclide from the bifunctional chelator used to label the protein. The objective of this study was to investigate the relationship between the thermodynamic stability of the (64)Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with (64)Cu using these chelators in tumor-bearing mice. The chelators [S-2-(aminobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH(2)-Bn-NOTA): 6-[p-(bromoacetamido)benzyl]-1, 4, 8, 11-tetraazacyclotetradecane-N, N', N'', N'''-tetraacetic acid (BAT-6): S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododocane tetraacetic acid (p-NH(2)-Bn-DOTA): 1,4,7,10-tetraazacyclododocane-N, N', N", N"'-tetraacetic acid (DOTA): and 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine (SarAr)] were conjugated to the anti-GD2 antibody ch14.18, and the modified antibody was labeled with (64)Cu and injected into mice bearing subcutaneous human melanoma tumors (M21) (n = 3-5 for each study). Biodistribution data were obtained from positron emission tomography images acquired at 1, 24 and 48 hours post-injection, and at 48 hours post-injection a full ex vivo biodistribution study was carried out. The biodistribution, including tumor targeting, was similar for all the radioimmunoconjugates. At 48 h post-injection, the only statistically significant differences in radionuclide uptake (p < 0.05) were between blood, liver, spleen and kidney. For example, liver uptake of [(64)Cu]ch14.18-p-NH(2)-Bn-NOTA was 4.74 ± 0.77 per cent of the injected dose per gram of tissue (%ID/g), and for [(64)Cu]ch14.18-SarAr was 8.06 ± 0.77 %ID/g. Differences in tumor targeting correlated with variations in tumor size rather than which BFC was used. The results of this study indicate that differences in the thermodynamic stability of these chelator-Cu(II) complexes were not associated with significant

  10. Improvement of the Targeting of Radiolabeled and Functionalized Liposomes with a Two-Step System Using a Bispecific Monoclonal Antibody (Anti-CEA × Anti-DTPA–In

    Directory of Open Access Journals (Sweden)

    Aurore eRauscher

    2015-11-01

    Full Text Available This study proposes liposomes as a new tool for pretargeted radioimmunotherapy (RIT in solid tumors. Tumor pretargeting is obtained by using a bispecific monoclonal antibody (BsmAb, anti-CEA x anti-DTPA-In and pegylated radioactive liposomes containing a lipid-hapten conjugate (DSPE-PEG-DTPA-In. In this work, the immunospecificity of tumor targeting is demonstrated both in vitro by fluorescence microscopy and in vivo by biodistribution studies.Methods: Carcinoembryonic antigen (CEA-expressing cells (LS174T were used either in cell culture or as xenografts in nude mice. Doubly fluorescent liposomes or doubly radiolabeled liposomes were respectively used for in vitro and in vivo studies. In each case, a tracer of the lipid bilayer (rhodamine or indium-111 (111In and a tracer of the aqueous phase (fluorescein or iodine-125 (125I were present. The targeting of liposomes was assessed with BsmAb for active targeting or without for passive targeting.Results: Data obtained with the lipid bilayer tracer showed a fluorescent signal on cell membranes two to three times higher for active than for passive targeting. This immunospecificity was confirmed in vivo with tumor uptake of 7.5 ± 2.4 % ID/g (percentage of injected dose per gram of tissue for active targeting versus 4.5 ± 0.45 % ID/g for passive targeting (p = 0.03. Regarding the aqueous phase tracer, results are slightly more contrasted. In vitro, the fluorescent tracer seems to be released in the extracellular matrix, which can be correlated with the in vivo data. Indeed, the tumor uptake of 125I is lower than that of 111In: 5.1 ± 2.5 % ID/g for active targeting and 2.7 ± 0.6 % ID/g for passive targeting, but resulted in more favorable tumor/organs ratios.Conclusion: This work demonstrated the tumor targeting immunospecificity of DSPE-PEG-DTPA-In liposomes by two different methods. This original and new approach suggests the potential of immunospecific targeting liposomes for the RIT of solid

  11. Design, Synthesis, and Evaluation of Near Infrared Fluorescent Multimeric RGD Peptides for Targeting Tumors

    Science.gov (United States)

    Ye, Yunpeng; Bloch, Sharon; Xu, Baogang; Achilefu, Samuel

    2008-01-01

    Molecular interactions between RGD peptides and integrins are known to mediate many biological and pathological processes. This has led to an increased interest in the development of RGD compounds with high affinity and improved selectivity for integrin receptors. In this study, we synthesized and evaluated a series of multimeric RGD compounds constructed on a dicarboxylic acid-containing near infrared (NIR) fluorescent dye (cypate) for tumor targeting. An array of NIR fluorescent RGD compounds were prepared efficiently, including an RGD monomer (cypate-(RGD)2-NH2), two RGD dimers (cypate-(RGD)2-NH2 and cypate-(RGD-NH2)2), a trimer (cypate-(RGD)3-NH2), two tetramers (cypate-(RGD)4-NH2 and cypate-[(RGD)2-NH2]2), a hexamer (cypate-[(RGD)3-NH2]2), and an octamer (cypate-[(RGD)4-NH2]2). The binding affinity of the multimeric RGD compounds for αvβ3 integrin receptor (ABIR) showed a remarkable increase relative to the monomer cypate-RGD-NH2. Generally, the divalent linear arrays of the multimeric RGD units bound the ABIR with slightly higher affinity than their monovalent analogues. These results suggest that the receptor binding affinity was not only dependent on the number of RGD moieties but also on the spatial alignments of the pendant peptides. Internalization of the compounds by ABIR-positive tumor cells (A549) was monitored by NIR fluorescence microscopy. The data showed that endocytosis of the octameric RGD derivative was significantly higher by comparison to other compounds in this study. In vivo noninvasive optical imaging and biodistribution data showed that the compounds were retained in A549 tumor tissue. These results clearly demonstrated that an array of simple RGD tripeptides on a NIR fluorescent dye core can be recognized by ABIR. Optimization of the spatial alignment of the RGD moieties through careful molecular design and library construction could induce multivalent ligand-receptor interactions useful for in vivo tumor imaging and tumor-targeted

  12. Dendritic cells fused with different pancreatic carcinoma cells induce different T-cell responses

    Directory of Open Access Journals (Sweden)

    Andoh Y

    2013-01-01

    Full Text Available Yoshiaki Andoh,1,2 Naohiko Makino,2 Mitsunori Yamakawa11Department of Pathological Diagnostics, 2Department of Gastroenterology, Yamagata University School of Medicine, Yamagata, JapanBackground: It is unclear whether there are any differences in the induction of cytotoxic T lymphocytes (CTL and CD4+CD25high regulatory T-cells (Tregs among dendritic cells (DCs fused with different pancreatic carcinomas. The aim of this study was to compare the ability to induce cytotoxicity by human DCs fused with different human pancreatic carcinoma cell lines and to elucidate the causes of variable cytotoxicity among cell lines.Methods: Monocyte-derived DCs, which were generated from peripheral blood mononuclear cells (PBMCs, were fused with carcinoma cells such as Panc-1, KP-1NL, QGP-1, and KP-3L. The induction of CTL and Tregs, and cytokine profile of PBMCs stimulated by fused DCs were evaluated.Results: The cytotoxicity against tumor targets induced by PBMCs cocultured with DCs fused with QGP-1 (DC/QGP-1 was very low, even though PBMCs cocultured with DCs fused with other cell lines induced significant cytotoxicity against the respective tumor target. The factors causing this low cytotoxicity were subsequently investigated. DC/QGP-1 induced a significant expansion of Tregs in cocultured PBMCs compared with DC/KP-3L. The level of interleukin-10 secreted in the supernatants of PBMCs cocultured with DC/QGP-1 was increased significantly compared with that in DC/KP-3L. Downregulation of major histocompatibility complex class I expression and increased secretion of vascular endothelial growth factor were observed with QGP-1, as well as in the other cell lines.Conclusion: The present study demonstrated that the cytotoxicity induced by DCs fused with pancreatic cancer cell lines was different between each cell line, and that the reduced cytotoxicity of DC/QGP-1 might be related to the increased secretion of interleukin-10 and the extensive induction of Tregs

  13. In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors

    Directory of Open Access Journals (Sweden)

    Ding Y

    2017-10-01

    Full Text Available Yuan Ding,1,* Wei Cui,2,* Dan Sun,1 Gui-Ling Wang,1 Yu Hei,1 Shuai Meng,1 Jian-Hua Chen,3 Ying Xie,1 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, 2School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 3School of Medicine, Jianghan University, Wuhan, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: In vivo evaluation of drug delivery vectors is essential for clinical translation. In BALB/c nude mice bearing human breast cancer tumors, we investigated the biocompatibility, pharmacokinetics, and pharmacodynamics of doxorubicin (DOX-loaded novel cell-penetrating peptide (CPP-modified pH-sensitive liposomes (CPPL (referred to as CPPL(DOX with an optimal CPP density of 4%. In CPPL, a polyethylene glycol (PEG derivative formed by conjugating PEG with stearate via acid-degradable hydrazone bond (PEG2000-Hz-stearate was inserted into the surface of liposomes, and CPP was directly attached to liposome surfaces via coupling with stearate to simultaneously achieve long circulation time in blood and improve the selectivity and efficacy of CPP for tumor targeting. Compared to PEGylated liposomes, CPPL enhanced DOX accumulation in tumors up to 1.9-fold (p<0.01 and resulted in more cell apoptosis as a result of DNA disruption as well as a relatively lower tumor growth ratio (T/C%. Histological examination did not show any signs of necrosis or inflammation in normal tissues, but large cell dissolving areas were found in tumors following the treatment of animals with CPPL(DOX. Our findings provide important and detailed information regarding the distribution of CPPL(DOX in vivo and reveal their abilities of tumor penetration and potential for the treatment of

  14. In vivo SPECT imaging of tumors by {sup 198,199}Au-labeled graphene oxide nanostructures

    Energy Technology Data Exchange (ETDEWEB)

    Fazaeli, Yousef [Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School, Nuclear Science and Technology Research Institute (NSTRI), P.O. Box 31485-498, Karaj (Iran, Islamic Republic of); Akhavan, Omid, E-mail: oakhavan@sharif.edu [Department of Physics, Sharif University of Technology (SUT), P.O. Box 11155-9161, Tehran (Iran, Islamic Republic of); Institute for Nanoscience and Nanotechnology, Sharif University of Technology (SUT), P.O. Box 14588-89694, Tehran (Iran, Islamic Republic of); Rahighi, Reza [Department of Physics, Sharif University of Technology (SUT), P.O. Box 11155-9161, Tehran (Iran, Islamic Republic of); Aboudzadeh, Mohammad Reza; Karimi, Elham; Afarideh, Hossein [Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School, Nuclear Science and Technology Research Institute (NSTRI), P.O. Box 31485-498, Karaj (Iran, Islamic Republic of)

    2014-12-01

    Graphene oxide (GO) sheets functionalized by aminopropylsilyl groups (8.0 wt.%) were labeled by {sup 198,199}Au nanoparticle radioisotopes (obtained through reduction of HAuCl{sub 4} in sodium citrate solution followed by thermal neutron irradiation) for fast in vivo targeting and SPECT imaging (high purity germanium-spectrometry) of tumors. Using instant thin layer chromatography method, the physicochemical properties of the amino-functionalized GO sheets labeled by {sup 198,199}Au NPs ({sup 198,199}Au@AF-GO) were found to be highly stable enough in organic phases, e.g. a human serum, to be reliably used in bioapplications. In vivo biodistribution of the {sup 198,199}Au@AF-GO composite was investigated in rats bearing fibrosarcoma tumor after various post-injection periods of time. The {sup 198,199}Au@AF-GO nanostructure exhibited a rapid as well as high tumor uptake (with uptake ratio of tumor to muscle of 167 after 4 h intravenous injection) that resulted in an efficient tumor targeting/imaging. Meantime, the low lipophilicity of the {sup 198,199}Au@AF-GO caused to its fast excretion (∼ 24 h) throughout the body by the kidneys (as also confirmed by the urinary tract). Because of the short half-life of {sup 198,199}Au radioisotopes, the {sup 198,199}Au@AF-GO with an excellent tumor targeting/imaging and fast washing out from the body can be suggested as one of the most effective and promising nanomaterials in nanotechnology-based cancer diagnosis and therapy. - Graphical abstract: Amino-functionalized graphene oxide sheets were labeled with radioactive gold nanoparticles as effective SPECT imaging and therapeutic agents. - Highlights: • GO sheets were functionalized by amino groups and labeled by Au NP radioisotopes. • Au@AF-GO nanocomposites were used for in vivo targeting and SPECT imaging of tumors. • In vivo biodistribution study showed high tumor uptake of the nanocomposites. • Low lipophilicity of the nanocomposite caused its fast excretion

  15. Hybrid MV-kV 3D respiratory motion tracking during radiation therapy with low imaging dose

    Science.gov (United States)

    Yan, Huagang; Li, Haiyun; Liu, Zhixiang; Nath, Ravinder; Liu, Wu

    2012-12-01

    A novel real-time adaptive MV-kV imaging framework for image-guided radiation therapy is developed to reduce the thoracic and abdominal tumor targeting uncertainty caused by respiration-induced intrafraction motion with ultra-low patient imaging dose. In our method, continuous stereoscopic MV-kV imaging is used at the beginning of a radiation therapy delivery for several seconds to measure the implanted marker positions. After this stereoscopic imaging period, the kV imager is switched off except for the times when no fiducial marker is detected in the cine-MV images. The 3D time-varying marker positions are estimated by combining the MV 2D projection data and the motion correlations between directional components of marker motion established from the stereoscopic imaging period and updated afterwards; in particular, the most likely position is assumed to be the position on the projection line that has the shortest distance to the first principal component line segment constructed from previous trajectory points. An adaptive windowed auto-regressive prediction is utilized to predict the marker position a short time later (310 ms and 460 ms in this study) to allow for tracking system latency. To demonstrate the feasibility and evaluate the accuracy of the proposed method, computer simulations were performed for both arc and fixed-gantry deliveries using 66 h of retrospective tumor motion data from 42 patients treated for thoracic or abdominal cancers. The simulations reveal that using our hybrid approach, a smaller than 1.2 mm or 1.5 mm root-mean-square tracking error can be achieved at a system latency of 310 ms or 460 ms, respectively. Because the kV imaging is only used for a short period of time in our method, extra patient imaging dose can be reduced by an order of magnitude compared to continuous MV-kV imaging, while the clinical tumor targeting accuracy for thoracic or abdominal cancers is maintained. Furthermore, no additional hardware is required with the

  16. Comparison of biological properties of 99mTc-labeled cyclic RGD Peptide trimer and dimer useful as SPECT radiotracers for tumor imaging.

