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

  1. THE PSYCHOLOGY OF SELF-IMMOLATION IN INDIA

    Mahla, V.P.; Bhargava, S. C.; Dogra, R.; S. Shome

    1992-01-01

    Four cases of attempted self immolation were investigated. The psychiatric evaluation was done according to DSM- III-R criteria. The findings are discussed with reference to the psychological and socio-cultural perspectives.

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

    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.

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

    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 ∼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 GeV protons

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

    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

  5. Self-immolative linkers in polymeric delivery systems

    Blencowe, Christopher A; Russell, Andrew T; Greco, Francesca; Hayes, Wayne; Thornthwaite, David W

    2011-01-01

    There has been significant interest in the methodologies of controlled release for a diverse range of applications spanning drug delivery, biological and chemical sensors, and diagnostics. The advancement in novel substrate-polymer coupling moieties has led to the discovery of self-immolative linkers. This new class of linker has gained popularity in recent years in polymeric release technology as a result of stable bond formation between protecting and leaving groups, which becomes labile up...

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

    Mohsen Rezaeian

    2014-01-01

    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 t...

  7. Self-immolation and its adverse life-events risk factors: results from an Iranian population

    Alireza Ahmadi; Schwebel, David C.; Shahrzad Bazargan-Hejazi

    2015-01-01

    Abstract: Background: Despite considerable loss of life by deliberate self-burning in low and middle-income countries, few scholars have examined psychiatric factors such as adverse life events that may be related to self-immolation. Methods: This case-control study investigated adverse life-events as risk factors for self-immolation patients admitted to a burn center serving the western region of Iran. Variables inves-tigated included the following adverse life-events: unplanned pregna...

  8. Self-immolation and its adverse life-events risk factors: results from an Iranian population

    Alireza Ahmadi

    2015-01-01

    Full Text Available Abstract: Background: Despite considerable loss of life by deliberate self-burning in low and middle-income countries, few scholars have examined psychiatric factors such as adverse life events that may be related to self-immolation. Methods: This case-control study investigated adverse life-events as risk factors for self-immolation patients admitted to a burn center serving the western region of Iran. Variables inves-tigated included the following adverse life-events: unplanned pregnancy, infertility, homelessness, financial hardship, problems with friends, intimate relationship break-up , school or university failure, anxiety about school/university performance, problems at work, personal history of suicide attempts, family history of suicide attempts, individual history of mental disorders, and malignant disease. Results: Financial hardship (OR=3.35, 95% CI=1.19-9.90, intimate relationship break-up (OR=5.45, 95% CI=1.20-11.99, and personal history of suicide attempts (OR=7.00, 95% CI=1.38-35.48 were associated with increased risk of self-immolation. Conclusions: This study suggests that financial hardship, intimate relationship break-ups, and personal history of suicide attempts are risk factors for self-immolation. Other variables studied did not play a role as individually protective or risk factors for self-immolation. Further study is needed to substantiate findings of this study and direct research toward tailoring culturally sensitive, empirically-supported interventions for prevention of self-immolation.

  9. What factors play a role in preventing self-immolation?Results from a case-control study in Iran

    Hosein Karim

    2015-07-01

    Full Text Available Abstract: Background: To investigate factors related to prevention of self-immolation in west of Iran. Methods: In a case-control study, 30 consecutive cases of deliberate self-inflicted burns admitted to the regional burn center (Imam Khomeini hospital in Kermanshah province, Iran were compared with controls selected from the community and matched by sex, age,district-county of residence, and rural vs urban living environment. The following characteristics relevant to preventing self immolation were collected from all cases and controls: main domestic fuel used in the household, awareness about complications of burn injuries, and use of counseling services. Results: Descriptive analyses revealed that kerosene was the main domestic fuel in the household for 83% of cases. Not surprisingly, the main means of self-immolation in 93% of the patients was kerosene, with other fuels such as petrol and domestic gas used in remaining cases. The majority of cases and controls were aware of the potential complications of burn injuries. Use of counseling services was more common in controls. Conclusions: All three aspects of preventing self-immolation – having kerosene and other fuels in the home, being aware of the complications of burn injuries, and using counseling services were present in both the cases and controls. This suggests a large portion of residents in rural Iran are potential self-immolation victims. Increasing preventive strategies may reduce risk of suicide by self-immolation.

  10. Epidemiology of Self-Immolation in the North-West of Iran

    2005-01-01

    Aim: This study was carried out to investigate the incidence, time trend, influencing factors and survival of self-immolation in the North-West of Iran. Methods: In this research, medical records of ninety eight cases who attempted suicide by selfimmolation between 1998 and 2003 were studied. Data collected included age, weight, sex, marital status, date of burn, length of stay in the hospital, body surface burned (in percent), external cause of death, psychiatric diagnosis of patients, and o...

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

    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.

  12. The Methylene Alkoxy Carbamate Self-Immolative Unit: Utilization for the Targeted Delivery of Alcohol-Containing Payloads with Antibody-Drug Conjugates.

    Kolakowski, Robert V; Haelsig, Karl T; Emmerton, Kim K; Leiske, Chris I; Miyamoto, Jamie B; Cochran, Julia H; Lyon, Robert P; Senter, Peter D; Jeffrey, Scott C

    2016-07-01

    A strategy for the conjugation of alcohol-containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self-immolative unit. A series of MAC β-glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution-dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of β-glucuronidase. To assess the MAC technology for ADCs, the potent microtubule-disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC β-glucuronide AE drug linker to the anti-CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self-immolative unit for alcohol-containing payloads within ADCs, a class that has not been widely exploited. PMID:27198854

  13. High efficiency diffusion molecular retention tumor targeting.

    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.

  14. Carbohydrate plasma expanders for passive tumor targeting

    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......Da and HES 450 kDa) and dextran (DEX 500 kDa). Particle size and molecular weight distribution were determined by asymmetric flow field-flow fractionation (AF4). The biodistribution was investigated non-invasively in nude mice using multispectral optical imaging. The most promising polymer conjugate was...

  15. Tumor targeting using liposomal antineoplastic drugs

    Jörg Huwyler

    2008-03-01

    Full Text Available Jörg Huwyler1, Jürgen Drewe2, Stephan Krähenbühl21University of Applied Sciences Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland; 2Department of Research and Division of Clinical Pharmacology, University Hospital Basel, Basel, SwitzerlandAbstract: During the last years, liposomes (microparticulate phospholipid vesicles have beenused with growing success as pharmaceutical carriers for antineoplastic drugs. Fields of application include lipid-based formulations to enhance the solubility of poorly soluble antitumordrugs, the use of pegylated liposomes for passive targeting of solid tumors as well as vector-conjugated liposomal carriers for active targeting of tumor tissue. Such formulation and drug targeting strategies enhance the effectiveness of anticancer chemotherapy and reduce at the same time the risk of toxic side-effects. The present article reviews the principles of different liposomal technologies and discusses current trends in this field of research.Keywords: tumor targeting, antineoplastic drugs, liposomes, pegylation, steric stabilization, immunoliposomes

  16. Intricacies for Posttranslational Tumor-Targeted Cytokine Gene Therapy

    Jeffry Cutrera

    2013-01-01

    Full Text Available The safest and most effective cytokine therapies require the favorable accumulation of the cytokine in the tumor environment. While direct treatment into the neoplasm is ideal, systemic tumor-targeted therapies will be more feasible. Electroporation-mediated transfection of cytokine plasmid DNA including a tumor-targeting peptide-encoding sequence is one method for obtaining a tumor-targeted cytokine produced by the tumor-bearing patient’s tissues. Here, the impact on efficacy of the location of targeting peptide, choice of targeting peptide, tumor histotype, and cytokine utilization are studied in multiple syngeneic murine tumor models. Within the same tumor model, the location of the targeting peptide could either improve or reduce the antitumor effect of interleukin (IL12 gene treatments, yet in other tumor models the tumor-targeted IL12 plasmid DNAs were equally effective regardless of the peptide location. Similarly, the same targeting peptide that enhances IL12 therapies in one model fails to improve the effect of either IL15 or PF4 for inhibiting tumor growth in the same model. These interesting and sometimes contrasting results highlight both the efficacy and personalization of tumor-targeted cytokine gene therapies while exposing important aspects of these same therapies which must be considered before progressing into approved treatment options.

  17. Macrocyclic Chelator Assembled RGD Multimers for Tumor Targeting

    Zhang, Xiaofen; Liu, Hongguang; Miao, Zheng; Kimura, Richard; Fan, Feiyue; Cheng, Zhen

    2011-01-01

    Macrocyclic chelators have been extensively used for complexation of metal ions. A widely used chelator, DOTA, has been explored as a molecular platform to assemble multiple bioactive peptides in this paper. The multivalent DOTA-peptide bioconjugates demonstrate promising tumor targeting ability.

  18. Prostate tumor targeting with polymer conjugate bearing a synthetic nonapeptide

    Pechar, Michal; Pola, Robert; Ulbrich, Karel; Fabra, A.