    Science.gov (United States)

    Zhao, Zuo-Quan; Yang, Yong; Fang, Wei; Liu, Shuang

    2016-11-01

    This study sought to evaluate a 99mTc-labeled trimeric cyclic RGD peptide (99mTc-4P-RGD3) as the new radiotracer for tumor imaging. The objective was to compare its biological properties with those of 99mTc-3P-RGD2 in the same animal model. HYNIC-4P-RGD3 was prepared by reacting 4P-RGD3 with excess HYNIC-OSu in the presence of diisopropylethylamine. 99mTc-4P-RGD3 was prepared using a kit formulation, and evaluated for its tumor-targeting capability and biodistribution properties in the BALB/c nude mice with U87MG human glioma xenografts. Planar and SPECT imaging studies were performed in athymic nude mice with U87MG glioma xenografts. For comparison purpose, 99mTc-3P-RGD2 (a αvβ3-targeted radiotracer currently under clinical evaluation for tumor imaging in cancer patients) was also evaluated in the same animal models. Blocking experiments were used to demonstrate the αvβ3 specificity of 99mTc-4P-RGD3. 99mTc-4P-RGD3 was prepared with >95% RCP and high specific activity (~200GBq/μmol). 99mTc-4P-RGD3 and 99mTc-3P-RGD2 shared almost identical tumor uptake and similar biodistribution properties. 99mTc-4P-RGD3 had higher uptake than 99mTc-3P-RGD2 in the intestines and kidneys; but it showed better metabolic stability. The U87MG tumors were clearly visualized by SPECT with excellent contrast with 99mTc-4P-RGD3 and 99mTc-3P-RGD2. Increasing peptide multiplicity from 3P-RGD2 to 4P-RGD3 offers no advantages with respect to the tumor-targeting capability. 99mTc-4P-RGD3 is as good a SPECT radiotracer as 99mTc-3P-RGD2 for imaging αvβ3-positive tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma.

    Science.gov (United States)

    Keyaerts, Marleen; Xavier, Catarina; Heemskerk, Johannes; Devoogdt, Nick; Everaert, Hendrik; Ackaert, Chloé; Vanhoeij, Marian; Duhoux, Francois P; Gevaert, Thierry; Simon, Philippe; Schallier, Denis; Fontaine, Christel; Vaneycken, Ilse; Vanhove, Christian; De Greve, Jacques; Lamote, Jan; Caveliers, Vicky; Lahoutte, Tony

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2) status is one of the major tumor characteristics in breast cancer to guide therapy. Anti-HER2 treatment has clear survival advantages in HER2-positive breast carcinoma patients. Heterogeneity in HER2 expression between primary tumor and metastasis has repeatedly been described, resulting in the need to reassess HER2 status during the disease course. To avoid repeated biopsy with potential bias due to tumor heterogeneity, Nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies, which are derived from unique heavy-chain-only antibodies, are the smallest antigen-binding antibody fragments and have ideal characteristics for PET imaging. The primary aims were assessment of safety, biodistribution, and dosimetry. The secondary aim was to investigate tumor-targeting potential. In total, 20 women with primary or metastatic breast carcinoma (score of 2+ or 3+ on HER2 immunohistochemical assessment) were included. Anti-HER2-Nanobody was labeled with (68)Ga via a NOTA derivative. Administered activities were 53-174 MBq (average, 107 MBq). PET/CT scans for dosimetry assessment were obtained at 10, 60, and 90 min after administration. Physical evaluation and blood analysis were performed for safety evaluation. Biodistribution was analyzed for 11 organs using MIM software; dosimetry was assessed using OLINDA/EXM. Tumor-targeting potential was assessed in primary and metastatic lesions. No adverse reactions occurred. A fast blood clearance was observed, with only 10% of injected activity remaining in the blood at 1 h after injection. Uptake was seen mainly in the kidneys, liver, and intestines. The effective dose was 0.043 mSv/MBq, resulting in an average of 4.6 mSv per patient. The critical organ was the urinary bladder wall, with a dose of 0.406 mGy/MBq. In patients with metastatic disease, tracer accumulation well above the background level was demonstrated in most identified sites of

  18. Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines

    Science.gov (United States)

    Klein, Christian; Waldhauer, Inja; Nicolini, Valeria G.; Freimoser-Grundschober, Anne; Nayak, Tapan; Vugts, Danielle J.; Dunn, Claire; Bolijn, Marije; Benz, Jörg; Stihle, Martine; Lang, Sabine; Roemmele, Michaele; Hofer, Thomas; van Puijenbroek, Erwin; Moser, Samuel; Ast, Oliver; Brünker, Peter; Gorr, Ingo H.; Neumann, Sebastian; Hinton, Heather; Crameri, Flavio; Gerdes, Christian; Bacac, Marina; van Dongen, Guus; Moessner, Ekkehard; Umaña, Pablo

    2017-01-01

    ABSTRACT We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the therapeutic index of IL-2 therapy by (a) preferential retention at the tumor by having a lower dissociation rate from CEA-expressing cancer cells vs. IL-2R-expressing cells, (b) avoiding any FcγR-binding and Fc effector functions and (c) reduced binding to endothelial cells expressing CD25; and (iii) improve the pharmacokinetics, and thus convenience of administration, of IL-2. The crystal structure of the IL2v-IL-2Rβγ complex was determined and CEA-IL2v activity was assessed using human immune effector cells. Tumor targeting was investigated in tumor-bearing mice using 89Zr-labeled CEA-IL2v. Efficacy studies were performed in (a) syngeneic mouse models as monotherapy and combined with anti-PD-L1, and in (b) xenograft mouse models in combination with ADCC-mediating antibodies. CEA-IL2v binds to CEA with pM avidity but not to CD25, and consequently did not preferentially activate Tregs. In vivo, CEA-IL2v demonstrated superior pharmacokinetics and tumor targeting compared with a wild-type IL-2-based CEA immunocytokine (CEA-IL2wt). CEA-IL2v strongly expanded NK and CD8+ T cells, skewing the CD8+:CD4+ ratio toward CD8+ T cells both in the periphery and in the tumor, and mediated single agent efficacy in syngeneic MC38-CEA and PancO2-CEA models. Combination with trastuzumab, cetuximab and imgatuzumab, all of human IgG1 isotype, resulted in superior efficacy compared with the monotherapies alone. Combined with anti-PD-L1, CEA-IL2v mediated superior efficacy over the respective

  19. Hybrid MV-kV 3D respiratory motion tracking during radiation therapy with low imaging dose.

    Science.gov (United States)

    Yan, Huagang; Li, Haiyun; Liu, Zhixiang; Nath, Ravinder; Liu, Wu

    2012-12-21

    A novel real-time adaptive MV-kV imaging framework for image-guided radiation therapy is developed to reduce the thoracic and abdominal tumor targeting uncertainty caused by respiration-induced intrafraction motion with ultra-low patient imaging dose. In our method, continuous stereoscopic MV-kV imaging is used at the beginning of a radiation therapy delivery for several seconds to measure the implanted marker positions. After this stereoscopic imaging period, the kV imager is switched off except for the times when no fiducial marker is detected in the cine-MV images. The 3D time-varying marker positions are estimated by combining the MV 2D projection data and the motion correlations between directional components of marker motion established from the stereoscopic imaging period and updated afterwards; in particular, the most likely position is assumed to be the position on the projection line that has the shortest distance to the first principal component line segment constructed from previous trajectory points. An adaptive windowed auto-regressive prediction is utilized to predict the marker position a short time later (310 ms and 460 ms in this study) to allow for tracking system latency. To demonstrate the feasibility and evaluate the accuracy of the proposed method, computer simulations were performed for both arc and fixed-gantry deliveries using 66 h of retrospective tumor motion data from 42 patients treated for thoracic or abdominal cancers. The simulations reveal that using our hybrid approach, a smaller than 1.2 mm or 1.5 mm root-mean-square tracking error can be achieved at a system latency of 310 ms or 460 ms, respectively. Because the kV imaging is only used for a short period of time in our method, extra patient imaging dose can be reduced by an order of magnitude compared to continuous MV-kV imaging, while the clinical tumor targeting accuracy for thoracic or abdominal cancers is maintained. Furthermore, no additional hardware is required

  20. Brain tumor magnetic targeting and biodistribution of superparamagnetic iron oxide nanoparticles linked with 70-kDa heat shock protein study by nonlinear longitudinal response

    Energy Technology Data Exchange (ETDEWEB)

    Shevtsov, Maxim A., E-mail: shevtsov-max@mail.ru [Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky Ave. 4, St. Petersburg 194064 (Russian Federation); A.L. Polenov Russian Research Scientific Institute of Neurosurgery, Mayakovsky str. 12, St. Petersburg 191014 (Russian Federation); Nikolaev, Boris P. [Research Institute of Highly Pure Biopreparations, Pudozhskaya str. 12, St. Petersburg 197110 (Russian Federation); Ryzhov, Vyacheslav A. [Petersburg Nuclear Physics Institute, NRC Kurchatov Institute, Gatchina 188300 (Russian Federation); Yakovleva, Ludmila Y. [Research Institute of Highly Pure Biopreparations, Pudozhskaya str. 12, St. Petersburg 197110 (Russian Federation); Dobrodumov, Anatolii V. [Institute of Macromolecular Compounds of the Russian Academy of Sciences (RAS), Bolshoi pr. 31, St. Petersburg 199004 (Russian Federation); Marchenko, Yaroslav Y. [Research Institute of Highly Pure Biopreparations, Pudozhskaya str. 12, St. Petersburg 197110 (Russian Federation); Margulis, Boris A. [Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky Ave. 4, St. Petersburg 194064 (Russian Federation); Pitkin, Emil [The Wharton School, University of Pennsylvania, 3730 Walnut St., Philadelphia, PA 19104 (United States); Guzhova, Irina V. [Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky Ave. 4, St. Petersburg 194064 (Russian Federation)

    2015-08-15

    Brain tumor targeting efficiency and biodistribution of the superparamagnetic nanoparticles conjugated with heat shock protein Hsp70 (SPION–Hsp70) were evaluated in experimental glioma model. Synthesized conjugates were characterized using the method of longitudinal nonlinear response of magnetic nanoparticles to a weak ac magnetic field with measurements of second harmonic of magnetization (NLR-M{sub 2}). Cellular interaction of magnetic conjugates was analyzed in 9L glioma cell culture. The biodistribution of the nanoparticles and their accumulation in tumors was assessed by the latter approach as well. The efficacy of Hsp70-conjugates for contrast enhancement in the orthotopic model of 9L glioma was assessed by MR imaging (11 T). Magnetic nanoparticles conjugated with Hsp70 had the relaxivity properties of the MR-negative contrast agents. Morphological observation and cell viability test demonstrated good biocompatibility of Hsp70-conjugates. Analysis of the T{sub 2}-weighted MR scans in tumor-bearing rats demonstrated the high efficacy of Hsp70-conjugates in contrast enhancement of the glioma in comparison to non-conjugated nanoparticles. High contrast enhancement of the glioma was provided by the accumulation of the SPION–Hsp70 particles in the glioma tissue (as shown by the histological assay). Biodistribution analysis by NLR-M{sub 2} measurements evidenced the many-fold increase (~40) in the tumor-to-normal brain uptake ratio in the Hsp70-conjugates treated animals. Biodistribution pattern of Hsp70-decorated nanoparticles differed from that of non-conjugated SPIONs. Coating of the magnetic nanoparticles with Hsp70 protein enhances the tumor-targeting ability of the conjugates that could be applied in the MR imaging of the malignant brain tumors. - Highlights: • Second-harmonic nonlinear magnetic response is used for biodistribution analysis. • NLR-M{sub 2} ensures high sensibility in detection of SPIONs in tissue. • SPION–Hsp70 conjugates

  1. Measuring cytotoxicity by bioluminescence imaging outperforms the standard chromium-51 release assay.

    Science.gov (United States)

    Karimi, Mobin A; Lee, Eric; Bachmann, Michael H; Salicioni, Ana Maria; Behrens, Edward M; Kambayashi, Taku; Baldwin, Cynthia L

    2014-01-01

    The chromium-release assay developed in 1968 is still the most commonly used method to measure cytotoxicity by T cells and by natural killer cells. Target cells are loaded in vitro with radioactive chromium and lysis is determined by measuring chromium in the supernatant released by dying cells. Since then, alternative methods have been developed using different markers of target cell viability that do not involve radioactivity. Here, we compared and contrasted a bioluminescence (BLI)-based cytotoxicity assay to the standard radioactive chromium-release assay using an identical set of effector cells and tumor target cells. For this, we stably transduced several human and murine tumor cell lines to express luciferase. When co-cultured with cytotoxic effector cells, highly reproducible decreases in BLI were seen in an effector to target cell dose-dependent manner. When compared to results obtained from the chromium release assay, the performance of the BLI-based assay was superior, because of its robustness, increased signal-to-noise ratio, and faster kinetics. The reduced/delayed detection of cytotoxicity by the chromium release method was attributable to the association of chromium with structural components of the cell, which are released quickly by detergent solubilization but not by hypotonic lysis. We conclude that the (BLI)-based measurement of cytotoxicity offers a superior non-radioactive alternative to the chromium-release assay that is more robust and quicker to perform.