    Valencia: Centro de Investigación Príncipe Felipe, 2008. s. 95. [International Symposium on Polymer Therapeutics: From Laboratory to Clinical Practice /7./. 26.05.2008-28.05.2008, Valencia] R&D Projects: GA ČR GA203/08/0543 Institutional research plan: CEZ:AV0Z40500505 Keywords : prostate * tumor targeting * polymer conjugate Subject RIV: CD - Macromolecular Chemistry

  19. Tumor targeting of radiolabeled antibodies using HYNIC chelate

    There is an increasing interest in the use of labeled antibodies for diagnosis of cancers as well as for therapy. Various radiolabeling methods have been used in order to obtain better tumor specific targeting for detection and therapy. It was generally used to tumor targeted immunotherapy and immunodetection that lym-1, mouse monoclonal antibody, was specific binding to surface antigen of Raji. The 3E8 antibody was produced from humanized anti-TAG-72 monoclonal antibody (AKA) by amino acid change in 95-99 residues of heavy chain complementary determinant regions (HCDRs) 3 using phage displayed library technology. In this study, we are investigating the usefulness of HYNIC chelate as a bifunctional chelating agent in radioimmunodetecton of tumor. Two types of antibodies, Lym-1 and 3E8, were used for the conjugation with HYNIC chelate. Lym-1 and 3E8 are specific antibodies to surface antigen of Non-Hogkin's lymphoma and TAG-72 antigen of colorectal carcinoma, respectively. We prepare HYNIC-antibody conjugates, determine radiolabeling yield with 99mTc and evaluate tumor targeting in tumor bearing nude mice model

  20. Tumor Targeting and Drug Delivery by Anthrax Toxin.

    Bachran, Christopher; Leppla, Stephen H

    2016-01-01

    Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery. PMID:27376328

  1. New method for large scale production of medically applicable Actinium-225 and Radium-223

    Alpha-emitters (211At, 212Bi, 213Bi, 223Ra, 225Ac) are promising for targeted radiotherapy of cancer. Only two alpha decays near a cell membrane result in 50% death of cancer cell and only a single decay inside the cell is required for this. 225Ac may be used either directly or as a mother radionuclide in 213Bi isotope generator. Production of 225Ac is provided by three main suppliers - Institute for Transuranium Elements in Germany, Oak Ridge National Laboratory in USA and Institute of Physics and Power Engineering in Obninsk, Russia. The current worldwide production of 225Ac is approximately 1.7 Ci per year that corresponds to only 100-200 patients that could be treated annually. The common approach for 225Ac production is separation from mother 229Th or irradiation of 226Ra with protons in a cyclotron. Both the methods have some practical limitations to be applied routinely. 225Ac can be also produced by irradiation of natural thorium with medium energy protons . Cumulative cross sections of 225Ac, 227Ac, 227Th, 228Th formations have been obtained recently. Thorium targets (1-9 g) were irradiated by 114-91 MeV proton beam (1-50 μA) at INR linear accelerator. After dissolution in 8 M HNO3 + 0.004 M HF thorium was removed by double LLX by HDEHP in toluene (1:1). Ac and REE were pre-concentrated and separated from Ra and most fission products by DGA-Resin (Triskem). After washing out by 0.01 M HNO3 Ac was separated from REE by TRU Resin (Triskem) in 3 M HNO3 media. About 6 mCi 225Ac were separated in hot cell with chemical yield 85%. The method may be upscaled for production of Ci amounts of the radionuclide. The main impurity is 227Ac (0.1% at the EOB) but it does not hinder 225Ac from being used for medical 225Ac/213Bi generators. (author)

  2. Synthesis of chelating agents for actinium 225 complexation and its application in radioimmunotherapy

    Immunotherapy with radiolabeled antibodies should allow fairly specific targeting of certain cancers. However, iodine 131 may not be the best isotope for tumor therapy because of its limited specific activity, low beta-energy, relatively long half life and strong gamma emission. Another approach to improve therapeutic efficacy is the use of replacement isotopes with better physical properties. Chelator that can hold radio-metals with high stability under physiological conditions are essential to avoid excessive damage to non-target cells; Moreover, the development of new bifunctional chelating agents is essential for this purpose. Accordingly, our efforts have been directed, for several years, to the synthesis of original chelating agents likely to form stable complexes in vivo with the numerous potential candidates for such applications. Therefore, we have developed a new simple and efficient synthesis pathway of 2-(4-iso-thio-cyanate-benzyl)-1,4,7,10,13,16- hexa-aza-cyclo-hexadecane- 1,4,7,10,13,16-hexa-acetic acid, though functionalized on the cycle by a termination allowed coupling to an antibody or any other biological substance such as a hapten. (author)

  3. A hybrid actuated microrobot using an electromagnetic field and flagellated bacteria for tumor-targeting therapy.

    Li, Donghai; Choi, Hyunchul; Cho, Sunghoon; Jeong, Semi; Jin, Zhen; Lee, Cheong; Ko, Seong Young; Park, Jong-Oh; Park, Sukho

    2015-08-01

    In this paper, we propose a new concept for a hybrid actuated microrobot for tumor-targeting therapy. For drug delivery in tumor therapy, various electromagnetic actuated microrobot systems have been studied. In addition, bacteria-based microrobot (so-called bacteriobot), which use tumor targeting and the therapeutic function of the bacteria, has also been proposed for solid tumor therapy. Compared with bacteriobot, electromagnetic actuated microrobot has larger driving force and locomotive controllability due to their position recognition and magnetic field control. However, because electromagnetic actuated microrobot does not have self-tumor targeting, they need to be controlled by an external magnetic field. In contrast, the bacteriobot uses tumor targeting and the bacteria's own motility, and can exhibit self-targeting performance at solid tumors. However, because the propulsion forces of the bacteria are too small, it is very difficult for bacteriobot to track a tumor in a vessel with a large bloodstream. Therefore, we propose a hybrid actuated microrobot combined with electromagnetic actuation in large blood vessels with a macro range and bacterial actuation in small vessels with a micro range. In addition, the proposed microrobot consists of biodegradable and biocompatible microbeads in which the drugs and magnetic particles can be encapsulated; the bacteria can be attached to the surface of the microbeads and propel the microrobot. We carried out macro-manipulation of the hybrid actuated microrobot along a desired path through electromagnetic field control and the micro-manipulation of the hybrid actuated microrobot toward a chemical attractant through the chemotaxis of the bacteria. For the validation of the hybrid actuation of the microrobot, we fabricated a hydrogel microfluidic channel that can generate a chemical gradient. Finally, we evaluated the motility performance of the hybrid actuated microrobot in the hydrogel microfluidic channel. We expect

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

    Hosoya, Hitomi; Andrey S Dobroff; 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

    2016-01-01

    The main goal in the emerging field of cancer nanomedicine is to generate, standardize, and produce multifunctional carriers designed to improve the response of drugs against tumors. Here we report the design, development, and preclinical validation of a ligand-directed bioinorganic platform that integrates tumor targeting, receptor-mediated cell internalization, photon-to-heat conversion, and drug delivery. This enabling hydrogel-based technology can accommodate a broad variety of ligands, n...

  5. Modulation of Hydrogel Nanoparticle Intracellular Trafficking by Multivalent Surface Engineering with Tumor Targeting Peptide†

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

    2013-01-01

    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-i...

  6. Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor

    Weon Sup Shin; Jiyou Han; Rajesh Kumar; Gyung Gyu Lee; Sessler, Jonathan L.; Jong-Hoon Kim; Jong Seung Kim

    2016-01-01

    We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38—a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a ...

  7. Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

    Bao, Qi; Zhao, Yue; Niess, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl-Walter; Huss, Ralf; Peter J Nelson; Bruns, Christiane J.

    2012-01-01

    Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associa...

  8. In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy

    Puvanakrishnan P

    2012-03-01

    Full Text Available Priyaveena Puvanakrishnan1, Jaesook Park1, Deyali Chatterjee2, Sunil Krishnan2, James W Tunnell11Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA; 2The UT MD Anderson Cancer Center, Houston, TX, USAAbstract: Gold nanoparticles (GNPs have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle’s geometric properties (eg, size and dosing strategy (eg, number and amount of injections. The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs and gold nanorods (GNRs for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.Keywords: gold nanorods, gold nanoshells, tumor targeting

  9. Iodinated hyaluronic acid oligomer-based nanoassemblies for tumor-targeted drug delivery and cancer imaging.

    Lee, Jae-Young; Chung, Suk-Jae; Cho, Hyun-Jong; Kim, Dae-Duk

    2016-04-01

    Nano-sized self-assemblies based on amphiphilic iodinated hyaluronic acid (HA) were developed for use in cancer diagnosis and therapy. 2,3,5-Triiodobenzoic acid (TIBA) was conjugated to an HA oligomer as a computed tomography (CT) imaging modality and a hydrophobic residue. Nanoassembly based on HA-TIBA was fabricated for tumor-targeted delivery of doxorubicin (DOX). Cellular uptake of DOX from nanoassembly, compared to a DOX solution group, was enhanced via an HA-CD44 receptor interaction, and subsequently, the in vitro antitumor efficacy of DOX-loaded nanoassembly was improved in SCC7 (CD44 receptor positive squamous cell carcinoma) cells. Cy5.5, a near-infrared fluorescence (NIRF) dye, was attached to the HA-TIBA conjugate and the in vivo tumor targetability of HA-TIBA nanoassembly, which is based on the interaction between HA and CD44 receptor, was demonstrated in a NIRF imaging study using an SCC7 tumor-xenografted mouse model. Tumor targeting and cancer diagnosis with HA-TIBA nanoassembly were verified in a CT imaging study using the SCC7 tumor-xenografted mouse model. In addition to efficient cancer diagnosis using NIRF and CT imaging modalities, improved antitumor efficacies were shown. HA and TIBA can be used to produce HA-TIBA nanoassembly that may be a promising theranostic nanosystem for cancers that express the CD44 receptor. PMID:26874284

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

    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. PMID:26839407

  11. Functionalized Single-Walled Carbon Nanotubes as Rationally Designed Vehicles for Tumor-Targeted Drug Delivery

    A novel single-walled carbon nanotube (SWNT)-based tumor-targeted drug delivery system (DDS) has been developed, which consists of a functionalized SWNT linked to tumor-targeting modules as well as prodrug modules. There are three key features of this nanoscale DDS: (a) use of functionalized SWNTs as a biocompatible platform for the delivery of therapeutic drugs or diagnostics, (b) conjugation of prodrug modules of an anticancer agent (taxoid with a cleavable linker) that is activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release, and (c) attachment of tumor-recognition modules (biotin and a spacer) to the nanotube surface. To prove the efficacy of this DDS, three fluorescent and fluorogenic molecular probes were designed, synthesized, characterized, and subjected to the analysis of the receptor-mediated endocytosis and drug release inside the cancer cells (L1210FR leukemia cell line) by means of confocal fluorescence microscopy. The specificity and cytotoxicity of the conjugate have also been assessed and compared with L1210 and human noncancerous cell lines. Then, it has unambiguously been proven that this tumor-targeting DDS works exactly as designed and shows high potency toward specific cancer cell lines, thereby forming a solid foundation for further development.

  12. Cholesterol-modified poly(lactide-co-glycolide) nanoparticles for tumor-targeted drug delivery.

    Lee, Jeong-Jun; Lee, Song Yi; Park, Ju-Hwan; Kim, Dae-Duk; Cho, Hyun-Jong

    2016-07-25

    Poly(lactide-co-glycolide)-cholesterol (PLGA-C)-based nanoparticles (NPs) were developed for the tumor-targeted delivery of curcumin (CUR). PLGA-C/CUR NPs with ∼200nm mean diameter, narrow size distribution, and neutral zeta potential were fabricated by a modified emulsification-solvent evaporation method. The existence of cholesterol moiety in PLGA-C copolymer was confirmed by proton nuclear magnetic resonance ((1)H NMR) analysis. In vitro stability of developed NPs after 24h incubation was confirmed in phosphate buffered saline (PBS) and serum media. Sustained (∼6days) and pH-responsive drug release profiles from PLGA-C NPs were presented. Blank PLGA and PLGA-C NPs exhibited a negligible cytotoxicity in Hep-2 (human laryngeal carcinoma) cells in the tested concentration range. According to the results of flow cytometry and confocal laser scanning microscopy (CLSM) studies, PLGA-C NPs presented an improved cellular accumulation efficiency, compared to PLGA NPs, in Hep-2 cells. Enhanced in vivo tumor targetability of PLGA-C NPs, compared to PLGA NPs, in Hep-2 tumor-xenografted mouse model was also verified by a real-time near-infrared fluorescence (NIRF) imaging study. Developed PLGA-C NPs may be a candidate of efficient and biocompatible nanosystems for tumor-targeted drug delivery and cancer imaging. PMID:27286639

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

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

    2016-07-01

    Correction for 'Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy' by Kyoung Sub Kim, et al., Nanoscale, 2016, DOI: 10.1039/c6nr02273a. PMID:27300478

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

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

    2016-06-01

    Correction for `Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy' by Kyoung Sub Kim, et al., Nanoscale, 2016, DOI: 10.1039/c6nr02273a.

  15. 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

    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.

  16. Hyaluronic acid-functionalized single-walled carbon nanotubes as tumor-targeting MRI contrast agent

    Hou L

    2015-07-01

    Full Text Available Lin Hou,* Huijuan Zhang,* Yating Wang, Lili Wang, Xiaomin Yang, Zhenzhong ZhangSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China*These authors contributed equally to this workAbstract: A tumor-targeting carrier, hyaluronic acid (HA-functionalized single-walled carbon nanotubes (SWCNTs, was explored to deliver magnetic resonance imaging (MRI contrast agents (CAs targeting to the tumor cells specifically. In this system, HA surface modification for SWCNTs was simply accomplished by amidation process and could make this nanomaterial highly hydrophilic. Cellular uptake was performed to evaluate the intracellular transport capabilities of HA-SWCNTs for tumor cells and the uptake rank was HA-SWCNTs> SWCNTs owing to the presence of HA, which was also evidenced by flow cytometry. The safety evaluation of this MRI CAs was investigated in vitro and in vivo. It revealed that HA-SWCNTs could stand as a biocompatible nanocarrier and gadolinium (Gd/HA-SWCNTs demonstrated almost no toxicity compared with free GdCl3. Moreover, GdCl3 bearing HA-SWCNTs could significantly increase the circulation time for MRI. Finally, to investigate the MRI contrast enhancing capabilities of Gd/HA-SWCNTs, T1-weighted MR images of tumor-bearing mice were acquired. The results suggested Gd/HA-SWCNTs had the highest tumor-targeting efficiency and T1-relaxivity enhancement, indicating HA-SWCNTs could be developed as a tumor-targeting carrier to deliver the CAs, GdCl3, for the identifiable diagnosis of tumor.Keywords: gadolinium, magnetic resonance, SWCNTs, hyaluronic acid, contrast agent

  17. Tumor-targeting Salmonella typhimurium A1-R arrests growth of breast-cancer brain metastasis

    Zhang, Yong; Miwa, Shinji; Zhang, Nan; Hoffman, Robert M.; Zhao, Ming

    2014-01-01

    Brain metastasis is a morbid, treatment-resistant, end-stage frequent occurrence in breast cancer patients. The aim of this study was to evaluate the efficacy of tumor-targeting Salmonella typhimurium A1-R on breast cancer brain metastases. High brain-metastatic variants of murine 4T1 breast cancer cells expressing red fluorescent protein (RFP) were injected orthotopically in the mammary fat pad in non-transgenic nude mice or in the left ventricle of non-transgenic nude mice and transgenic nu...

  18. Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody

    Schwartz, J; O' Donoghue, J A; Humm, J L [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); Jaggi, J S [Bristol-Myers Squibb, Plainsboro, NJ (United States); Ruan, S; Larson, S M [Nuclear Medicine Service Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); McDevitt, M; Scheinberg, D A, E-mail: schwarj1@mskcc.org [Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10065 (United States)

    2011-02-07

    Clinical therapeutic studies using {sup 225}Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of {sup 225}Ac. The purpose of this study was to determine the amount of {sup 225}Ac and non-equilibrium progeny in the mouse kidney after the injection of {sup 225}Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with {sup 225}Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess {sup 213}Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess {sup 213}Bi reaching the kidney ({gamma}-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq{sup -1}, of which 0.46 (SD 0.16) Gy kBq{sup -1} (i.e. 60%) was due to non-equilibrium excess {sup 213}Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess {sup 213}Bi (0.31 (SD 0.11) Gy kBq{sup -1}) represented {approx}46% of the total. For the medulla the dose contribution from excess {sup 213}Bi (0.81 (SD 0.28) Gy kBq{sup -1}) was {approx}80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq{sup -1} following administration of {sup 225}Ac-huM195 with non-equilibrium excess {sup 213}Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of {sup 225}Ac radioimmunotherapy.

  19. Purification of radium-226 for the manufacturing of actinium-225 in a cyclotron for alpha-immunotherapy

    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.

  20. In vivo tomographic imaging with fluorescence and MRI using tumor-targeted dual-labeled nanoparticles

    Zhang Y

    2013-12-01

    Full Text Available Yue Zhang,1 Bin Zhang,1 Fei Liu,1,2 Jianwen Luo,1,3 Jing Bai1 1Department of Biomedical Engineering, School of Medicine, 2Tsinghua-Peking Center for Life Sciences, 3Center for Biomedical Imaging Research, Tsinghua University, Beijing, People's Republic of China Abstract: Dual-modality imaging combines the complementary advantages of different modalities, and offers the prospect of improved preclinical research. The combination of fluorescence imaging and magnetic resonance imaging (MRI provides cross-validated information and direct comparison between these modalities. Here, we report on the application of a novel tumor-targeted, dual-labeled nanoparticle (NP, utilizing iron oxide as the MRI contrast agent and near infrared (NIR dye Cy5.5 as the fluorescent agent. Results of in vitro experiments verified the specificity of the NP to tumor cells. In vivo tumor targeting and uptake of the NPs in a mouse model were visualized by fluorescence and MR imaging collected at different time points. Quantitative analysis was carried out to evaluate the efficacy of MRI contrast enhancement. Furthermore, tomographic images were also acquired using both imaging modalities and cross-validated information of tumor location and size between these two modalities was revealed. The results demonstrate that the use of dual-labeled NPs can facilitate the dual-modal detection of tumors, information cross-validation, and direct comparison by combing fluorescence molecular tomography (FMT and MRI. Keywords: dual-modality, fluorescence molecular tomography (FMT, magnetic resonance imaging (MRI, nanoparticle

  1. Electrosprayed nanocomposites based on hyaluronic acid derivative and Soluplus for tumor-targeted drug delivery.

    Lee, Song Yi; Lee, Jeong-Jun; Park, Ju-Hwan; Lee, Jae-Young; Ko, Seung-Hak; Shim, Jae-Seong; Lee, Jongkook; Heo, Moon Young; Kim, Dae-Duk; Cho, Hyun-Jong

    2016-09-01

    Nanocomposite (NC) based on hyaluronic acid-ceramide (HACE) and Soluplus (SP) was fabricated by electrospraying for the tumor-targeted delivery of resveratrol (RSV). Amphiphilic property of both HACE and SP has been used to entrap RSV in the internal cavity of NC. Electrospraying with established experimental conditions produced HACE/SP/RSV NC with 230nm mean diameter, narrow size distribution, negative zeta potential, and >80% drug entrapment efficiency. Sustained and pH-dependent drug release profiles were observed in drug release test. Cellular uptake efficiency of HACE/SP NC was higher than that of SP NC, mainly based on HA-CD44 receptor interaction, in MDA-MB-231 (CD44 receptor-positive human breast cancer) cells. Selective tumor targetability of HACE/SP NC, compared to SP NC, was also confirmed in MDA-MB-231 tumor-xenograted mouse model using a near-infrared fluorescence (NIRF) imaging. According to the results of pharmacokinetic study in rats, decreased in vivo clearance and increased half-life of RSV in NC group, compared to drug solution group, were shown. Given that these experimental results, developed HACE/SP NC can be a promising theranostic nanosystem for CD44 receptor-expressed cancers. PMID:27208440

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

    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.

  3. In situ crosslinked smart polypeptide nanoparticles for multistage responsive tumor-targeted drug delivery

    Yi, Huqiang; Liu, Peng; Sheng, Nan; Gong, Ping; Ma, Yifan; Cai, Lintao

    2016-03-01

    Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(l-lysine)-b-poly(l-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic-cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible zeta potential around -30 mV at pH 7.4, but switched to +15 mV at pH 5.0. Moreover, FD-NPs effectively loaded DOX with a loading capacity at 15.7 wt%. At pH 7.4, only 24.5% DOX was released within 60 h. However, at pH 5.0, the presence of 10 mM DTT dramatically accelerated DOX release with over 90% of DOX released within 10 h. Although the FD-NPs only enhanced DOX uptake in FA receptor positive (FR+) cancer cells at pH 7.4, a weak acidic condition promoted FD-NP-facilitated DOX uptake in both FR+ HeLa and FR- A549 cells, as well as significantly improving cellular binding and end/lysosomal escape. In vivo studies in a HeLa cancer model demonstrated that the charge-reversible FD-NPs delivered DOX into tumors more effectively than charge-irreversible nanoparticles. Hence, these multistage responsive FD-NPs would serve as highly efficient drug vectors for targeted cancer chemotherapy.Smart tumor-targeted drug delivery is crucial for improving the effect of chemotherapy and reducing the adverse effects. Here, we synthesized a smart polypeptide copolymer based on n-butylamine-poly(l-lysine)-b-poly(l-cysteine) (PLL-PLC) with functionalization of folic acid (FA) and 1,2-dicarboxylic-cyclohexene anhydride (DCA) for multistage responsive tumor-targeted drug delivery. The copolymers (FA-PLL(DCA)-PLC) spontaneously crosslinked in situ to form redox and pH dual responsive FA-PLL(DCA)-PLC nanoparticles (FD-NPs), which had a reversible

  4. Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor

    Shin, Weon Sup; Han, Jiyou; Kumar, Rajesh; Lee, Gyung Gyu; Sessler, Jonathan L.; Kim, Jong-Hoon; Kim, Jong Seung

    2016-07-01

    We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38—a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a cancer targeting unit (biotin). Upon light activation in cancer cells, PT-1 interferes with DNA re-ligation, diminishes the expression of topoisomerase I, and enhances the expression of inter alia mitochondrial apoptotic genes, death receptors, and caspase enzymes, inducing DNA damage and eventually leading to apoptosis. In vitro and in vivo studies showed significant inhibition of cancer growth and the hybrid system PT-1 thus shows promise as a programmed photo-therapeutic (“phototheranostic”).