  2. Construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles for multifunctional intracellular drug delivery.

    Science.gov (United States)

    Song, Nijia; Ding, Mingming; Pan, Zhicheng; Li, Jiehua; Zhou, Lijuan; Tan, Hong; Fu, Qiang

    2013-12-09

    New strategies for the construction of versatile nanovehicles to overcome the multiple challenges of targeted delivery are urgently needed for cancer therapy. To address these needs, we developed a novel targeting-clickable and tumor-cleavable polyurethane nanomicelle for multifunctional delivery of antitumor drugs. The polyurethane was synthesized from biodegradable poly(ε-caprolactone) (PCL) and L-lysine ethyl ester diisocyanate (LDI), further extended by a new designed L-cystine-derivatized chain extender bearing a redox-responsive disulfide bond and clickable alkynyl groups (Cys-PA), and finally terminated by a detachable methoxyl-poly(ethylene glycol) with a highly pH-sensitive benzoic-imine linkage (BPEG). The obtained polymers show attractive self-assembly characteristics and stimuli-responsiveness, good cytocompatibility, and high loading capacity for doxorubicin (DOX). Furthermore, folic acid (FA) as a model targeting ligand was conjugated to the polyurethane micelles via an efficient click reaction. The decoration of FA results in an enhanced cellular uptake and improved drug efficacy toward FA-receptor positive HeLa cancer cells in vitro. As a proof-of-concept, this work provides a facile approach to the design of extracellularly activatable nanocarriers for tumor-targeted and programmed intracellular drug delivery.

  3. Phthalocyanine-loaded graphene nanoplatform for imaging-guided combinatorial phototherapy.

    Science.gov (United States)

    Taratula, Olena; Patel, Mehulkumar; Schumann, Canan; Naleway, Michael A; Pang, Addison J; He, Huixin; Taratula, Oleh

    2015-01-01

    We report a novel cancer-targeted nanomedicine platform for imaging and prospect for future treatment of unresected ovarian cancer tumors by intraoperative multimodal phototherapy. To develop the required theranostic system, novel low-oxygen graphene nanosheets were chemically modified with polypropylenimine dendrimers loaded with phthalocyanine (Pc) as a photosensitizer. Such a molecular design prevents fluorescence quenching of the Pc by graphene nanosheets, providing the possibility of fluorescence imaging. Furthermore, the developed nanoplatform was conjugated with poly(ethylene glycol), to improve biocompatibility, and with luteinizing hormone-releasing hormone (LHRH) peptide, for tumor-targeted delivery. Notably, a low-power near-infrared (NIR) irradiation of single wavelength was used for both heat generation by the graphene nanosheets (photothermal therapy [PTT]) and for reactive oxygen species (ROS)-production by Pc (photodynamic therapy [PDT]). The combinatorial phototherapy resulted in an enhanced destruction of ovarian cancer cells, with a killing efficacy of 90%-95% at low Pc and low-oxygen graphene dosages, presumably conferring cytotoxicity to the synergistic effects of generated ROS and mild hyperthermia. An animal study confirmed that Pc loaded into the nanoplatform can be employed as a NIR fluorescence agent for imaging-guided drug delivery. Hence, the newly developed Pc-graphene nanoplatform has the significant potential as an effective NIR theranostic probe for imaging and combinatorial phototherapy.

  4. Initial laboratory experience with a novel ultrasound probe for standard and single-port robotic kidney surgery: increasing console surgeon autonomy and minimizing instrument clashing.

    Science.gov (United States)

    Yakoubi, Rachid; Autorino, Riccardo; Laydner, Humberto; Guillotreau, Julien; White, Michael A; Hillyer, Shahab; Spana, Gregory; Khanna, Rakesh; Isaac, Wahib; Haber, Georges-Pascal; Stein, Robert J; Kaouk, Jihad H

    2012-06-01

    The aim of this study was to evaluate a novel ultrasound probe specifically developed for robotic surgery by determining its efficiency in identifying renal tumors. The study was carried out using the Da Vinci™ surgical system in one female pig. Renal tumor targets were created by percutaneous injection of a tumor mimic mixture. Single-port and standard robotic partial nephrectomy were performed. Intraoperative ultrasound was performed using both standard laparoscopic probe and the new ProART™ Robotic probe. Probe maneuverability and ease of handling for tumor localization were recorded. The standard laparoscopic probe was guided by the assistant. Significant clashing with robotic arms was noted during the single-port procedure. The novel robotic probe was easily introduced through the assistant trocar, and held by the console surgeon using the robotic Prograsp™ with no registered clashing in the external operative field. The average time for grasping the new robotic probe was less than 10 s. Once inserted and grasped, no limitation was found in terms of instrument clashing during the single-port procedure. This novel ultrasound probe developed for robotic surgery was noted to be user-friendly when performing porcine standard and especially single-port robotic partial nephrectomy. Copyright © 2011 John Wiley & Sons, Ltd.

  5. Fabrication of polymer-platinum(II) complex nanomicelle from mPEG-g-alpha,beta-poly [(N-amino acidyl)-DL-aspartamide] and cis-dichlorodiammine platinum(II) and its cytotoxicity.

    Science.gov (United States)

    Wang, Chengyun; Gong, Yanbao; Fan, Naiqian; Liu, Shunying; Luo, Shufang; Yu, Jiahui; Huang, Jin

    2009-04-01

    The aim of research is to develop and optimize delivery system for cis-dichlorodiammine platinum(II) (CDDP) based on polymer-metal complex nanomicelles with controllable particle size in order to achieve the passive tumor targeting. In particular, graft copolymers, mPEG-g-alpha,beta-poly [(N-amino acidyl)-DL-aspartamide] (mPEG-g-PAAsp) were synthesized by the ring-opening reaction of polysuccinimide with mPEG-NH(2) (M(w): 2000 and 5000 Da), and then with l-aspartic acid and l-glutamic acid, respectively. mPEG-g-PAAsp-CDDP complex nanomicelles were fabricated from mPEG-g-PAAsp and CDDP. The formation of mPEG-g-PAAsp-CDDP nanomicelles was confirmed by fluorescence spectrophotoscopy, electrical conductivity and particle size measurements. It was found that all the nanomicelles showed spherical shapes with clear core-shell structures and narrow size distributions. Their sizes ranged from 80 to 160 nm, suggesting of their passive targeting potential to tumor tissue. With the increase of the molecular weight of mPEG, the sizes of mPEG-g-PAAsp-CDDP micelles showed a tendency to increase. mPEG-g-PAAsp-CDDP nanomicelles showed linear gradual drug release profiles in 40 h, suggestion of their sustained drug release behaviors. Compared with CDDP, mPEG-g-PAAsp-CDDP micelles showed essential decreased cytotoxicity to Bel-7402 cell line.

  6. MR-Guided High-Intensity Focused Ultrasound Ablation of Breast Cancer with a Dedicated Breast Platform

    Energy Technology Data Exchange (ETDEWEB)

    Merckel, Laura G., E-mail: L.G.Merckel-2@umcutrecht.nl [University Medical Center Utrecht, Department of Radiology (Netherlands); Bartels, Lambertus W., E-mail: W.Bartels@umcutrecht.nl [University Medical Center Utrecht, Image Sciences Institute (Netherlands); Koehler, Max O., E-mail: max.kohler@philips.com [Philips Healthcare (Finland); Bongard, H. J. G. Desiree van den, E-mail: D.vandenBongard@umcutrecht.nl [University Medical Center Utrecht, Department of Radiotherapy (Netherlands); Deckers, Roel, E-mail: R.Deckers-2@umcutrecht.nl [University Medical Center Utrecht, Image Sciences Institute (Netherlands); Mali, Willem P. Th. M., E-mail: W.Mali@umcutrecht.nl [University Medical Center Utrecht, Department of Radiology (Netherlands); Binkert, Christoph A., E-mail: Christoph.Binkert@ksw.ch [Cantonal Hospital Winterthur, Department of Radiology (Switzerland); Moonen, Chrit T., E-mail: C.Moonen@umcutrecht.nl [University Medical Center Utrecht, Image Sciences Institute (Netherlands); Gilhuijs, Kenneth G. A., E-mail: K.G.A.Gilhuijs@umcutrecht.nl; Bosch, Maurice A. A. J. van den, E-mail: mbosch@umcutrecht.nl [University Medical Center Utrecht, Department of Radiology (Netherlands)

    2013-04-15

    Optimizing the treatment of breast cancer remains a major topic of interest. In current clinical practice, breast-conserving therapy is the standard of care for patients with localized breast cancer. Technological developments have fueled interest in less invasive breast cancer treatment. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a completely noninvasive ablation technique. Focused beams of ultrasound are used for ablation of the target lesion without disrupting the skin and subcutaneous tissues in the beam path. MRI is an excellent imaging method for tumor targeting, treatment monitoring, and evaluation of treatment results. The combination of HIFU and MR imaging offers an opportunity for image-guided ablation of breast cancer. Previous studies of MR-HIFU in breast cancer patients reported a limited efficacy, which hampered the clinical translation of this technique. These prior studies were performed without an MR-HIFU system specifically developed for breast cancer treatment. In this article, a novel and dedicated MR-HIFU breast platform is presented. This system has been designed for safe and effective MR-HIFU ablation of breast cancer. Furthermore, both clinical and technical challenges are discussed, which have to be solved before MR-HIFU ablation of breast cancer can be implemented in routine clinical practice.

  7. Toward a cancer therapy with boron-rich oligomeric phosphate diesters that target the cell nucleus

    Science.gov (United States)

    Nakanishi, Akira; Guan, Lufeng; Kane, Robert R.; Kasamatsu, Harumi; Hawthorne, M. Frederick

    1999-01-01

    The viability of boron neutron capture therapy depends on the development of tumor-targeting agents that contain large numbers of boron-10 (10B) atoms and are readily taken up by cells. Here we report on the selective uptake of homogeneous fluorescein-labeled nido-carboranyl oligomeric phosphate diesters (nido-OPDs) by the cell nucleus and their long-term retention after their delivery into the cytoplasm of TC7 cells by microinjection. All nido-OPDs accumulated in the cell nucleus within 2 h after microinjection. However, nido-OPDs in which the carborane cage was located on a side chain attached to the oligomeric backbone were redistributed between both the cytoplasm and nucleus after 24 h of incubation, whereas nido-OPDs in which the carborane cage was located along the oligomeric backbone remained primarily in the nucleus. Furthermore, cell-free incubation of digitonin-permeabilized TC7 cells with the nido-OPDs resulted in nuclear accumulation of the compounds, thus corroborating the microinjection studies. Our observation of fluorescence primarily located in the cell nucleus indicates that nuclear-specific uptake of sufficient amounts of 10B for effective boron neutron capture therapy (≈108–109 10B atoms/tumor cell) via nido-OPDs is achievable. PMID:9874802

  8. Development of application technology of radiation-resistant microorganism

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Ho; Lim, Sang Yong; Joe, Min Ho; Jung, Jin Woo; Jung, Sun Wook; Song, Du Sup; Choi, Young Ji [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2009-02-15

    The scope of the project is divided into of three parts; (i) to define the survival strategy of radiation-resistant microbes, especially Deinococcus (ii) acquisition of gene resources encoding the novel protein and related with the production of functional materials (iii) development of control technology against radiation-resistant microbes. To this aim, first, the whole transcriptional response of the D. radiodurans strain haboring pprI mutation, which plays an important role in radiation resistance, was analyzed by cDNA microarray. The anti-oxidant activity of the major carotenoid of D. radiodurans, deinoxanthin, was analyzed and the strain was constructed, in which the gene necessary for bio- synthesis of deinoxanthin is deleted. The response to cadmium of D. radiodurans was also investigated through cDNA microarray analysis. Radiogenic therapy, one of the cancer treatments, is designed to use radiation-inducible gene for the treatment. To develop the gene-transfer vehicle for radiogenic therapy, we have investigated the virulence mechanism of Salmonella, which is tumor-targeting bacteria and studied the synergistic effect of some anti-cancer agents on radiation treatment for cancer. Finally, we confirmed that irradiation could decompose a fungus toxin, patulin, into various harmless by-products.