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

    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.

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

    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.

  7. Iodine-125-labeled cRGD-gold nanoparticles as tumor-targeted radiosensitizer and imaging agent

    Su, Ning; Dang, Yajie; Liang, Guangli; Liu, Guizhi

    2015-04-01

    Research interests on radiosensitive property of gold nanoparticles (GNPs) are rapidly raised because of the extensively proved in vitro effectiveness and clinical necessity. However, the issue of targeted accumulation of GNPs in tumor tissues hindered the transference to in vivo applications. In this study, hybrid nano-sized cyclic Arg-Gly-Asp-conjugated GNPs (cRGD-GNPs) integrated with radioactive iodine-125 was fabricated as tumor-targeted radiosensitizer. Therapeutic effects, including acute apoptosis (2 days post treatment) and long-term influence (up to 21 days), were investigated on NCI-H446 tumor-bearing mice via Tc-99 m-Annexin V SPECT and volume measurements, respectively. Apoptosis and volume loss were consistent in showing that tumor growth was effectively suppressed via the treatment of 125I-cRGD-GNP sensitized radiotherapy (RT), a more significantly radiosensitive effect than the treatment of non-targeted GNPs with RT, RT treatment alone, and no treatment. SPECT/CT images showed that the uptake of cRGD-GNPs by tumor tissues reached the peak target/non-target value of 4.76 at around 2 h post injection, and dynamic radioactivity monitoring showed that 125I-cRGD-GNPs maintained about 2.5% of injected dosage at 55 h post injection. For long-term influence, a significant radiosensitized RT-induced volume loss was observed. Hence, cyclic RGD conjugation makes the GNP-based radiosensitizer tumor targeting, offering a new modality for enhancing radiotherapeutic efficacy. Additionally, the introduction of I-125 serves as both a therapeutic factor and a radiotracer for in vivo tracking of GNPs.

  8. Screening tumor-targeting bacteriophage particles by pre-clearing phage display

    Phage display technique provides a powerful approach for the discovery of new tumor-specific peptides. However, the peptides isolated through this technique usually did not possess high tumor-specific property. A pre-clearing step was introduced to increase the efficiency of biopanning by removal of particles that could interact with ubiquitously expressed cellular receptors in the non-target organs. The randomized Ph. D-CX7C phage library (Phage III) was first pre-cleared in normal mice to reduce vasculature- or organ-targeting phages to get the pre-cleared phage library, and then the tumor-targeting bacteriophage particles (Phage I) were screened from pre-clearing phage library in S180 tumor-bearing mice.The biodistribution results of 99mTc-labeled phages in mice bearing S180 tumor show that the uptake of 99mTc-labeled Phage I in tumor is high but low in normal organs, and the tumor-to-liver and tumor-to-spleen ratios of 99mTc-labeled Phage I are higher than those of 99mTc-labeled Phage II (tumor-specific phages screened from the original CX7C library) and Phage III (unscreened phages from the original CX7C library). It indicates that the yield of tumor-targeting bacteriophage particles could be improved and the non-specific binding in organs becomes weak. Consequently, the pre-clearing phage display method could improve the yield of positive hits by reducing the non-target organ accumulation of bacteriophage particles. (authors)

  9. A multifunctional metal-organic framework based tumor targeting drug delivery system for cancer therapy

    Wang, Xiao-Gang; Dong, Zhi-Yue; Cheng, Hong; Wan, Shuang-Shuang; Chen, Wei-Hai; Zou, Mei-Zhen; Huo, Jia-Wei; Deng, He-Xiang; Zhang, Xian-Zheng

    2015-09-01

    Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free ``green'' post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects.Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free ``green'' post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects. Electronic supplementary information (ESI) available

  10. Tragedy of women's self-immolation in Iran and developing communities: a review

    Suhrabi, Zainab; Delpisheh, Ali; Taghinejad, Hamid

    2012-01-01

    Committing Suicide is an awful way to die as well as a historical psycho-social problem of human community worldwide. 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 Baltic region, Africa (including Egypt), The Middle East (including Iran), The Far East, particularly India and Vietnam. Its rate has ranged from10 per 100,000 peop...

  11. Tumor targeting and imaging with dual-peptide conjugated multifunctional liposomal nanoparticles

    Rangger C

    2013-12-01

    Full Text Available Christine Rangger,1 Anna Helbok,1 Jane Sosabowski,2 Christian Kremser,3 Gottfried Koehler,4 Ruth Prassl,5,6 Fritz Andreae,7 Irene J Virgolini,1 Elisabeth von Guggenberg,1 Clemens Decristoforo11Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria; 2Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK; 3Department of Radiology, Innsbruck Medical University, Innsbruck, 4Department of Computational and Structural Biology, Max Perutz Laboratories, University of Vienna, Wien, 5Institute of Biophysics, Medical University of Graz, Graz, 6Ludwig Boltzmann Institute for Lung Vascular Research, 7piCHEM Research and Development, Graz, AustriaBackground: The significant progress in nanotechnology provides a wide spectrum of nanosized material for various applications, including tumor targeting and molecular imaging. The aim of this study was to evaluate multifunctional liposomal nanoparticles for targeting approaches and detection of tumors using different imaging modalities. The concept of dual-targeting was tested in vitro and in vivo using liposomes derivatized with an arginine-glycine-aspartic acid (RGD peptide binding to αvβ3 integrin receptors and a substance P peptide binding to neurokinin-1 receptors.Methods: For liposome preparation, lipids, polyethylene glycol building blocks, DTPA-derivatized lipids for radiolabeling, lipid-based RGD and substance P building blocks and imaging labels were combined in defined molar ratios. Liposomes were characterized by photon correlation spectroscopy and zeta potential measurements, and in vitro binding properties were tested using fluorescence microscopy. Standardized protocols for radiolabeling were developed to perform biodistribution and micro-single photon emission computed tomography/computed tomography (SPECT/CT studies in nude mice bearing glioblastoma and/or melanoma tumor xenografts. Additionally, an initial magnetic resonance

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

    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

  13. Monte Carlo simulations of dose distributions with necrotic tumor targeted radioimmunotherapy

    Radio-resistant hypoxic tumor cells are significant contributors to the locoregional recurrences and distant metastases that mark failure of radiotherapy. Due to restricted tissue oxygenation, chronically hypoxic tumor cells frequently become necrotic and thus there is often an association between chronically hypoxic and necrotic tumor regions. This simulation study is the first in a series to determine the feasibility of hypoxic cell killing after first targeting adjacent areas of necrosis with either an α- or β-emitting radioimmunoconjugate. - Highlights: • A representative necrotic tumor geometry was created in the Geant4 Monte Carlo toolkit. • Custom designed particle tracking was performed allowing for separation of deposited doses from different decay particles. • Post-processing of the data included relative biological effectiveness of the different decay particles and effects of cell oxygenation. • Physical and equivalent doses resulting from 177Lu and 212Pb were compared by means of dose maps and dose profiles. • 212Pb appears to be a promising isotope for necrotic tumor targeted α-therapy and will be pursued in future in vivo studies

  14. Spontaneous arrangement of a tumor targeting hyaluronic acid shell on irinotecan loaded PLGA nanoparticles.

    Giarra, Simona; Serri, Carla; Russo, Luisa; Zeppetelli, Stefania; De Rosa, Giuseppe; Borzacchiello, Assunta; Biondi, Marco; Ambrosio, Luigi; Mayol, Laura

    2016-04-20

    The arrangement of tumor targeting hyaluronic acid (HA) moieties on irinotecan (IRIN)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) has been directed by means of a gradient of lipophilicity between the oil and water phases of the emulsion used to produce the NPs. PLGA constitutes the NP bulk while HA is superficially exposed, with amphiphilic poloxamers acting as a bridge between PLGA and HA. Differential scanning calorimetry, zeta potential analyses and ELISA tests were employed to support the hypothesis of polymer assembly in NP formulations. The presence of flexible HA chains on NP surface enhances NP size stability over time due to an increased electrostatic repulsion between NPs and a higher degree of hydration of the device surface. IRIN in vitro release kinetics can be sustained up to 7-13 days. In vitro biologic studies indicated that HA-containing NPs were more toxic than bare PLGA NPs against CD44-overexpressing breast carcinoma cells (HS578T), therefore indicating their ability to target CD44 receptor. PMID:26876867

  15. Fabrication of a nanocarrier system through self-assembly of plasma protein and its tumor targeting

    Human serum albumin (HSA) nanoparticles hold great promise as a nanocarrier system for targeted drug delivery. The objective of this study was to explore the possibility of preparing size controllable albumin nanoparticles using the disulfide bond breaking reagent β-mercaptoethanol (β-ME). The results showed that the protein concentration and temperature had positive effects on the sizes of the albumin nanoparticles, while pH had a negative effect on the rate of nanoparticle formation. The addition of β-ME induced changes in HSA secondary structure and exposed the hydrophobic core of HSA, leading to the formation of nanoparticles. Human serum albumin nanoparticles could be internalized by MCF-7 cells and mainly accumulated in cytoplasm. After injection in tumor bearing mice, the HSA nanoparticles accumulated in tumor tissues, demonstrating the targeting ability of the nanoparticles. Therefore, human serum albumin can be fabricated into nanoparticles by breaking the disulfide bonds and these nanoparticles exhibit high tumor targeting ability. Human serum albumin nanoparticles could be ideal for the targeted delivery of pharmacologically active substances.