  9. Antiproliferative activity of extracts prepared from three species of Reishi on cultured human normal and tumor cell lines.

    Science.gov (United States)

    Katagata, Yohtaro; Sasaki, Fumiyuki

    2010-01-01

    The present study investigated the growth of human fibrosarcoma (HT-1080) and fibroblast (SF-TY) cells in combination with water-soluble (WS) and high molecular component (HMC) fractions prepared from Reishi (R), Rokkaku-Reishi (2R) and Apple Rokkaku-Reishi (A2R). Each WS fraction exhibited dose-and time-dependent inhibition of the growth of the HT-1080 and SF-TY cells. The extracts exhibited marked antiproliferative activity against the HT-1080 cells. The HMC fractions inhibited cell growth dose-and time-dependently in the HT-1080 cells only, and not in the SF-TY cells, suggesting that HMC fractions selectively inhibit HT-1080 cells. Among the HMC fractions, A2R is a strong candidate for anti-tumor targeting since its fraction exhibited better inhibition than the R and 2R fractions. Furthermore, the volume of the A2R fraction was approximately five times greater than that of the others, and included four proteins (molecular mass 9, 13, 22 and 40 kDa) detected by SDS-PAGE. Three of these (13, 22 and 40 kDa) were confirmed to be glycosylated with the Periodic Acid-Schiff Stain kit. These results suggest that A2R may possess anti-tumor activity and, in particular, that the protein components of A2R may act to selectively inhibit the growth of HT-1080 cells.

  10. Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma

    Science.gov (United States)

    Benezra, Miriam; Penate-Medina, Oula; Zanzonico, Pat B.; Schaer, David; Ow, Hooisweng; Burns, Andrew; DeStanchina, Elisa; Longo, Valerie; Herz, Erik; Iyer, Srikant; Wolchok, Jedd; Larson, Steven M.; Wiesner, Ulrich; Bradbury, Michelle S.

    2011-01-01

    Nanoparticle-based materials, such as drug delivery vehicles and diagnostic probes, currently under evaluation in oncology clinical trials are largely not tumor selective. To be clinically successful, the next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations. Here, we describe our full characterization of an approximately 7-nm diameter multimodal silica nanoparticle, exhibiting what we believe to be a unique combination of structural, optical, and biological properties. This ultrasmall cancer-selective silica particle was recently approved for a first-in-human clinical trial. Optimized for efficient renal clearance, it concurrently achieved specific tumor targeting. Dye-encapsulating particles, surface functionalized with cyclic arginine–glycine–aspartic acid peptide ligands and radioiodine, exhibited high-affinity/avidity binding, favorable tumor-to-blood residence time ratios, and enhanced tumor-selective accumulation in αvβ3 integrin–expressing melanoma xenografts in mice. Further, the sensitive, real-time detection and imaging of lymphatic drainage patterns, particle clearance rates, nodal metastases, and differential tumor burden in a large-animal model of melanoma highlighted the distinct potential advantage of this multimodal platform for staging metastatic disease in the clinical setting. PMID:21670497

  11. Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA.

    Science.gov (United States)

    Taratula, Oleh; Garbuzenko, Olga B; Chen, Alex M; Minko, Tamara

    2011-12-01

    A tumor targeted mesoporous silica nanoparticles (MSN)-based drug delivery system (DDS) was developed for inhalation treatment of lung cancer. The system was capable of effectively delivering inside cancer cells anticancer drugs (doxorubicin and cisplatin) combined with two types of siRNA targeted to MRP1 and BCL2 mRNA for suppression of pump and nonpump cellular resistance in non-small cell lung carcinoma, respectively. Targeting of MSN to cancer cells was achieved by the conjugation of LHRH peptide on the surface of MSN via poly(ethylene glycol) spacer. The delivered anticancer drugs and siRNA preserved their specific activity leading to the cell death induction and inhibition of targeted mRNA. Suppression of cellular resistance by siRNA effectively delivered inside cancer cells and substantially enhanced the cytotoxicity of anticancer drugs. Local delivery of MSN by inhalation led to the preferential accumulation of nanoparticles in the mouse lungs, prevented the escape of MSN into the systemic circulation, and limited their accumulation in other organs. The experimental data confirm that the developed DDS satisfies the major prerequisites for effective treatment of non-small cell lung carcinoma. Therefore, the proposed cancer-targeted MSN-based system for complex delivery of drugs and siRNA has high potential in the effective treatment of lung cancer.

  12. Targeted therapy using nanotechnology: focus on cancer.

    Science.gov (United States)

    Sanna, Vanna; Pala, Nicolino; Sechi, Mario

    2014-01-01

    Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication.

  13. Cancer Nanotechnology: The impact of passive and active targeting in the era of modern cancer biology☆

    Science.gov (United States)

    Bertrand, Nicolas; Wu, Jun; Xu, Xiaoyang; Kamaly, Nazila; Farokhzad, Omid C

    2014-01-01

    Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000’s. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential “retention” in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers. PMID:24270007

  14. Hyaluronic Acid Modified Tantalum Oxide Nanoparticles Conjugating Doxorubicin for Targeted Cancer Theranostics.

    Science.gov (United States)

    Jin, Yushen; Ma, Xibo; Feng, Shanshan; Liang, Xiao; Dai, Zhifei; Tian, Jie; Yue, Xiuli

    2015-12-16

    Theranostic tantalum oxide nanoparticles (TaOxNPs) of about 40 nm were successfully developed by conjugating functional molecules including polyethylene glycol (PEG), near-infrared (NIR) fluorescent dye, doxorubicin (DOX), and hyaluronic acid (HA) onto the surface of the nanoparticles (TaOx@Cy7-DOX-PEG-HA NPs) for actively targeting delivery, pH-responsive drug release, and NIR fluorescence/X-ray CT bimodal imaging. The obtained nanoagent exhibits good biocompatibility, high cumulative release rate in the acidic microenvironments, long blood circulation time, and superior tumor-targeting ability. Both in vitro and in vivo experiments show that it can serve as an excellent contrast agent to simultaneously enhance fluorescence imaging and CT imaging greatly. Most importantly, such a nanoagent could enhance the therapeutic efficacy of the tumor greatly and the tumor growth inhibition was evaluated to be 87.5%. In a word, multifunctional TaOx@Cy7-DOX-PEG-HA NPs can serve as a theranostic nanomedicine for fluorescence/X-ray CT bimodal imaging, remote-controlled therapeutics, enabling personalized detection, and treatment of cancer with high efficacy.

  15. Optimizing the synthesis of red- and near-infrared CuInS2 and AgInS2 semiconductor nanocrystals for bioimaging.

    Science.gov (United States)

    Liu, Liwei; Hu, Rui; Law, Wing-Chueng; Roy, Indrajit; Zhu, Jing; Ye, Ling; Hu, Siyi; Zhang, Xihe; Yong, Ken-Tye

    2013-10-21

    This work reports the study of optimization of the reaction parameters on the synthesis of high quality CuInS2 and AgInS2 nanocrystals for bioimaging applications. The concentration of reaction precursors (e.g. Ag, Cu, In and S) plays a key role in determining the emission profile of these ternary quantum dots (QDs). By carefully varying the precursor compositions, the emission of QD can be tuned from red to near infrared (NIR) region. Taking the advantages of NIR emission, which possesses minimal absorption in biological tissues, we have also prepared water-dispersible CuInS2/ZnS and AgInS2/ZnS nanocrystals and demonstrated the high biocompatibility for both deep tissue penetration and tumor targeting. The QDs were stabilized in Pluronic F127 block copolymer micelles, offering us optically and colloidally stable contrast agents for in vitro and in vivo imaging. Two-photon excitation of QD has also been demonstrated, accomplishing a NIR-to-NIR transaction. This study devotes the key steps in promoting the use of ternary QDs as low-toxic, photostable, and cadmium-free semiconductor nanocrystal formulation for multiple imaging applications.

  16. Two birds, one stone: dual targeting of the cancer cell surface and subcellular mitochondria by the galectin-3-binding peptide G3-C12.

    Science.gov (United States)

    Sun, Wei; Li, Lian; Li, Li-Jia; Yang, Qing-Qing; Zhang, Zhi-Rong; Huang, Yuan

    2017-06-01

    Active tumor-targeting approaches using specific ligands have drawn considerable attention over the years. However, a single ligand often fails to simultaneously target the cancer cell surface and subcellular organelles, which limits the maximum therapeutic efficacy of delivered drugs. We describe a polymeric delivery system modified with the G3-C12 peptide for sequential dual targeting. In this study, galectin-3-targeted G3-C12 peptide was conjugated onto the N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer for the delivery of D(KLAKLAK)2 (KLA) peptide. G3-C12-HPMA-KLA exhibited increased receptor-mediated internalization into galectin-3-overexpressing PC-3 cells. Furthermore, G3-C12 peptide also directed HPMA-KLA conjugates to mitochondria. This occurred because the apoptosis signal triggered the accumulation of galectin-3 in mitochondria, and the G3-C12 peptide that specifically bound to galectin-3 was trafficked along with its receptor intracellularly. As a result, G3-C12-HPMA-KLA disrupted the mitochondrial membrane, increased the generation of reactive oxygen species (ROS) and induced cytochrome c release, which ultimately resulted in enhanced cytotoxicity. An in vivo study revealed that the G3-C12 peptide significantly enhanced the tumor accumulation of the KLA conjugate. In addition, G3-C12-HPMA-KLA exhibited the best therapeutic efficacy and greatly improved the animal survival rate. Our work demonstrates that G3-C12 is a promising ligand with dual-targeting functionality.

  17. RNA sequencing identifies specific PIWI-interacting small non-coding RNA expression patterns in breast cancer.

    Science.gov (United States)

    Hashim, Adnan; Rizzo, Francesca; Marchese, Giovanna; Ravo, Maria; Tarallo, Roberta; Nassa, Giovanni; Giurato, Giorgio; Santamaria, Gianluca; Cordella, Angela; Cantarella, Concita; Weisz, Alessandro

    2014-10-30

    PIWI-interacting small non-coding RNAs (piRNAs) are genetic and epigenetic regulatory factors in germline cells, where they maintain genome stability, are involved in RNA silencing and regulate gene expression. We found that the piRNA biogenesis and effector pathway are present in human breast cancer (BC) cells and, analyzing smallRNA-Seq data generated from BC cell lines and tumor biopsies, we identified >100 BC piRNAs, including some very abundant and/or differentially expressed in mammary epithelial compared to BC cells, where this was influenced by estrogen or estrogen receptor β, and in cancer respect to normal breast tissues. A search for mRNAs targeted by the BC piRNome revealed that eight piRNAs showing a specific expression pattern in breast tumors target key cancer cell pathways. Evidence of an active piRNA pathway in BC suggests that these small non-coding RNAs do exert transcriptional and post-transcriptional gene regulatory actions also in cancer cells.

  18. Fabrication of a graphene/C60 nanohybrid via γ-cyclodextrin host-guest chemistry for photodynamic and photothermal therapy.

    Science.gov (United States)

    Hu, Zhen; Wang, Cheng; Zhao, Feng; Xu, Xirong; Wang, Shuhong; Yu, Long; Zhang, Dayu; Huang, Yudong

    2017-06-29

    The wonderful chemical structures and characteristics of low-dimensional carbon materials have exciting applications in life sciences. In the present study, we developed a facile strategy to conjugate C60 with graphene via host-guest chemistry for targeted phototherapy. A versatile carrier based on folic acid-functionalized graphene (GO-FA) and comprising γ-cyclodextrin (γ-CD) at its surface was assembled via π-π interaction, creating hybrid structures with drug storage and tumor targeting properties. This γ-CD-modified graphene (GO-FA/Py-γ-CD) is capable of hosting pristine C60 molecules for the fabrication of a GO-FA/Py-γ-CD/C60 nanohybrid. The hybridization of GO-FA, γ-CD, and C60 hinders the aggregation of C60, promotes cellular uptake, enhances light absorption, and finally demonstrates enhanced phototherapy effects of GO-FA/Py-γ-CD/C60. Under Xe lamp irradiation (2 W cm-2) for 4 min, GO-FA/Py-γ-CD/C60 simultaneously causes heating and intracellular ROS production, which further significantly reduces the cell viability to 16.2% at low content of loading (30 μg mL-1). Moreover, it represents an excellent tumor killing efficiency, better than that of the other reported graphene/C60 nanohybrids; thus, this material is suitable for applications in phototherapy of cancer.

  19. Hydrophobically modified polysaccharide-based on polysialic acid nanoparticles as carriers for anticancer drugs.

    Science.gov (United States)

    Jung, Bom; Shim, Man-Kyu; Park, Min-Ju; Jang, Eun Hyang; Yoon, Hong Yeol; Kim, Kwangmeyung; Kim, Jong-Ho

    2017-03-30

    This study presented the development of hydrophobically modified polysialic acid (HPSA) nanoparticles, a novel anticancer drug nanocarrier that increases therapeutic efficacy without causing nonspecific toxicity towards normal cells. HPSA nanoparticles were prepared by 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC)/N-hydroxysuccinimide (NHS) coupling between N-deacetylated polysialic acid (PSA) and 5β-cholanic acid. The physicochemical characteristics of HPSA nanoparticles (zeta-potential, morphology and size) were measured, and in vitro cytotoxicity and cellular uptake of PSA and HPSA nanoparticles were tested in A549 cells. In vivo cancer targeting of HPSA nanoparticles was evaluated by labeling PSA and HPSA nanoparticles with Cy5.5, a near-infrared fluorescent dye, for imaging. HPSA nanoparticles showed improved cancer-targeting ability compared with PSA. Doxorubicin-loaded HPSA (DOX-HPSA) nanoparticles were prepared using a simple dialysis method. An analysis of the in vitro drug-release profile and drug-delivery behavior showed that DOX was effectively released from DOX-HPSA nanoparticles. In vivo cancer therapy with DOX-HPSA nanoparticles in mice showed antitumor effects that resembled those of free DOX. Moreover, DOX-HPSA nanoparticles had low toxicity toward other organs, reflecting their tumor-targeting property. Hence, HPSA nanoparticles are considered a potential nanocarrier for anticancer agents. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Multifunctional Nanoparticles for Brain Tumor Diagnosis and Therapy

    Science.gov (United States)

    Cheng, Yu; Morshed, Ramin; Auffinger, Brenda; Tobias, Alex L.; Lesniak, Maciej S.

    2013-01-01

    Brain tumors are a diverse group of neoplasms that often carry a poor prognosis for patients. Despite tremendous efforts to develop diagnostic tools and therapeutic avenues, the treatment of brain tumors remains a formidable challenge in the field of neuro-oncology. Physiological barriers including the blood-brain barrier result in insufficient accumulation of therapeutic agents at the site of a tumor, preventing adequate destruction of malignant cells. Furthermore, there is a need for improvements in brain tumor imaging to allow for better characterization and delineation of tumors, visualization of malignant tissue during surgery, and tracking of response to chemotherapy and radiotherapy. Multifunctional nanoparticles offer the potential to improve upon many of these issues and may lead to breakthroughs in brain tumor management. In this review, we discuss the diagnostic and therapeutic applications of nanoparticles for brain tumors with an emphasis on innovative approaches in tumor targeting, tumor imaging, and therapeutic agent delivery. Clinically feasible nanoparticle administration strategies for brain tumor patients are also examined. Furthermore, we address the barriers towards clinical implementation of multifunctional nanoparticles in the context of brain tumor management. PMID:24060923

  1. Preparation of poly(β-L-malic acid)-based charge-conversional nanoconjugates for tumor-specific uptake and cellular delivery.

    Science.gov (United States)

    Zhou, Qing; Yang, Tiehong; Qiao, Youbei; Guo, Songyan; Zhu, Lin; Wu, Hong

    2015-01-01

    In this study, a multifunctional poly(β-L-malic acid)-based nanoconjugate with a pH-dependent charge conversional characteristic was developed for tumor-specific drug delivery. The short branched polyethylenimine-modified poly(β-L-malic acid) (PEPM) was first synthesized. Then, the fragment HAb18 F(ab')2 and 2,3-dimethylmaleic anhydride were covalently attached to the PEPM to form the nanoconjugate, HDPEPM. In this nanoconjugate, the 2,3-dimethylmaleic anhydride, the shielding group, could shield the positive charge of the conjugate at pH 7.4, while it was selectively hydrolyzed in the tumor extracellular space (pH 6.8) to expose the previously-shielded positive charge. To study the anticancer activity, the anticancer drug, doxorubicin, was covalently attached to the nanoconjugate. The doxorubicin-loaded HDPEPM nanoconjugate was able to efficiently undergo a quick charge conversion from -11.62 mV to 9.04 mV in response to the tumor extracellular pH. The electrostatic interaction between the positively charged HDPEPM nanoconjugates and the negatively charged cell membrane significantly enhanced their cellular uptake, resulting in the enhanced anticancer activity. Also, the tumor targetability of the nanoconjugates could be further improved via the fragment HAb18 F(ab')2 ligand-receptor-mediated tumor cell-specific endocytosis.

  2. Activated Charge-Reversal Polymeric Nano-System: The Promising Strategy in Drug Delivery for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Yichen Hu

    2016-04-01

    Full Text Available Various polymeric nanoparticles (NPs with optimal size, tumor-targeting functionalization, or microenvironment sensitive characteristics have been designed to solve several limitations of conventional chemotherapy. Nano-sized polymeric drug carrier systems have remarkably great advantages in drug delivery and cancer therapy, which are still plagued with severe deficiencies, especially insufficient cellular uptake. Recently, surface charge of medical NPs has been demonstrated to play an important role in cellular uptake. NPs with positive charge show higher affinity to anionic cell membranes such that with more efficient cellular internalization, but otherwise cause severe aggregation and fast clearance in circulation. Thus, surface charge-reversal NPs, specifically activated at the tumor site, have shown to elegantly resolve the enhanced cellular uptake in cancer cells vs. non-specific protein adsorption dilemma. Herein, this review mainly focuses on the effect of tumor-site activated surface charge reversal NPs on tumor treatment, including the activated mechanisms and various applications in suppressing cancer cells, killing cancer stem cell and overcoming multidrug resistance, with the emphasis on recent research in these fields. With the comprehensive and in-depth understanding of the activated surface charge reversal NPs, this approach might arouse great interest of scientific research on enhanced efficient polymeric nano-carriers in cancer therapy.

  3. Preparation and biological activity studies of resveratrol loaded ionically cross-linked chitosan-TPP nanoparticles.

    Science.gov (United States)

    Wu, Jie; Wang, Yaping; Yang, Hao; Liu, Xiangyu; Lu, Zhong

    2017-11-01

    Nanoparticles with size range of 10-500nm can be efficiently delivered into cancer cells by the Enhanced Permeability and Retention (EPR) effect. Here, we prepared resveratrol (Res) loaded chitosan (CS) nanoparticles with the size of 172-217nm by an ionic cross-linking method, with sodium tripolyphosphate (TPP) as the cross-linking agent, to improve the stability, solubility and tumors targeting of the natural anti-cancer drug Res. The prepared Res loaded CS-TPP nanoparticles presented long-term storage stability and UV light stability. The cumulative drug release from nanoparticles in mimetic tumor tissue condition (pH 6.5) was higher than that in physiological condition (pH 7.4). Further, Res-loaded CS-TPP nanoparticles maintained the antioxidant activity of Res even after UV light irradiation. Cell viability study shows that the as prepared drug loaded nanoparticles had similar antiproliferative activity on hepatocellular carcinoma cells SMMC 7721 and lower cytotoxicity on normal hepatocyte cells L02 compared with free Res. Fluorescence microscopy observation revealed that the nanoparticles were efficiently taken in by SMMC 7721 cells. This work indicates the potential use of drug loaded CS-TPP nanoparticles for the efficient delivery of bioactive Res for chemotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Exploiting macrophages as targeted carrier to guide nanoparticles into glioma.

    Science.gov (United States)

    Pang, Liang; Qin, Jing; Han, Limei; Zhao, Wenjie; Liang, Jianming; Xie, Zhongyi; Yang, Pei; Wang, Jianxin

    2016-06-14

    The restriction of anti-cancer drugs entry to tumor sites in the brain is a major impediment to the development of new strategies for the treatment of glioma. Based on the finding that macrophages possess an intrinsic homing property enabling them to migrate to tumor sites across the endothelial barriers in response to the excretion of cytokines/chemokines in the diseased tissues, we exploited macrophages as 'Trojan horses' to carry drug-loading nanoparticles (NPs), pass through barriers, and offload them into brain tumor sites. Anticancer drugs were encapsulated in nanoparticles to avoid their damage to the cells. Drug loading NPs was then incubated with RAW264.7 cells in vitro to prepare macrophage-NPs (M-NPs). The release of NPs from M-NPs was very slow in medium of DMEM and 10% FBS and significantly accelerated when LPS and IFN-γ were added to mimic tumor inflammation microenvironment. The viability of macrophages was not affected when the concentration of doxorubicin lower than 25 μg/ml. The improvement of cellular uptake and penetration into the core of glioma spheroids of M-NPs compared with NPs was verified in in vitro studies. The tumor-targeting efficiency of NPs was also significantly enhanced after loading into macrophages in nude mice bearing intracranial U87 glioma. Our results provided great potential of macrophages as an active biocarrier to deliver anticancer drugs to the tumor sites in the brain and improve therapeutic effects of glioma.

  5. Clinically applicable Monte Carlo-based biological dose optimization for the treatment of head and neck cancers with spot-scanning proton therapy

    CERN Document Server

    Tseung, H Wan Chan; Kreofsky, C R; Ma, D; Beltran, C

    2016-01-01

    Purpose: To demonstrate the feasibility of fast Monte Carlo (MC) based inverse biological planning for the treatment of head and neck tumors in spot-scanning proton therapy. Methods: Recently, a fast and accurate Graphics Processor Unit (GPU)-based MC simulation of proton transport was developed and used as the dose calculation engine in a GPU-accelerated IMPT optimizer. Besides dose, the dose-averaged linear energy transfer (LETd) can be simultaneously scored, which makes biological dose (BD) optimization possible. To convert from LETd to BD, a linear relation was assumed. Using this novel optimizer, inverse biological planning was applied to 4 patients: 2 small and 1 large thyroid tumor targets, and 1 glioma case. To create these plans, constraints were placed to maintain the physical dose (PD) within 1.25 times the prescription while maximizing target BD. For comparison, conventional IMRT and IMPT plans were created for each case in Eclipse (Varian, Inc). The same critical structure PD constraints were use...

  6. Antibody or Antibody Fragments: Implications for Molecular Imaging and Targeted Therapy of Solid Tumors

    Directory of Open Access Journals (Sweden)

    Katerina T. Xenaki

    2017-10-01

    Full Text Available The use of antibody-based therapeutics has proven very promising for clinical applications in cancer patients, with multiple examples of antibodies and antibody–drug conjugates successfully applied for the treatment of solid tumors and lymphomas. Given reported recurrence rates, improvements are clearly still necessary. A major factor limiting the efficacy of antibody-targeted cancer therapies may be the incomplete penetration of the antibody or antibody–drug conjugate into the tumor. Incomplete tumor penetration also affects the outcome of molecular imaging, when using such targeting agents. From the injection site until they arrive inside the tumor, targeting molecules are faced with several barriers that impact intratumoral distribution. The primary means of antibody transport inside tumors is based on diffusion. The diffusive penetration inside the tumor is influenced by both antibody properties, such as size and binding affinity, as well as tumor properties, such as microenvironment, vascularization, and targeted antigen availability. Engineering smaller antibody fragments has shown to improve the rate of tumor uptake and intratumoral distribution. However, it is often accompanied by more rapid clearance from the body and in several cases also by inherent destabilization and reduction of the binding affinity of the antibody. In this perspective, we discuss different cancer targeting approaches based on antibodies or their fragments. We carefully consider how their size and binding properties influence their intratumoral uptake and distribution, and how this may affect cancer imaging and therapy of solid tumors.

  7. Proton Radiation Therapy for Head and Neck Cancer: A Review of the Clinical Experience to Date

    Energy Technology Data Exchange (ETDEWEB)

    Holliday, Emma B.; Frank, Steven J., E-mail: sjfrank@mdanderson.org

    2014-06-01

    Proton beam radiation has been used for cancer treatment since the 1950s, but recent increasing interest in this form of therapy and the construction of hospital-based and clinic-based facilities for its delivery have greatly increased both the number of patients and the variety of tumors being treated with proton therapy. The mass of proton particles and their unique physical properties (ie, the Bragg peak) allow proton therapy to spare normal tissues distal to the tumor target from incidental irradiation. Initial observations show that proton therapy is particularly useful for treating tumors in challenging locations close to nontarget critical structures. Specifically, improvements in local control outcomes for patients with chordoma, chonodrosarcoma, and tumors in the sinonasal regions have been reported in series using proton. Improved local control and survival outcomes for patients with cancer of the head and neck region have also been seen with the advent of improvements in better imaging and multimodality therapy comprising surgery, radiation therapy, and chemotherapy. However, aggressive local therapy in the proximity of critical normal structures to tumors in the head and neck region may produce debilitating early and late toxic effects. Great interest has been expressed in evaluating whether proton therapy can improve outcomes, especially early and late toxicity, when used in the treatment of head and neck malignancies. This review summarizes the progress made to date in addressing this question.