  16. Bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles as novel tumor targeting carriers

    In this study, we have developed a novel carrier, micelle-type bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles (NPs), for the detection and treatment of pancreatic cancer. These NPs contained 4-arm-PEG as corona, and PLGA as core, the particle surface was conjugated with cyclo(arginine-glycine-aspartate) (cRGD) as ligand for in vivo tumor targeting. The hydrodynamic size of the NPs was determined to be 150-180 nm and the critical micellar concentration (CMC) was estimated to be 10.5 mg l-1. Our in vitro study shows that these NPs by themselves had negligible cytotoxicity to human pancreatic cancer (Panc-1) and human glioblastoma (U87) cell lines. Near infrared (NIR) microscopy and flow cytometry demonstrated that the cRGD conjugated PLGA-4-arm-PEG polymeric NPs were taken up more efficiently by U87MG glioma cells, over-expressing the αvβ3 integrin, when compared with the non-targeted NPs. Whole body imaging showed that the cRGD conjugated PLGA-4-arm-PEG branched polymeric NPs had the highest accumulation in the pancreatic tumor site of mice at 48 h post-injection. Physical, hematological, and pathological assays indicated low in vivo toxicity of this NP formulation. These studies on the ability of these bioconjugated PLGA-4-arm-PEG polymeric NPs suggest that the prepared polymeric NPs may serve as a promising platform for detection and targeted drug delivery for pancreatic cancer.

  17. Image-guided and tumor-targeted drug delivery with radiolabeled unimolecular micelles.

    Guo, Jintang; Hong, Hao; Chen, Guojun; Shi, Sixiang; Zheng, Qifeng; Zhang, Yin; Theuer, Charles P; Barnhart, Todd E; Cai, Weibo; Gong, Shaoqin

    2013-11-01

    Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)-poly(L-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N', N-triacetic acid (NOTA, a macrocyclic chelator for (64)Cu) (abbreviated as PAMAM-PLA-b-PEG-TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti-cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physical encapsulation. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. TRC105-conjugated unimolecular micelles showed a CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with non-targeted unimolecular micelles, which was further validated by cellular uptake in CD105-negative MCF-7 cells. In 4T1 murine breast tumor-bearing mice, (64)Cu-labeled targeted micelles exhibited a much higher level of tumor accumulation than (64)Cu-labeled non-targeted micelles, measured by serial non-invasive positron emission tomography (PET) imaging and confirmed by biodistribution studies. These unimolecular micelles formed by dendritic amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics. PMID:23932288

  18. RGD-modified lipid disks as drug carriers for tumor targeted drug delivery

    Gao, Jie; Xie, Cao; Zhang, Mingfei; Wei, Xiaoli; Yan, Zhiqiang; Ren, Yachao; Ying, Man; Lu, Weiyue

    2016-03-01

    Melittin, the major component of the European bee venom, is a potential anticancer candidate due to its lytic properties. However, in vivo applications of melittin are limited due to its main side effect, hemolysis, especially when applied through intravenous administration. The polyethylene glycol-stabilized lipid disk is a novel type of nanocarrier, and the rim of lipid disks has a high affinity to amphiphilic peptides. In our study, a c(RGDyK) modified lipid disk was developed as a tumor targeted drug delivery system for melittin. Cryo-TEM was used to confirm the shape and size of lipid disks with or without c(RGDyK) modification. In vitro and in vivo hemolysis analyses revealed that the hemolysis effect significantly decreased after melittin associated with lipid disks. Importantly, the results of our in vivo biodistribution and tumor growth inhibitory experiments showed that c(RGDyK) modification increased the distribution of lipid disks in the tumor and the anticancer efficacy of melittin loaded lipid disks. Thus, we successfully achieved a targeted drug delivery system for melittin and other amphiphilic peptides with a good therapeutic effect and low side effects.

  19. Octreotide-Mediated Tumor-Targeted Drug Delivery via a Cleavable Doxorubicin-Peptide Conjugate.

    Lelle, Marco; Kaloyanova, Stefka; Freidel, Christoph; Theodoropoulou, Marily; Musheev, Michael; Niehrs, Christof; Stalla, Günter; Peneva, Kalina

    2015-12-01

    Although recent methods for targeted drug delivery have addressed many of the existing problems of cancer therapy associated with undesirable side effects, significant challenges remain that have to be met before they find significant clinical relevance. One such area is the delicate chemical bond that is applied to connect a cytotoxic drug with targeting moieties like antibodies or peptides. Here we describe a novel platform that can be utilized for the preparation of drug-carrier conjugates in a site-specific manner, which provides excellent versatility and enables triggered release inside cancer cells. Its key feature is a cleavable doxorubicin-octreotide bioconjugate that targets overexpressed somatostatin receptors on tumor cells, where the coupling between the two components was achieved through the first cleavable disulfide-intercalating linker. The tumor targeting ability and suppression of adrenocorticotropic hormone secretion in AtT-20 cells by both octreotide and the doxorubicin hybrid were determined via a specific radioimmunoassay. Both substances reduced the hormone secretion to a similar extent, which demonstrated that the tumor homing peptide is able to interact with the relevant cell surface receptors after the attachment of the drug. Effective drug release was quickly accomplished in the presence of the physiological reducing agent glutathione. We also demonstrate the relevance of this scaffold in biological context in cytotoxicity assays with pituitary, pancreatic, and breast cancer cell lines. PMID:26524088

  20. Matrix metalloproteinase-mediation of tumor targeting human recombinant tumor necrosis factor-α fusion protein.

    Ren, Hui; Shao, Xin; Zeng, Liang; Wang, Fa; Huang, Di-Nan; Hou, Gan

    2015-08-01

    The aim of the present study was to use genetic engineering in order to establish an efficient tumor necrosis factor (TNF)-α fusion protein with low toxicity, which may be used to target tumors. Four types of matrix metalloproteinase (MMP)-mediated tumor targeting human recombinant TNF-α (rhTNF-α) fusion protein vectors were constructed. These were subsequently introduced into Escherichia coli. rhTNF-α fusion protein with a glutathione S-transferase (GST)-tag was purified using GST resin affinity chromatography, and GST-tags were digested using factor Xa. The cytotoxic effects of the fusion protein on L929 cells were determined using MTT assays. At a concentration of 1 pM, the GST-tagged fusion protein exerted no cytotoxic effects on the cells, compared with the negative control cells (P=0.975>0.05). However, at a concentration of 1000 pM, the deblocking fusion protein exerted greater cytotoxic effects on L929 cells, compared with positive control cells (Peffects on healthy cells. PMID:25891416

  1. Synthesis and Evaluation of Folate-Conjugated Phenanthraquinones for Tumor-Targeted Oxidative Chemotherapy

    Kumar, Ajay; Chelvam, Venkatesh; Sakkarapalayam, Mahalingam; Li, Guo; Sanchez-Cruz, Pedro; Piñero, Natasha S.; Low, Philip S.; Alegria, Antonio E.

    2016-01-01

    Almost all cells are easily killed by exposure to potent oxidants. Indeed, major pathogen defense mechanisms in both animal and plant kingdoms involve production of an oxidative burst, where host defense cells show an invading pathogen with reactive oxygen species (ROS). Although cancer cells can be similarly killed by ROS, development of oxidant-producing chemotherapies has been limited by their inherent nonspecificity and potential toxicity to healthy cells. In this paper, we describe the targeting of an ROS-generating molecule selectively to tumor cells using folate as the tumor-targeting ligand. For this purpose, we exploit the ability of 9,10-phenanthraquinone (PHQ) to enhance the continuous generation of H2O2 in the presence of ascorbic acid to establish a constitutive source of ROS within the tumor mass. We report here that incubation of folate receptor-expressing KB cells in culture with folate-PHQ plus ascorbate results in the death of the cancer cells with an IC50 of ~10 nM (folate-PHQ). We also demonstrate that a cleavable spacer linking folate to PHQ is significantly inferior to a noncleavable spacer, in contrast to most other folate-targeted therapeutic agents. Unfortunately, no evidence for folate-PHQ mediated tumor regression in murine tumor models is obtained, suggesting that unanticipated impediments to generation of cytotoxic quantities of ROS in vivo are encountered. Possible mechanisms and potential solutions to these unanticipated results are offered. PMID:27066312

  2. Green design "bioinspired disassembly-reassembly strategy" applied for improved tumor-targeted anticancer drug delivery.

    Wang, Ruoning; Gu, Xiaochen; Zhou, Jianping; Shen, Lingjia; Yin, Lifang; Hua, Peiying; Ding, Yang

    2016-08-10

    In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy. PMID:27238442

  3. Change of tumor target volume during waiting time for intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma

    Objective: To determine the influence of change in tumor target volume of nasopharyngeal carcinoma (NPC) while waiting for intensity modulated radiation therapy (IMRT). Methods: From March 2005 to December 2005, 31 patients with nasopharyngeal carcinoma received IMRT as the initial treatment at the Cancer Hospital of Chinese Academic of Medical Sciences. The original simulation CT scan was acquired before IMRT planning. A second CT scan was acquired before the start of radiotherapy. Wait- ing time was defined as the duration between CT simulation and start of radiotherapy. CT-CT fusion was used to minimize the error of delineation between the first tumor target volume (GTV) and the second tumor target volume (sGTV). Tumor target volume was calculated by treatment planning system. T test was carried out to analyse the difference between GTV and sGTV. Pearson correlation and multivariate linear regression was used to analyse the influence factor of the change betweent GTV and sGTV. Results: Median waiting time was 18 days (range, 9-27 days). There were significant differences between GTV and sGTV of both primary tumor (P=0.009) and metastatic lymphoma (P=0.005 ). Both Pearson correlation and multivariate linear regression showed that the change of primary tumor target volume had significant correlation with the first tumor target volume but had no significant correlation with the waiting time, sex, age, T stage and N stage (1992 Chinese Fuzhou Staging Classification). Conclusions: Within the range of the waiting time ob- served in our study, large volume primary tumor would have had a significant increase in volume, but whether the therapeutic effect would be influenced or not would need to be proved by study of large number of cases. Patients with large volume tumor should be considered to reduce the influence of waiting time by enlarging gross target volume and clinical targe volume and by neoadjuveant chemotherapy. For avoiding the unnecessary high-dose to normal