  8. Ferritin nanocages: A biological platform for drug delivery, imaging and theranostics in cancer.

    Science.gov (United States)

    Truffi, Marta; Fiandra, Luisa; Sorrentino, Luca; Monieri, Matteo; Corsi, Fabio; Mazzucchelli, Serena

    2016-05-01

    Nowadays cancer represents a prominent challenge in clinics. Main achievements in cancer management would be the development of highly accurate and specific diagnostic tools for early detection of cancer onset, and the generation of smart drug delivery systems for targeted chemotherapy release in cancer cells. In this context, protein-based nanocages hold a tremendous potential as devices for theranostics purposes. In particular, ferritin has emerged as an excellent and promising protein-based nanocage thanks to its unique architecture, surface properties and high biocompatibility. By exploiting natural recognition of the Transferrin Receptor 1, which is overexpressed on tumor cells, ferritin nanocages may ensure a proper drug delivery and release. Moreover, researchers have applied surface functionalities on ferritin cages for further providing active tumor targeting. Encapsulation strategies of non metal-containing drugs within ferritin cages have been explored and successfully performed with encouraging results. Various preclinical studies have demonstrated that nanoformulation within ferritin nanocages significantly improved targeted therapy and accurate imaging of cancer cells. Aims of this review are to describe structure and functions of ferritin nanocages, and to provide an overview about the nanotechnological approaches implemented for applying them to cancer diagnosis and treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come

    Science.gov (United States)

    Yingchoncharoen, Phatsapong; Kalinowski, Danuta S.

    2016-01-01

    Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number of cytotoxic chemotherapeutics are highly hydrophobic, which limits their utility in cancer therapy. Finally, many chemotherapeutic agents exhibit short half-lives that curtail their efficacy. As a result of these deficiencies, many current treatments lead to side effects, noncompliance, and patient inconvenience due to difficulties in administration. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems known commonly as nanoparticles. Among these delivery systems, lipid-based nanoparticles, particularly liposomes, have shown to be quite effective at exhibiting the ability to: 1) improve the selectivity of cancer chemotherapeutic agents; 2) lower the cytotoxicity of anticancer drugs to normal tissues, and thus, reduce their toxic side effects; 3) increase the solubility of hydrophobic drugs; and 4) offer a prolonged and controlled release of agents. This review will discuss the current state of lipid-based nanoparticle research, including the development of liposomes for cancer therapy, different strategies for tumor targeting, liposomal formulation of various anticancer drugs that are commercially available, recent progress in liposome technology for the treatment of cancer, and the next generation of lipid-based nanoparticles. PMID:27363439

  10. Dual in vivo quantification of integrin-targeted and protease-activated agents in cancer using fluorescence molecular tomography (FMT).

    Science.gov (United States)

    Kossodo, Sylvie; Pickarski, Maureen; Lin, Shu-An; Gleason, Alexa; Gaspar, Renee; Buono, Chiara; Ho, Guojie; Blusztajn, Agnieszka; Cuneo, Garry; Zhang, Jun; Jensen, Jayme; Hargreaves, Richard; Coleman, Paul; Hartman, George; Rajopadhye, Milind; Duong, Le Thi; Sur, Cyrille; Yared, Wael; Peterson, Jeffrey; Bednar, Bohumil

    2010-10-01

    Integrins, especially α(v)β(3) and α(v)β(5), are upregulated in tumor cells and activated endothelial cells and as such, serve as cancer biomarkers. We developed a novel near-infrared-labeled optical agent for the in vivo detection and quantification of α(v)β(3)/α(v)β(5). A small peptidomimetic α(v)β(3) antagonist was synthesized, coupled to a near-infrared fluorescent (NIRF) dye, and tested for binding specificity using integrin-overexpressing cells, inhibition of vitronectin-mediated cell attachment, binding to tumor and endothelial cells in vitro, and competition studies. Pharmacokinetics, biodistribution, specificity of tumor targeting, and the effect of an antiangiogenic treatment were assessed in vivo. The integrin NIRF agent showed strong selectivity towards α(v)β(3/)α(v)β(5) in vitro and predominant tumor distribution in vivo, allowing noninvasive and real-time quantification of integrin signal in tumors. Antiangiogenic treatment significantly inhibited integrin signal in vivo but had no effect on a cathepsin-cleavable NIR agent. Simultaneous imaging revealed different patterns of distribution reflecting the underlying differences in integrin and cathepsin biology during tumor progression. NIRF-labeled integrin antagonists allow noninvasive molecular fluorescent imaging and quantification of tumors in vivo, improving and providing more refined approaches for cancer detection and treatment monitoring.

  11. Salmonella mediated the hemagglutinating virus of Japan-envelope transfer suppresses tumor growth.

    Science.gov (United States)

    Lee, Che-Hsin; Nishikawa, Tomoyuki; Kaneda, Yasufumi

    2017-05-23

    Salmonella can target to tumor microenvironments after systemic treatment. The hemagglutinating virus of Japan-envelope (HVJ-E) induced apoptosis in tumor cells without toxicity in normal cells. Current HVJ-E therapeutic strategies, aimed at using HVJ-E for intratumor treatment, have shown great promise in animal models but have achieved only limited systemic treatment. The purpose of this study was to investigate the modulation of the anti-tumor efficiency of HVJ-E by coating the particles with poly (allylamine hydrochloride) (PAH), designated as P-HVJ-E. Treatment with P-HVJ-E resulted in decreased hemagglutinating activity and maintained tumor cell-selective apoptosis and anti-tumor immunity. The use of Salmonella as a coating for P-HVJ-E (PHS) enhanced the antitumor activity and maintained the tumor-targeting activity. Treatment with PHS resulted in delayed tumor growth in tumor-bearing mice. Furthermore, a Western blot assay of the tumors revealed that HVJ-E targeted to the tumor after systemic treatment with PHS. These results indicate that Salmonella coating viral particles may provide a new approach for tumor therapy.

  12. Bacteria-mediated in vivo delivery of quantum dots into solid tumor

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Ying [Single-molecule and Nanobiology Lab., Dept. of Biophysics, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Zhou, Mei [Dept. of Radiation Medicine, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Luo, Dan; Wang, Lijun; Hong, Yuankai [Single-molecule and Nanobiology Lab., Dept. of Biophysics, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Yang, Yepeng, E-mail: yangyepeng@bjmu.edu.cn [Dept. of Radiation Medicine, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Sha, Yinlin, E-mail: shyl@hsc.pku.edu.cn [Single-molecule and Nanobiology Lab., Dept. of Biophysics, School of Basic Medical Sciences, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China); Biomed-X Center, Peking University, Peking University, No. 38 Xue Yuan Road, Beijing 100091 (China)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer New approach using the probiotic Bifidobacterium bifidum as a vehicle to deliver QDs into the deep tissue of solid tumors in vivo was achieved. Black-Right-Pointing-Pointer Bifidobacterium bifidum delivery system has intrinsic biocompatibility. Black-Right-Pointing-Pointer The targeting efficacy was improved by folic acids. -- Abstract: Semiconductor nanocrystals, so-called quantum dots (QDs), promise potential application in bioimaging and diagnosis in vitro and in vivo owing to their high-quality photoluminescence and excellent photostability as well as size-tunable spectra. Here, we describe a biocompatible, comparatively safe bacteria-based system that can deliver QDs specifically into solid tumor of living animals. In our strategy, anaerobic bacterium Bifidobacterium bifidum (B. bifidum) that colonizes selectively in hypoxic regions of animal body was successfully used as a vehicle to load with QDs and transported into the deep tissue of solid tumors. The internalization of lipid-encapsuled QDs into B. bifidum was conveniently carried by electroporation. To improve the efficacy and specificity of tumor targeting, the QDs-carrying bacterium surface was further conjugated with folic acids (FAs) that can bind to the folic acid receptor overexpressed tumor cells. This new approach opens a pathway for delivering different types of functional cargos such as nanoparticles and drugs into solid tumor of live animals for imaging, diagnosis and therapy.

  13. A new target ligand Ser-Glu for PEPT1-overexpressing cancer imaging.

    Science.gov (United States)

    Dai, Tongcheng; Li, Na; Zhang, Lingzhi; Zhang, Yuanxing; Liu, Qin

    2016-01-01

    Nanoparticles functionalized with active target ligands have been widely used for tumor-specific diagnosis and therapy. The target ligands include antibodies, peptides, proteins, small molecules, and nucleic acid aptamers. Here, we utilize dipeptide Ser-Glu (DIP) as a new ligand to functionalize polymer-based fluorescent nanoparticles (NPs) for pancreatic cancer target imaging. We demonstrate that in the first step, Ser-Glu-conjugated NPs (NPs-DIP) efficiently bind to AsPC-1 and in the following NPs-DIP are internalized into AsPC-1 in vitro. The peptide transporter 1 inhibition experiment reveals that the targeting effects mainly depend on the specific binding of DIP to peptide transporter 1, which is remarkably upregulated in pancreatic cancer cells compared with varied normal cells. Furthermore, NPs-DIP specifically accumulate in the site of pancreatic tumor xenograft and are further internalized into the tumor cells in vivo after intravenous administration, indicating that DIP successfully enhanced nanoparticles internalization efficacy into tumor cells in vivo. This work establishes Ser-Glu to be a new tumor-targeting ligand and provides a promising tool for future tumor diagnostic or therapeutic applications.

  14. Effective targeting of gemcitabine to pancreatic cancer through PEG-cored Flt-1 antibody-conjugated dendrimers.

    Science.gov (United States)

    Öztürk, Kıvılcım; Esendağlı, Güneş; Gürbüz, Mustafa Ulvi; Tülü, Metin; Çalış, Sema

    2017-01-30

    Tumor-targeted delivery of anticancer drugs using dendrimers has been recognized as a promising strategy to increase efficiency and reduce adverse effects of chemotherapy. Herein, we developed a dendrimer-based drug delivery system targeting Flt-1 (a receptor for vascular endothelial growth factors (VEGF)) receptor to improve therapeutic efficacy of gemcitabine in pancreatic cancer. Synthesized polyethylene glycol (PEG)-cored PAMAM dendrimers, which bear anionic carboxylic acid groups on the surface were modified with PEG chains, which were then conjugated with Flt-1 antibody. Following structural and chemical characterization studies, gemcitabine HCl-dendrimer inclusion complexes were successfully prepared. These complexes were efficiently engulfed by Flt-1 expressing pancreatic cancer cells, which enhanced the cytotoxicity of gemcitabine. Moreover, pancreatic tumors established in mice were highly targeted by PEG-cored Flt-1 antibody-conjugated dendrimers and increased accumulation of these gemcitabine-loaded complexes exhibited satisfactory in vivo anti-cancer efficacy. In conclusion, dendrimer-based targeted delivery of chemotherapeutics may serve as a promising approach for the treatment of malignancies such as pancreatic cancer that do not benefit from conventional chemotherapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Tweaking Dendrimers and Dendritic Nanoparticles for Controlled Nano-bio Interactions: Potential Nanocarriers for Improved Cancer Targeting

    Science.gov (United States)

    Bugno, Jason; Hsu, Hao-Jui; Hong, Seungpyo

    2016-01-01

    Nanoparticles have shown great promise in the treatment of cancer, with a demonstrated potential in targeted drug delivery. Among a myriad of nanocarriers that have been recently developed, dendrimers have attracted a great deal of scientific interests due to their unique chemical and structural properties that allow for precise engineering of their characteristics. Despite this, the clinical translation of dendrimers has been hindered due to their drawbacks, such as scale-up issues, rapid systemic elimination, inefficient tumor accumulation, and limited drug loading. In order to overcome these limitations, a series of reengineered dendrimers have been recently introduced using various approaches, including: i) modifications of structure and surfaces; ii) integration with linear polymers; and iii) hybridization with other types of nanocarriers. Chemical modifications and surface engineering have tailored dendrimers to improve their pharmacokinetics and tissue permeation. Copolymerization of dendritic polymers with linear polymers has resulted in various amphiphilic copolymers with self-assembly capabilities and improved drug loading efficiencies. Hybridization with other nanocarriers integrates advantageous characteristics of both systems, which includes prolonged plasma circulation times and enhanced tumor targeting. This review provides a comprehensive summary of the newly emerging drug delivery systems that involve reengineering of dendrimers in an effort to precisely control their nano-bio interactions, mitigating their inherent weaknesses. PMID:26453160

  16. Rapid Generation of In Vitro Multicellular Spheroids for the Study of Monoclonal Antibody Therapy

    Directory of Open Access Journals (Sweden)

    Yen T. Phung, Dario Barbone, V. Courtney Broaddus, Mitchell Ho

    2011-01-01

    Full Text Available Tumor microenvironments present significant barriers to penetration by antibodies and immunoconjugates and are difficult to study in vitro. Cells cultured as monolayers typically exhibit less resistance to therapy than those grown in vivo. Therefore, it is important to develop an alternative research model that better represents in vivo tumors. We have developed a protocol to produce multicellular spheroids, a simple and more relevant model of in vivo tumors that allows for further investigations of the microenvironmental effects on drug penetration and tumor cell killing. The protocol is used to produce in vitro three-dimensional tumor spheroids from established human cancer cell lines and primary cancer cells isolated from patients without the use of any extracellular components. To study the ability of tumor-targeting immunoconjugates to penetrate these tumor spheroids in vitro, we have used an immunotoxin targeting mesothelin, a surface protein expressed in malignant mesotheliomas. This method for producing consistent, reproducible 3D spheroids may allow for improved testing of novel monoclonal antibodies and other agents for their ability to penetrate solid tumors for cancer therapy.

  17. Glatiramer Acetate, Dimethyl Fumarate and Monomethyl Fumarate Up-Regulate the Expression of CCR10 on the Surface of Natural Killer Cells and Enhance their Chemotaxis and Cytotoxicity. Implications for Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Azzam Maghazachi

    2016-10-01

    Full Text Available In vitro harnessing of immune cells is the most important advance in the field of cancer immunotherapy. Results shown in the current paper may be used to harness natural killer (NK cells in vitro. It is observed that drugs used to treat multiple sclerosis such as glatiramer acetate, dimethyl fumarate and monomethyl fumarate up-regulate the expression of chemokines receptor 10 (CCR10 on the surface of human IL-2-activated NK cells. This is corroborated with increased chemotaxis of these cells towards the concentration gradients of the ligands for CCR10, namely CCL27 and CCL28. It is also demonstrated that these three drugs enhance NK cell cytotoxicity against tumor target cells, an activity that is abrogated by prior incubation of the cells with anti-CCR10 antibody. Because CCL27 and CCL28 are secreted by selective tumor types such as malignant melanoma, squamous cell carcinomas and colorectal cancer, respectively, it is hypothesized that activated NK cells may be harnessed in vitro with any of these drugs before utilizing them as a therapeutic modality for cancer.

  18. A multi-functional nanoplatform for tumor synergistic phototherapy

    Science.gov (United States)

    Zhang, Huijuan; Jiao, Xiaojing; Chen, Qianqian; Ji, Yandan; Zhang, Xiaoge; Zhu, Xing; Zhang, Zhenzhong

    2016-02-01

    Phototherapy, which mainly includes photothermal treatment (PTT) and photodynamic treatment (PDT), is a photo-initiated, noninvasive and effective approach for cancer treatment. The high accumulation of photosensitizers (PSs) in a targeted tumor is still a major challenge for efficient light conversion, to generate reactive oxygen species (ROS) and local hyperthermia. In this study, a simple and efficient hyaluronic acid (HA)-modified nanoplatform (HA-TiO2@MWCNTs) with high tumor-targeting ability, excellent phototherapy efficiency, low light-associated side effects and good water solubility was developed. It could be an effective carrier to load hematoporphyrin monomethyl ether (HMME), owing to the tubular conjugate structure. Apart from this, the as-prepared TiO2@MWCNTs nanocomposites could also be used as PSs for tumor PTT and PDT. Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly better than those of single treatment manner. In addition, this drug delivery system could realize high ratio of drug loading, sustained drug release, prolonged circulation in vivo and active targeted accumulation in tumor. These results suggest that HA-TiO2@MWCNTs/HMME has high potential for tumor synergistic phototherapy as a smart theranostic nanoplatform.

  19. Microencapsulation of therapeutic bispecific antibodies producing cells: immunotherapeutic organoids for cancer management.

    Science.gov (United States)

    Saenz del Burgo, Laura; Compte, Marta; Aceves, Mónica; Hernández, Rosa María; Sanz, Laura; Álvarez-Vallina, Luis; Pedraz, Jose Luis

    2015-02-01

    Regardless of the important therapeutic advances developed over the last years for the management of cancer, the fact is that many patients still suffer from a tremendous reduction on their quality of life due to lack of complete selectivity of conventionally administered chemotherapeutic drugs. In the search of more efficacious tumor-targeted therapies, the use of bispecific antibodies (bsAbs) capable of simultaneous binding to tumor-associated antigens and to an activating receptor, such as CD3, has emerged as a promising approach. With the intention to complementing and improving this cancer immunotherapy, human HEK-293 cells have been genetically modified ex vivo to secrete a recombinant anti-CEA (carcinoembryonic antigen) × anti-CD3 bsAb. After encapsulation in alginate-poly-l-lysine microcapsules, bsAb-secreting HEK-293 cells were monitorized for several weeks. This system has proved to be feasible for the maintenance of cell growth and recombinant antibody production giving proof-of-concept of its use as immunotherapeutic organoids in cancer treatment.

  20. The performance of PEGylated nanocapsules of perfluorooctyl bromide as an ultrasound contrast agent.

    Science.gov (United States)

    Díaz-López, Raquel; Tsapis, Nicolas; Santin, Mathieu; Bridal, Sharon Lori; Nicolas, Valérie; Jaillard, Danielle; Libong, Danielle; Chaminade, Pierre; Marsaud, Véronique; Vauthier, Christine; Fattal, Elias

    2010-03-01

    The surface of polymeric nanocapsules used as ultrasound contrast agents (UCAs) was modified with PEGylated phospholipids in order to escape recognition and clearance by the mononuclear phagocyte system and achieve passive tumor targeting. Nanocapsules consisted of a shell of poly(lactide-co-glycolide) (PLGA) encapsulating a liquid core of perfluorooctyl bromide (PFOB). They were decorated with poly(ethylene glycol-2000)-grafted distearoylphosphatidylethanolamine (DSPE-PEG) incorporated in the organic phase before the solvent emulsification-evaporation process. The influence of DSPE-PEG concentration on nanocapsule size, surface charge, morphology, hydrophobicity and complement activation was evaluated. Zeta potential measurements, Hydrophobic interaction chromatography and complement activation provide evidence of DSPE-PEG presence at nanocapsule surface. Electronic microscopy reveals that the core/shell structure is preserved up to 2.64 mg of DSPE-PEG for 100 mg PLGA. In vivo ultrasound imaging was performed in mice bearing xenograft tumor with MIA PaCa-2 cells, either after an intra-tumoral or intravenous injection of nanocapsules. Tumor was observed only after the intra-tumoral injection. Despite the absence of echogenic signal in the tumor after intravenous injection of nanocapsules, histological analysis reveals their accumulation within the tumor tissue demonstrating that tissue distribution is not the unique property required for ultrasound contrast agents to be efficient. (c) 2009 Elsevier Ltd. All rights reserved.

  1. Interior engineering of a viral nanoparticle and its tumor homing properties.

    Science.gov (United States)

    Wen, Amy M; Shukla, Sourabh; Saxena, Pooja; Aljabali, Alaa A A; Yildiz, Ibrahim; Dey, Sourav; Mealy, Joshua E; Yang, Alice C; Evans, David J; Lomonossoff, George P; Steinmetz, Nicole F

    2012-12-10

    The development of multifunctional nanoparticles for medical applications is of growing technological interest. A single formulation containing imaging and/or drug moieties that is also capable of preferential uptake in specific cells would greatly enhance diagnostics and treatments. There is growing interest in plant-derived viral nanoparticles (VNPs) and establishing new platform technologies based on these nanoparticles inspired by nature. Cowpea mosaic virus (CPMV) serves as the standard model for VNPs. Although exterior surface modification is well-known and has been comprehensively studied, little is known of interior modification. Additional functionality conferred by the capability for interior engineering would be of great benefit toward the ultimate goal of targeted drug delivery. Here, we examined the capacity of empty CPMV (eCPMV) particles devoid of RNA to encapsulate a wide variety of molecules. We systematically investigated the conjugation of fluorophores, biotin affinity tags, large molecular weight polymers such as poly(ethylene glycol) (PEG), and various peptides through targeting reactive cysteines displayed selectively on the interior surface. Several methods are described that mutually confirm specific functionalization of the interior. Finally, CPMV and eCPMV were labeled with near-infrared fluorophores and studied side-by-side in vitro and in vivo. Passive tumor targeting via the enhanced permeability and retention effect and optical imaging were confirmed using a preclinical mouse model of colon cancer. The results of our studies lay the foundation for the development of the eCPMV platform in a range of biomedical applications.

  2. A simulation study for radiation treatment planning based on the atomic physics of the proton-boron fusion reaction

    Science.gov (United States)

    Kim, Sunmi; Yoon, Do-Kun; Shin, Han-Back; Jung, Joo-Young; Kim, Moo-Sub; Kim, Kyeong-Hyeon; Jang, Hong-Seok; Suh, Tae Suk

    2017-03-01

    The purpose of this research is to demonstrate, based on a Monte Carlo simulation code, the procedure of radiation treatment planning for proton-boron fusion therapy (PBFT). A discrete proton beam (60 - 120 MeV) relevant to the Bragg peak was simulated using a Monte Carlo n-particle extended (MCNPX, Ver. 2.6.0, National Laboratory, Los Alamos NM, USA) simulation code. After computed tomography (CT) scanning of a virtual water phantom including air cavities, the acquired CT images were converted using the simulation source code. We set the boron uptake regions (BURs) in the simulated water phantom to achieve the proton-boron fusion reaction. Proton sources irradiated the BUR, in the phantom. The acquired dose maps were overlapped with the original CT image of the phantom to analyze the dose volume histogram (DVH). We successfully confirmed amplifications of the proton doses (average: 130%) at the target regions. From the DVH result for each simulation, we acquired a relatively accurate dose map for the treatment. A simulation was conducted to characterize the dose distribution and verify the feasibility of proton-boron fusion therapy (PBFT). We observed a variation in proton range and developed a tumor-targeting technique for treatment that was more accurate and powerful than both conventional proton therapy and boron-neutron capture therapy.

  3. Scattered and Fluorescent Photon Track Reconstruction in a Biological Tissue

    Directory of Open Access Journals (Sweden)

    Maria N. Kholodtsova

    2014-01-01

    Full Text Available Appropriate analysis of biological tissue deep regions is important for tumor targeting. This paper is concentrated on photons’ paths analysis in such biotissue as brain, because optical probing depth of fluorescent and excitation radiation differs. A method for photon track reconstruction was developed. Images were captured focusing on the transparent wall close and parallel to the source fibres, placed in brain tissue phantoms. The images were processed to reconstruct the photons most probable paths between two fibres. Results were compared with Monte Carlo simulations and diffusion approximation of the radiative transfer equation. It was shown that the excitation radiation optical probing depth is twice more than for the fluorescent photons. The way of fluorescent radiation spreading was discussed. Because of fluorescent and excitation radiation spreads in different ways, and the effective anisotropy factor, geff, was proposed for fluorescent radiation. For the brain tissue phantoms it were found to be 0.62±0.05 and 0.66±0.05 for the irradiation wavelengths 532 nm and 632.8 nm, respectively. These calculations give more accurate information about the tumor location in biotissue. Reconstruction of photon paths allows fluorescent and excitation probing depths determination. The geff can be used as simplified parameter for calculations of fluorescence probing depth.

  4. CRISPR-Cas9 as a Powerful Tool for Efficient Creation of Oncolytic Viruses

    Directory of Open Access Journals (Sweden)

    Ming Yuan

    2016-03-01

    Full Text Available The development of oncolytic viruses has led to an emerging new class of cancer therapeutics. Although the safety profile has been encouraging, the transition of oncolytic viruses to the clinical setting has been a slow process due to modifications. Therefore, a new generation of more potent oncolytic viruses needs to be exploited, following our better understanding of the complex interactions between the tumor, its microenvironment, the virus, and the host immune response. The conventional method for creation of tumor-targeted oncolytic viruses is based on homologous recombination. However, the creation of new mutant oncolytic viruses with large genomes remains a challenge due to the multi-step process and low efficiency of homologous recombination. The CRISPR-associated endonuclease Cas9 has hugely advanced the potential to edit the genomes of various organisms due to the ability of Cas9 to target a specific genomic site by a single guide RNA. In this review, we discuss the CRISPR-Cas9 system as an efficient viral editing method for the creation of new oncolytic viruses, as well as its potential future applications in the development of oncolytic viruses. Further, this review discusses the potential of off-target effects as well as CRISPR-Cas9 as a tool for basic research into viral biology.

  5. A Double-Switch Cell Fusion-Inducible Transgene Expression System for Neural Stem Cell-Based Antiglioma Gene Therapy

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    Yumei Luo

    2015-01-01

    Full Text Available Recent progress in neural stem cell- (NSC- based tumor-targeted gene therapy showed that NSC vectors expressing an artificially engineered viral fusogenic protein, VSV-G H162R, could cause tumor cell death specifically under acidic tumor microenvironment by syncytia formation; however, the killing efficiency still had much room to improve. In the view that coexpression of another antitumoral gene with VSV-G can augment the bystander effect, a synthetic regulatory system that triggers transgene expression in a cell fusion-inducible manner has been proposed. Here we have developed a double-switch cell fusion-inducible transgene expression system (DoFIT to drive transgene expression upon VSV-G-mediated NSC-glioma cell fusion. In this binary system, transgene expression is coregulated by a glioma-specific promoter and targeting sequences of a microRNA (miR that is highly expressed in NSCs but lowly expressed in glioma cells. Thus, transgene expression is “switched off” by the miR in NSC vectors, but after cell fusion with glioma cells, the miR is diluted and loses its suppressive effect. Meanwhile, in the syncytia, transgene expression is “switched on” by the glioma-specific promoter. Our in vitro and in vivo experimental data show that DoFIT successfully abolishes luciferase reporter gene expression in NSC vectors but activates it specifically after VSV-G-mediated NSC-glioma cell fusion.