  4. Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

    Kos, Petra; Lächelt, Ulrich; Herrmann, Annika; Mickler, Frauke Martina; Döblinger, Markus; He, Dongsheng; Krhač Levačić, Ana; Morys, Stephan; Bräuchle, Christoph; Wagner, Ernst

    2015-03-01

    Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing

  5. Construction, expression and tumor targeting of a single-chain Fv against human colorectal carcinoma

    Jin Fang; Hong-Bin Jin; Jin-Dan Song

    2003-01-01

    AIM: A single-chain antibody fragment, ND-1scFv, against human colorectal carcinoma was constructed and expressed in E.coli, and its biodistribution and pharmacokinetic properties were studied in mice bearing tumor.METHODS: VH and VL genes were amplified from hybridoma cell IC-2, secreting monoclonal antibody ND-1, by RT-PCR,and connected by linker (Gly4Ser)3 to form scFv gene, which was cloned into expression vector pET 28a(+) and finally expressed in E.coli. The expressed product ND-1scFv was purified by metal affinity chromatography using Ni-NTA, its purity and biological activity were determined using SDSPAGE and ELISA. ND-1scFv was labeled with 99mTc, and then injected into mice bearing colorectal carcinoma xenograft for phamacokinetic study in vivo.RESULTS: SDS-PAGE analysis showed that the relative molecular weight of recombinant protein was 30kDa with purity of 94%. ELIAS assay revealed that ND-1scFv retained the immunoactivity of parent mAb, being capable of binding specifically to human colorectal carcinoma cell line expressing associated antigen. Radiolabeled ND-1scFv exhibited rapid tumor targeting, with specific distribution in mice bearing colorectal carcinoma xenograft observed as early as 1 h following injection. In vivo pharmacokinetic studies also demonstrated that ND-1scFv had very rapid plasma clearance (T1/2α of 5.7 min, T1/2β of 2.6 h).CONCLUSION: ND-1scFv shows significant immunoactivity,and better pharmacokinetic and biodistribution characteristics compared with intact mAbs, demonstrating the possibility as a carrier for tumor-imaging.

  6. Tumor targetability and antitumor effect of docetaxel-loaded hydrophobically modified glycol chitosan nanoparticles.

    Hwang, Ho-Young; Kim, In-San; Kwon, Ick Chan; Kim, Yong-Hee

    2008-05-22

    Hydrophobically modified glycol chitosan (HGC) nanoparticles, a new nano-sized drug carrier, were prepared by introducing a hydrophobic molecule, cholanic acid, to water soluble glycol chitosan. The HGC nanoparticles were easily loaded with the anticancer drug docetaxel (DTX) using a dialysis method, and the resulting docetaxel-loaded HGC (DTX-HGC) nanoparticles formed spontaneously self-assembled aggregates with a mean diameter of 350 nm in aqueous condition. The DTX-HGC nanoparticles were well dispersed and stable for 2 weeks under physiological conditions (pH 7.4 and 37 degrees C) and a sustained drug release profile, in vitro. In addition, the DTX-HGC nanoparticles were reasonably stable in the presence of excess bovine serum albumin, which suggested that the DTX-HGC nanoparticles might also be stable in the blood stream. The DTX-HGC nanoparticles exhibited a distinctive deformability in aqueous conditions, in that they could easily pass through a filter membrane with 200 nm pores despite their mean diameter of 350 nm. We also evaluated the time-dependent excretion profile, in vivo biodistribution, prolonged circulation time, and tumor targeting ability of DTX-HGC nanoparticles by using a non-invasive live animal imaging technology. Finally, under optimal conditions for cancer therapy, the DTX-HGC nanoparticles showed higher antitumor efficacy such as reduced tumor volume and increased survival rate in A549 lung cancer cells-bearing mice and strongly reduced the anticancer drug toxicity compared to that of free DTX in tumor-bearing mice. Together our results showed that the anticancer loaded nano-sized drug carriers are a promising nano-sized drug formulation for cancer therapy. PMID:18374444

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

    Highlights: ► Non-infectious and protease-deficient Bacillus anthracis protein expression system. ► Successful expression and purification of a tumor-targeted fusion protein drug. ► Very low endotoxin contamination of purified protein. ► Efficient protein secretion simplifies purification. ► 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 (TGFα). 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 TGFα). 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.

  8. RGD-modified pH-sensitive liposomes for docetaxel tumor targeting.

    Chang, Minglu; Lu, Shanshan; Zhang, Fang; Zuo, Tiantian; Guan, Yuanyuan; Wei, Ting; Shao, Wei; Lin, Guimei

    2015-05-01

    Phosphatidylethanolamine-based pH-sensitive liposomes of various compositions have been described as efficient systems for delivery of therapeutic molecules into tumor cells. The aim of this work was to develop a drug delivery system based on pH-sensitive liposomes (PLPs) that were modified with arginine-glycine-aspartic acid (RGD) peptide to enhance the effectiveness of docetaxel treatment. Docetaxel/coumarin-6 loaded PLPs were prepared by the thin-film dispersion method and characterized in detail, including by particle size, polydispersity, zeta potential and drug encapsulation efficiency. In vitro studies using MCF-7, HepG2and A549 cells were employed to investigate cytotoxicity and cellular uptake of the drug solution or docetaxel/coumarin-6 loaded PLPs. The accumulation of 7-nitro-2-1,3-benzoxadiazol-4-yl (NBD)-labeled liposomes in vivo was studied through tumor section imaging of xenograft mouse models of MCF-7 24h after intravenous administration. The particle size of the non-coated or RGD modified PLPs ranged between 146 and 129nm. Drug release in vitro was modestly prolonged and had good pH sensitivity. In the in vitro study, RGD-coated PLPs showed higher cytotoxicity and cellular uptake relative to non-coated ones. The results of the in vivo study showed that RGD-coated PLPs had higher fluorescence, which suggested a more efficient accumulation than normal PLPs in tumors. In conclusion, these results confirmed RGD-modified PLPs as a potential drug delivery system to achieve controlled release and tumor targeting. PMID:25851582

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

    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.

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

    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.

  11. Preparation and imaging study of tumor-targeting MRI contrast agent based on Fe3O4 nanoparticles

    The detection and diagnosis of early hypoxic tumor is the key for successful cancer therapy, which remains a challenge for radiologists because contrast agents could hardly reach it. Herein, a tumor-targeting MRI contrast agent was prepared by conjugating the small-molecule inhibitor of carbonic anhydrase (CA IX) that is overexpressed in hypoxic tumor, mafenide, onto the surface of Fe3O4 magnetic nanoparticles (MNPs) to improve the sensitivity of MRI for early tumor diagnosis. The tumor-targeting MNP (Fe3O4-SO2NH2) showed enhanced MRI contrasting performance both in vitro and in vivo in comparison with the non-targeting control, which made it a promising contrast agent for the detection and diagnosis of early hypoxic tumor. (author)

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

    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

  13. In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles

    Chen, Feng; Hong, Hao; Zhang, Yin; Valdovinos, Hector F.; Shi, Sixiang; Kwon, Glen S.; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo

    2013-01-01

    Since the first use of biocompatible mesoporous silica (mSiO2) nanoparticles as drug delivery vehicles, in vivo tumor targeted imaging and enhanced anti-cancer drug delivery has remained a major challenge. In this work, we describe the development of functionalized mSiO2 nanoparticles for actively targeted positron emission tomography (PET) imaging and drug delivery in 4T1 murine breast tumor-bearing mice. Our structural design involves the synthesis, surface functionalization with thiol grou...

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

    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.; Ming ZHAO

    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...

  15. In vivo tumor targeting and image-guided drug delivery with antibody-conjugated, radiolabeled mesoporous silica nanoparticles.

    Chen, Feng; Hong, Hao; Zhang, Yin; Valdovinos, Hector F; Shi, Sixiang; Kwon, Glen S; Theuer, Charles P; Barnhart, Todd E; Cai, Weibo

    2013-10-22

    Since the first use of biocompatible mesoporous silica (mSiO2) nanoparticles as drug delivery vehicles, in vivo tumor targeted imaging and enhanced anticancer drug delivery has remained a major challenge. In this work, we describe the development of functionalized mSiO2 nanoparticles for actively targeted positron emission tomography (PET) imaging and drug delivery in 4T1 murine breast tumor-bearing mice. Our structural design involves the synthesis, surface functionalization with thiol groups, PEGylation, TRC105 antibody (specific for CD105/endoglin) conjugation, and (64)Cu-labeling of uniform 80 nm sized mSiO2 nanoparticles. Systematic in vivo tumor targeting studies clearly demonstrated that (64)Cu-NOTA-mSiO2-PEG-TRC105 could accumulate prominently at the 4T1 tumor site via both the enhanced permeability and retention effect and TRC105-mediated binding to tumor vasculature CD105. As a proof-of-concept, we also demonstrated successful enhanced tumor targeted delivery of doxorubicin (DOX) in 4T1 tumor-bearing mice after intravenous injection of DOX-loaded NOTA-mSiO2-PEG-TRC105, which holds great potential for future image-guided drug delivery and targeted cancer therapy. PMID:24083623

  16. In Vivo Bio-distribution and Efficient Tumor Targeting of Gelatin/Silica Nanoparticles for Gene Delivery

    Zhao, Xueqin; Wang, Jun; Tao, SiJie; Ye, Ting; Kong, Xiangdong; Ren, Lei

    2016-04-01

    The non-viral gene delivery system is an attractive alternative to cancer therapy. The clinical success of non-viral gene delivery is hampered by transfection efficiency and tumor targeting, which can be individually overcome by addition of functional modules such as cell penetration or targeting. Here, we first engineered the multifunctional gelatin/silica (GS) nanovectors with separately controllable modules, including tumor-targeting aptamer AGRO100, membrane-destabilizing peptide HA2, and polyethylene glycol (PEG), and then studied their bio-distribution and in vivo transfection efficiencies by contrast resonance imaging (CRI). The results suggest that the sizes and zeta potentials of multifunctional gelatin/silica nanovectors were 203-217 nm and 2-8 mV, respectively. Functional GS-PEG nanoparticles mainly accumulated in the liver and tumor, with the lowest uptake by the heart and brain. Moreover, the synergistic effects of tumor-targeting aptamer AGRO100 and fusogenic peptide HA2 promoted the efficient cellular internalization in the tumor site. More importantly, the combined use of AGRO100 and PEG enhanced tumor gene expression specificity and effectively reduced toxicity in reticuloendothelial system (RES) organs after intravenous injection. Additionally, low accumulation of GS-PEG was observed in the heart tissues with high gene expression levels, which could provide opportunities for non-invasive gene therapy.

  17. In Vivo Bio-distribution and Efficient Tumor Targeting of Gelatin/Silica Nanoparticles for Gene Delivery.

    Zhao, Xueqin; Wang, Jun; Tao, SiJie; Ye, Ting; Kong, Xiangdong; Ren, Lei

    2016-12-01

    The non-viral gene delivery system is an attractive alternative to cancer therapy. The clinical success of non-viral gene delivery is hampered by transfection efficiency and tumor targeting, which can be individually overcome by addition of functional modules such as cell penetration or targeting. Here, we first engineered the multifunctional gelatin/silica (GS) nanovectors with separately controllable modules, including tumor-targeting aptamer AGRO100, membrane-destabilizing peptide HA2, and polyethylene glycol (PEG), and then studied their bio-distribution and in vivo transfection efficiencies by contrast resonance imaging (CRI). The results suggest that the sizes and zeta potentials of multifunctional gelatin/silica nanovectors were 203-217 nm and 2-8 mV, respectively. Functional GS-PEG nanoparticles mainly accumulated in the liver and tumor, with the lowest uptake by the heart and brain. Moreover, the synergistic effects of tumor-targeting aptamer AGRO100 and fusogenic peptide HA2 promoted the efficient cellular internalization in the tumor site. More importantly, the combined use of AGRO100 and PEG enhanced tumor gene expression specificity and effectively reduced toxicity in reticuloendothelial system (RES) organs after intravenous injection. Additionally, low accumulation of GS-PEG was observed in the heart tissues with high gene expression levels, which could provide opportunities for non-invasive gene therapy. PMID:27071682

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

    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, 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, <10 kDa) HA has been reported to provoke inflammatory responses, such as induction of cytokines, chemokines, reactive nitrogen species and growth factors. Herein, we prepared and characterized two types of HA coated (LMw and HMw) lipid-based targeted and stabilized nanoparticles (tsNPs) and tested their binding to tumor cells expressing the HA receptor (CD44), systemic immunotoxicity, and biodistribution in tumor bearing mice. In vitro, the Mw of the surface anchored HA had a significant influence on the affinity towards CD44 on B16F10 murine 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

  19. Tumor targeting chitosan nanoparticles for dual-modality optical/MR cancer imaging.

    Nam, Taehwan; Park, Sangjin; Lee, Seung-Young; Park, Kyeongsoon; Choi, Kuiwon; Song, In Chan; Han, Moon Hee; Leary, James J; Yuk, Simseok Andrew; Kwon, Ick Chan; Kim, Kwangmeyung; Jeong, Seo Young

    2010-04-21

    We report tumor targeting nanoparticles for optical/MR dual imaging based on self-assembled glycol chitosan to be a potential multimodal imaging probe. To develop an optical/MR dual imaging probe, biocompatible and water-soluble glycol chitosan (M(w) = 50 kDa) were chemically modified with 5beta-cholanic acid (CA), resulting in amphiphilic glycol chitosan-5beta-cholanic acid conjugates (GC-CA). For optical imaging near-infrared fluorescence (NIRF) dye, Cy5.5, was conjugated to GC-CA resulting in Cy5-labeled GC-CA conjugates (Cy5.5-GC-CA). Moreover, in order to chelate gadolinium (Gd(III)) in the Cy5.5-GC-CA conjugates, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was directly conjugated in Cy5.5-GC-CA. Finally, the excess GdCl(3) was added to DOTA modified Cy5.5-GC-CA conjugates in distilled water (pH 5.5). The freshly prepared Gd(III) encapsulated Cy5.5-GC-CA conjugates were spontaneously self-assembled into stable Cy5.5 labeled and Gd(III) encapsulated chitosan nanoparticles (Cy5.5-CNP-Gd(III)). The Cy5.5-CNP-Gd(III) was spherical in shape and approximately 350 nm in size. From the cellular experiment, it was demonstrated that Cy5.5-CNP-Gd(III) were efficiently taken up and distributed in cytoplasm (NIRF filter; red). When the Cy5.5-GC-Gd(III) were systemically administrated into the tail vein of tumor-bearing mice, large amounts of nanoparticles were successfully localized within the tumor, which was confirmed by noninvasive near-infrared fluorescence and MR imaging system simultaneously. These results revealed that the dual-modal imaging probe of Cy5.5-CNP-Gd(III) has the potential to be used as an optical/MR dual imaging agent for cancer treatment. PMID:20201550

  20. RGD-modified poly(D,L-lactic acid nanoparticles enhance tumor targeting of oridonin

    Xu J

    2012-01-01

    -PLA-NPs or ORI solution. Consistent with these observations, ORI-PLA-RGD-NPs showed greater antitumor efficacy than ORI-PLA-RGD-NPs or ORI solution, as reflected by the decreased tumor growth and the prolonged survival time of mice bearing H22 tumors.Conclusion: The tumor-targeting efficiency and subsequent antitumor efficacy of ORI is increased by incorporation into ORI-PLA-RGD-NPs.Keywords: ORI, antitumor activity, RGD, poly(D,L-lactic acid, nanoparticles

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

    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

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

    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.

  3. Dual actions of albumin packaging and tumor targeting enhance the antitumor efficacy and reduce the cardiotoxicity of doxorubicin in vivo

    Zheng K

    2015-08-01

    Full Text Available Ke Zheng,1 Rui Li,2 Xiaolei Zhou,2 Ping Hu,2 Yaxin Zhang,2 Yunmei Huang,3 Zhuo Chen,2 Mingdong Huang2 1College of Chemistry, Fuzhou University, Fuzhou, People’s Republic of China; 2State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, People’s Republic of China; 3Fujian Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China Abstract: Doxorubicin (DOX is an effective chemotherapy drug used to treat different types of cancers. However, DOX has severe side effects, especially life-threatening cardiotoxicity. We herein report a new approach to reduce the toxicity of DOX by embedding DOX inside human serum albumin (HSA. HSA is further fused by a molecular biology technique with a tumor-targeting agent, amino-terminal fragment of urokinase (ATF. ATF binds with a high affinity to urokinase receptor, which is a cell-surface receptor overexpressed in many types of tumors. The as-prepared macromolecule complex (ATF–HSA:DOX was not as cytotoxic as free DOX to cells in vitro, and was mainly localized in cell cytosol in contrast to DOX that was localized in cell nuclei. However, in tumor-bearing mice, ATF–HSA:DOX was demonstrated to have an enhanced tumor-targeting and antitumor efficacy compared with free DOX. More importantly, histopathological examinations of the hearts from the mice treated with ATF–HSA:DOX showed a significantly reduced cardiotoxicity compared with hearts from mice treated with free DOX. These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening its antitumor efficacy. Such a tumor-targeted albumin packaging strategy can also be applied to other antitumor drugs. Keywords: amino-terminal fragment of urokinase, urokinase receptor, drug carrier, human serum albumin, doxorubicin, cytotoxicity

  4. Nanoparticles Modified With Tumor-targeting scFv Deliver siRNA and miRNA for Cancer Therapy

    Chen, Yunching; Zhu, Xiaodong; Zhang, Xiaoju; Liu, Bin; Huang, Leaf

    2010-01-01

    Targeted delivery of RNA-based therapeutics for cancer therapy remains a challenge. We have developed a LPH (liposome-polycation-hyaluronic acid) nanoparticle formulation modified with tumor-targeting single-chain antibody fragment (scFv) for systemic delivery of small interfering RNA (siRNA) and microRNA (miRNA) into experimental lung metastasis of murine B16F10 melanoma. The siRNAs delivered by the scFv targeted nanoparticles efficiently downregulated the target genes (c-Myc/MDM2/VEGF) in t...

  5. Preparation and bioevaluation of a 99mTc-labeled chlorambucil analog as a tumor targeting agent

    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 [99mTc(CO)3(H2O)3]+ 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.

  6. Cytotoxicity, tumor targeting and PET imaging of sub-5 nm KGdF4 multifunctional rare earth nanoparticles

    Cao, Xinmin; Cao, Fengwen; Xiong, Liqin; Yang, Yang; Cao, Tianye; Cai, Xi; Hai, Wangxi; Li, Biao; Guo, Yixiao; Zhang, Yimin; Li, Fuyou

    2015-08-01

    Ultrasmall sub-5 nm KGdF4 rare earth nanoparticles were synthesized as multifunctional probes for fluorescent, magnetic, and radionuclide imaging. The cytotoxicity of these nanoparticles in human glioblastoma U87MG and human non-small cell lung carcinoma H1299 cells was evaluated, and their application for in vitro and in vivo tumor targeted imaging has also been demonstrated.Ultrasmall sub-5 nm KGdF4 rare earth nanoparticles were synthesized as multifunctional probes for fluorescent, magnetic, and radionuclide imaging. The cytotoxicity of these nanoparticles in human glioblastoma U87MG and human non-small cell lung carcinoma H1299 cells was evaluated, and their application for in vitro and in vivo tumor targeted imaging has also been demonstrated. Electronic supplementary information (ESI) available: Details of the experimental section as well as EDXA, XRD, zeta potential, FTIR, TGA, stability, TEM, Z scanning, ICP-MS, and MicroPET/CT images. See DOI: 10.1039/c5nr03374h

  7. Multiple cues on the physiochemical, mesenchymal, and intracellular trafficking interactions with nanocarriers to maximize tumor target efficiency.