  6. Erythrocyte membrane-coated gold nanocages for targeted photothermal and chemical cancer therapy

    Science.gov (United States)

    Zhu, Dao-Ming; Xie, Wei; Xiao, Yu-Sha; Suo, Meng; Zan, Ming-Hui; Liao, Qing-Quan; Hu, Xue-Jia; Chen, Li-Ben; Chen, Bei; Wu, Wen-Tao; Ji, Li-Wei; Huang, Hui-Ming; Guo, Shi-Shang; Zhao, Xing-Zhong; Liu, Quan-Yan; Liu, Wei

    2018-02-01

    Recently, red blood cell (RBC) membrane-coated nanoparticles have attracted much attention because of their excellent immune escapability; meanwhile, gold nanocages (AuNs) have been extensively used for cancer therapy due to their photothermal effect and drug delivery capability. The combination of the RBC membrane coating and AuNs may provide an effective approach for targeted cancer therapy. However, few reports have shown the utilization of combining these two technologies. Here, we design erythrocyte membrane-coated gold nanocages for targeted photothermal and chemical cancer therapy. First, anti-EpCam antibodies were used to modify the RBC membranes to target 4T1 cancer cells. Second, the antitumor drug paclitaxel (PTX) was encapsulated into AuNs. Then, the AuNs were coated with the modified RBC membranes. These new nanoparticles were termed EpCam–RPAuNs. We characterized the capability of the EpCam–RPAuNs for selective tumor targeting via exposure to near-infrared irradiation. The experimental results demonstrate that EpCam–RPAuNs can effectively generate hyperthermia and precisely deliver the antitumor drug PTX to targeted cells. We also validated the biocompatibility of the EpCam–RAuNs in vitro. By combining the molecularly modified targeting RBC membrane and AuNs, our approach provides a new way to design biomimetic nanoparticles to enhance the surface functionality of nanoparticles. We believe that EpCam–RPAuNs can be potentially applied for cancer diagnoses and therapies.

  7. Folate receptor-targeting gold nanoclusters as fluorescence enzyme mimetic nanoprobes for tumor molecular colocalization diagnosis.

    Science.gov (United States)

    Hu, Dehong; Sheng, Zonghai; Fang, Shengtao; Wang, Yanan; Gao, Duyang; Zhang, Pengfei; Gong, Ping; Ma, Yifan; Cai, Lintao

    2014-01-01

    Nanoprobes with enzyme-like properties attracted a growing interest in early screening and diagnosis of cancer. To achieve high accuracy and specificity of tumor detection, the design and preparation of enzyme mimetic nanoprobes with high enzyme activity, tumor targeting and excellent luminescence property is highly desirable. Herein, we described a novel kind of fluorescence enzyme mimetic nanoprobe based on folate receptor-targeting Au nanoclusters. The nanoprobes exhibited excellent stability, low cytotoxicity, high fluorescence and enzyme activity. We demonstrated that the nanoprobes could be used for tumor tissues fluorescence/visualizing detection. For the same tumor tissue slice, the nanoprobes peroxidase staining and fluorescent staining were obtained simultaneously, and the results were mutually complementary. Therefore, the fluorescence enzyme mimetic nanoprobes could provide a molecular colocalization diagnosis strategy, efficiently avoid false-positive and false-negative results, and further improve the accuracy and specificity of cancer diagnoses. By examining different clinical samples, we demonstrated that the nanoprobes could distinguish efficiently cancerous cells from normal cells, and exhibit a clinical potential for cancer diagnosis.

  8. One-Dimensional Supramolecular Nanoplatforms for Theranostics Based on Co-Assembly of Peptide Amphiphiles.

    Science.gov (United States)

    Kim, Inhye; Han, Eun Hee; Ryu, Jooyeon; Min, Jin-Young; Ahn, Hyungju; Chung, Young-Ho; Lee, Eunji

    2016-10-10

    We report a simple and facile strategy for the preparation of multifunctional nanoparticles with programmable properties using self-assembly of precisely designed block amphiphiles in an aqueous solution-state. Versatile, supramolecular nanoplatform for personalized needs, particularly-theranostics, was fabricated by coassembly of peptide amphiphiles (PAs) in aqueous solution, replacing time-consuming and inaccessible chemical synthesis. Fibrils, driven by the assembly of hydrophobic β-sheet-forming peptide block, were utilized as a nanotemplate for drug loading within their robust core. PAs were tagged with octreotide [somatostatin (SST) analogue] for tumor-targeting or were conjugated with paramagnetic metal ion (Gd3+)-chelating 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for magnetic resonance (MR) imaging. The two PA types were coassembled to integrate each PA function into original fibrillar nanotemplates. The adoption of a bulky target-specific cyclic octreotide and β-sheet-forming peptide with enhanced hydrophobicity led to a morphological transition from conventional fibrils to helical fibrils. The resulting one-dimensional nanoaggregates allowed the successful intracellular delivery of doxorubicin (DOX) to MCF-7 cancer cells overexpressing SST receptor (SSTR) and MR imaging by enabling high longitudinal (T1) relaxivity of water protons. Correlation between the structural nature of fibrils formed by PA coassembly and contrast efficacy was elucidated. The coassembly of PAs with desirable functions may thus be a useful strategy for the generation of tailor-made biocompatible nanomaterials.

  9. Targeted superparamagnetic iron oxide nanoparticles for early detection of cancer: Possibilities and challenges.

    Science.gov (United States)

    Bakhtiary, Zahra; Saei, Amir Ata; Hajipour, Mohammad J; Raoufi, Mohammad; Vermesh, Ophir; Mahmoudi, Morteza

    2016-02-01

    Nanomedicine, the integration of nanotechnological tools in medicine demonstrated promising potential to revolutionize the diagnosis and treatment of various human health conditions. Nanoparticles (NPs) have shown much promise in diagnostics of cancer, especially since they can accommodate targeting molecules on their surface, which search for specific tumor cell receptors upon injection into the blood stream. This concentrates the NPs in the desired tumor location. Furthermore, such receptor-specific targeting may be exploited for detection of potential metastases in an early stage. Some NPs, such as superparamagnetic iron oxide NPs (SPIONs), are also compatible with magnetic resonance imaging (MRI), which makes their clinical translation and application rather easy and accessible for tumor imaging purposes. Furthermore, multifunctional and/or theranostic NPs can be used for simultaneous imaging of cancer and drug delivery. In this review article, we will specifically focus on the application of SPIONs in early detection and imaging of major cancer types. Super-paramagnetic iron oxide nanoparticles (SPIONs) have been reported by many to be useful as an MRI contrast agent in the detection of tumors. To further enhance the tumor imaging, SPIONs can be coupled with tumor targeting motifs. In this article, the authors performed a comprehensive review on the current status of using targeted SPIONS in tumor detection and also the potential hurdles to overcome. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Photosensitizing Nanoparticles and The Modulation of Reactive Oxygen Species generation

    Directory of Open Access Journals (Sweden)

    Dayane Batista Tada

    2015-05-01

    Full Text Available The association of PhotoSensitizer (PS molecules with nanoparticles (NPs forming photosensitizing NPs, has emerged as a therapeutic strategy to improve PS tumor targeting, to protect PS from deactivation reactions and to enhance both PS solubility and circulation time. Since association with NPs usually alters PS photophysical and photochemical properties, photosensitizing NPs are an important tool to modulate reactive oxygen species (ROS generation. Depending on the design of the photosensitizing NP, i.e., type of PS, the NP material and the method applied for the construction of the photosensitizing NP, the deactivation routes of the excited state can be controlled, allowing the generation of either singlet oxygen or other ROS. Controlling the type of generated ROS is desirable not only in biomedical applications, as in Photodynamic Therapy where the type of ROS affects therapeutic efficiency, but also in other technological relevant fields like energy conversion, where the electron and energy transfer processes are necessary to increase the efficiency of photoconversion cells. The current review highlights some of the recent developments in the design of Photosensitizing NPs aimed at modulating the primary photochemical events after light absorption.

  11. RGD-based strategies for improving antitumor activity of paclitaxel-loaded liposomes in nude mice xenografted with human ovarian cancer.

    Science.gov (United States)

    Zhao, Hui; Wang, Jian-Cheng; Sun, Qi-Shi; Luo, Chun-Lei; Zhang, Qiang

    2009-01-01

    Tumor-targeting drug delivery systems are being the ideal carrier for systemic administration of antiproliferative drugs. RGD peptide (arginine-glycine-aspartic acid) modified liposomes containing paclitaxel (RGD-SSL-PTX). The arginine-glycine-aspartic acid tripeptide (RGD) modified sterically stabilized liposomes (SSL) containing paclitaxel (PTX) (RGD-SSL-PTX), which could increase targeting to tumor by binding with the integrin receptors overexpressed on tumor cells. The encapsulation efficiency was more than 90% and the mean particle size was of 120 nm with a narrow size distribution. It was indicated that significant cytotoxicity (3.5 times lower IC(50)) was found in the SKOV-3 human ovarian cancer cells treated with RGD-SSL-PTX preparation, as well as the intracellular uptake of liposomes (a 6.21-fold increase in fluorescence intensity), when compared to those of non-targeted liposomes (SSL). For in vivo antitumor activity, it was shown in the present study that RGD-SSL-PTX preparation had the strongest tumor growth inhibition among the test formulations (P < 0.05) in BALB/c nude mice xenografted with SKOV-3 solid tumor. Meanwhile, there was no significant change in the body weight of the animals treated with RGD-SSL-PTX for intravenous injection at a dose of 12.5 mg/kg. It was suggested that the RGD-SSL-PTX preparation might have a great advantage over present-day chemotherapy with Taxol in curing those tumors overexpressing integrin receptors.

  12. The anti-tumoral efficacy of a docetaxel-loaded liposomal drug delivery system modified with transferrin for ovarian cancer.

    Science.gov (United States)

    Yuan, M Q; Zhu, F; Lou, J Y; Yuan, W M; Fu, L; Liu, S; Zhang, Z Z; Liu, C Y; He, Q

    2014-04-01

    To reduce the toxic effect on normal cells and improve the treatment effects of docetaxel, a novel transferrin modified docetaxel-loaded long circulating liposome for ovarian tumor was established for the first time. The transferrin-modified long-circulating liposomes loaded with docetaxel (TF-LP-DOC) were prepared by the post-insertion method and exhibited excellent characteristics in terms of particle size, encapsulation efficiency and stability. We investigated the targeting efficiencies of liposomes by the cellular uptake in vitro and biodistribution in vivo, and identified the therapeutic effects using cytotoxicity experiment (in vitro)and tumor growth inhibition (in vivo) on ovarian cancer. The in vitro and in vivo results showed that TF-LP-DOC were successfully established and presented an enhanced targeting ability. With decreased side effect and improved anti-tumor efficacy of chemotherapeutic drugs, TF-LP-DOC proved itself to be a very promising tumor targeted drug delivery system. © Georg Thieme Verlag KG Stuttgart · New York.

  13. Preparation of hollow core/shell Fe3O4@graphene oxide composites as magnetic targeting drug nanocarriers.

    Science.gov (United States)

    Wang, Junmei; Fang, Jianjun; Fang, Pan; Li, Xian; Wu, Shijie; Zhang, Wenjing; Li, Sufang

    2017-03-01

    A main challenge for anticancer drugs is that the drugs can not arrive the cancer tissue at right time. In this work, a magnetic targeting nanoparticle based on hollow Fe 3 O 4 /graphene oxide (Fe 3 O 4 /GO) was developed as a potential tumor targeting drug carriers. The morphology results showed the Fe 3 O 4 nanoparticles were uniformly wrapped by graphene oxide. After coating with graphene oxide, the Fe 3 O 4 /GO showed a higher saturation magnetization of 71.47 emu g -1 as compared to neat Fe 3 O 4 nanoparticles. The drug loading and releasing experiment indicated the obtained Fe 3 O 4 /GO has a good loading capacity of of 0.41 mg mg -1 for 5-fluorouracil (5-FU) and a positive sensitive of acidic atmosphere. The CCK-8 assays of CMEC viability demonstrated the hollow Fe 3 O 4 /GO nanocarriers do not statistically exhibit toxicity with the concentration increasing from 2.5 to 40 μg mL -1 in vitro. These results suggested the prepared Fe 3 O 4 /GO has a potential application in anticancer drugs nanocarriers.

  14. Bifunctional Elastin-like Polypeptide Nanoparticles Bind Rapamycin and Integrins and Suppress Tumor Growth in Vivo.

    Science.gov (United States)

    Dhandhukia, Jugal P; Shi, Pu; Peddi, Santosh; Li, Zhe; Aluri, Suhaas; Ju, Yaping; Brill, Dab; Wang, Wan; Janib, Siti M; Lin, Yi-An; Liu, Shuanglong; Cui, Honggang; MacKay, J Andrew

    2017-11-15

    Recombinant protein-polymer scaffolds such as elastin-like polypeptides (ELPs) offer drug-delivery opportunities including biocompatibil