    Kim, Sang-Woo; Khang, Dongwoo

    2015-01-01

    Over the past 60 years, numerous medical strategies have been employed to overcome neoplasms. In fact, with the exception of lung, bronchial, and pancreatic cancers, the 5-year survival rate of most cancers currently exceeds 70%. However, the quality of life of patients during chemotherapy remains unsatisfactory despite the increase in survival rate. The side effects of current chemotherapies stem from poor target efficiency at tumor sites due to the uncontrolled biodistribution of anticancer agents (ie, conventional or current approved nanodrugs). This review discusses the effective physiochemical factors for determining biodistribution of nanocarriers and, ultimately, increasing tumor-targeting probability by avoiding the reticuloendothelial system. Second, stem cell-conjugated nanotherapeutics was addressed to maximize the tumor searching ability and to inhibit tumor growth. Lastly, physicochemical material properties of anticancer nanodrugs were discussed for targeting cellular organelles with modulation of drug-release time. A better understanding of suggested topics will increase the tumor-targeting ability of anticancer drugs and, ultimately, promote the quality of life of cancer patients during chemotherapy. PMID:26124658

  8. Multiple cues on the physiochemical, mesenchymal, and intracellular trafficking interactions with nanocarriers to maximize tumor target efficiency

    Kim SW

    2015-06-01

    Full Text Available Sang-Woo Kim, Dongwoo Khang Nanomedicine Laboratory, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, South Korea Abstract: Over the past 60 years, numerous medical strategies have been employed to overcome neoplasms. In fact, with the exception of lung, bronchial, and pancreatic cancers, the 5-year survival rate of most cancers currently exceeds 70%. However, the quality of life of patients during chemotherapy remains unsatisfactory despite the increase in survival rate. The side effects of current chemotherapies stem from poor target efficiency at tumor sites due to the uncontrolled biodistribution of anticancer agents (ie, conventional or current approved nanodrugs. This review discusses the effective physiochemical factors for determining biodistribution of nanocarriers and, ultimately, increasing tumor-targeting probability by avoiding the reticuloendothelial system. Second, stem cell-conjugated nanotherapeutics was addressed to maximize the tumor searching ability and to inhibit tumor growth. Lastly, physicochemical material properties of anticancer nanodrugs were discussed for targeting cellular organelles with modulation of drug-release time. A better understanding of suggested topics will increase the tumor-targeting ability of anticancer drugs and, ultimately, promote the quality of life of cancer patients during chemotherapy. Keywords: cancer, anticancer nanodrugs, mesenchymal stem cell, intracellular trafficking

  9. Self-assembled micelles of amphiphilic poly(L-phenylalanine-b-poly(L-serine polypeptides for tumor-targeted delivery

    Zhao ZM

    2014-12-01

    Full Text Available Ziming Zhao,1,2,* Yu Wang,1,2,* Jin Han,1,2 Keli Wang,1 Dan Yang,1,2 Yihua Yang,1,2 Qian Du,1,2 Yuanjian Song,3 Xiaoxing Yin1,2 1Department of Pharmacy, 2Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, 3Department of Basic Medical Sciences, Xuzhou Medical College, Xuzhou, People’s Republic of China *These authors contributed equally to this work Abstract: The aim of this work was to design, synthesize, and characterize self-assembled micelles based on polypeptides as a potential antitumor drug carrier. Amphiphilic poly(L-phenylalanine-b-poly(L-serine (PFS polypeptides were obtained through the polymerization of N-carboxyanhydride. As a novel hydrophilic segment, poly(L-serine was utilized to enhance tumor targeting due to a large demand of tumors for serine. PFS could self-assemble into micelles with an average diameter of 110–240 nm and a slightly negative charge. PFS polypeptides adopted random coil in pH 7.4 phosphate-buffered saline and could partly transform to a-helix induced by trifluoroethanol. PFS micelles with a low critical micelle concentration of 4.0 µg mL-1 were stable in pH 5–9 buffers and serum albumin solution. PFS micelles had a loading capacity of 3.8% for coumarin-6 and exhibited a sustained drug release. Coumarin-6 loaded rhodamine B isothiocyanate-labeled PFS micelles were incubated with Huh-7 tumor cells to study the correlation between drugs and carriers during endocytosis. The uptake of drugs was consistent with the micelles, illustrating that the intracellular transport of drugs highly depended on the micelles. PFS micelles diffused in whole cytoplasm while coumarin-6 assumed localized distribution, suggesting that the micelles could release the loaded drugs in particular areas. The internalization mechanism of PFS micelles was involved with clathrin-mediated endocytosis and macropinocytosis. Excess serine inhibited the uptake of PFS micelles, which demonstrated that serine receptors played

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

    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). PMID:27276066

  11. Peptide-Mediated Tumor Targeting by a Degradable Nano Gene Delivery Vector Based on Pluronic-Modified Polyethylenimine

    Wu, Zhaoyong; Zhan, Shuyu; Fan, Wei; Ding, Xueying; Wu, Xin; Zhang, Wei; Fu, Yinghua; Huang, Yueyan; Huang, Xuan; Chen, Rubing; Li, Mingjuan; Xu, Ningyin; Zheng, Yongxia; Ding, Baoyue

    2016-03-01

    Polyethylenimine (PEI) is considered to be a promising non-viral gene delivery vector. To solve the toxicity versus efficacy and tumor-targeting challenges of PEI used as gene delivery vector, we constructed a novel non-viral vector DR5-TAT-modified Pluronic-PEI (Pluronic-PEI-DR5-TAT), which was based on the attachment of low-molecular-weight polyethylenimine (LMW-PEI) to the amphiphilic polymer Pluronic to prepare Pluronic-modified LMW-PEI (Pluronic-PEI). This was then conjugated to a multifunctional peptide containing a cell-penetrating peptide (TAT) and a synthetic peptide that would bind to DR5—a receptor that is overexpressed in cancer cells. The vector showed controlled degradation, favorable DNA condensation and protection performance. The Pluronic-PEI-DR5-TAT/DNA complexes at an N/P ratio of 15:1 were spherical nanoparticles of 122 ± 11.6 nm and a zeta potential of about 22 ± 2.8 mV. In vitro biological characterization results indicated that Pluronic-PEI-DR5-TAT/DNA complexes had a higher specificity for the DR5 receptor and were taken up more efficiently by tumor cells than normal cells, compared to complexes formed with PEI 25 kDa or Pluronic-PEI. Thus, the novel complexes showed much lower cytotoxicity to normal cells and higher gene transfection efficiency in tumor cells than that exhibited by PEI 25 kDa and Pluronic-PEI. In summary, our novel, degradable non-viral tumor-targeting vector is a promising candidate for use in gene therapy.

  12. Peptide-Mediated Tumor Targeting by a Degradable Nano Gene Delivery Vector Based on Pluronic-Modified Polyethylenimine.

    Wu, Zhaoyong; Zhan, Shuyu; Fan, Wei; Ding, Xueying; Wu, Xin; Zhang, Wei; Fu, Yinghua; Huang, Yueyan; Huang, Xuan; Chen, Rubing; Li, Mingjuan; Xu, Ningyin; Zheng, Yongxia; Ding, Baoyue

    2016-12-01

    Polyethylenimine (PEI) is considered to be a promising non-viral gene delivery vector. To solve the toxicity versus efficacy and tumor-targeting challenges of PEI used as gene delivery vector, we constructed a novel non-viral vector DR5-TAT-modified Pluronic-PEI (Pluronic-PEI-DR5-TAT), which was based on the attachment of low-molecular-weight polyethylenimine (LMW-PEI) to the amphiphilic polymer Pluronic to prepare Pluronic-modified LMW-PEI (Pluronic-PEI). This was then conjugated to a multifunctional peptide containing a cell-penetrating peptide (TAT) and a synthetic peptide that would bind to DR5-a receptor that is overexpressed in cancer cells. The vector showed controlled degradation, favorable DNA condensation and protection performance. The Pluronic-PEI-DR5-TAT/DNA complexes at an N/P ratio of 15:1 were spherical nanoparticles of 122 ± 11.6 nm and a zeta potential of about 22 ± 2.8 mV. In vitro biological characterization results indicated that Pluronic-PEI-DR5-TAT/DNA complexes had a higher specificity for the DR5 receptor and were taken up more efficiently by tumor cells than normal cells, compared to complexes formed with PEI 25 kDa or Pluronic-PEI. Thus, the novel complexes showed much lower cytotoxicity to normal cells and higher gene transfection efficiency in tumor cells than that exhibited by PEI 25 kDa and Pluronic-PEI. In summary, our novel, degradable non-viral tumor-targeting vector is a promising candidate for use in gene therapy. PMID:26932761

  13. VALIDATION OF NEUROTENSIN TETRA-BRANCHED PEPTIDES AS TUMOR TARGETING AGENTS IN PANCREAS, COLON AND BLADDER CARCINOMA

    N. Ravenni

    2012-05-01

    Full Text Available The identification of new tumor targeting agents, which might allow either cancer cell tracing or ther- apy, is a crucial issue in cancer research. Membrane receptors for endogenous peptides such as neu- rotensin, somatostatin, bombesin and many others are over-expressed in different human cancers and could therefore be targeted as tumor-specific antigens. In the meantime the extremely short half-life of pep- tides impeded their development for effective pep- tide-based tumor targeting strategies. We synthesized tetra-branched neurotensin peptides (NT4, which ensure extremely long half-life main- taining peptide specificity and increasing avidity through multimeric binding. Moreover this bio-syn- thetical strategy allows a considerable modularity of peptides through the conjugation of different func- tional unit, such as fluorophore, radioactive moieties or chemotherapeutic drugs. Aim of our studies is to validate NT4 for cancer cell tracing in different human tumors. In this view we use fluorophore-conjugated NT4 to discriminate be- tween tumor and healthy tissue obtained by surgical samples from pancreas, colon and bladder carcinoma. Peptide binding on tumor and healthy biopsies was measured in each patient by quantitative analysis of confocal microscopy images. These results show a considerable difference in fluorescence emission be- tween healthy and tumor samples in colon, pancreas and bladder cancer, opening the way to the develop- ment of NT4 as selective diagnostic tools for these pathologies. Moreover our peptides can be conju- gated with different chemotherapeutic moieties in order to allow the selective killing of tumor cells.

  14. Preparation of HIFU-triggered tumor-targeted hyaluronic acid micelles for controlled drug release and enhanced cellular uptake.

    Zheng, Shaohui; Jin, Zhen; Han, Jiwon; Cho, Sunghoon; Nguyen, Van Du; Ko, Seong Young; Park, Jong-Oh; Park, Sukho

    2016-07-01

    In this study, a novel type of high intensity focused ultrasound (HIFU)-triggered active tumor-targeting polymeric micelle was prepared and investigated for controlled drug release and enhanced cellular uptake. Amphiphilic hyaluronic acid (HA) conjugates were synthesized to form docetaxel loaded micelles in aqueous conditions with high encapsulation efficiencies of over 80%. The micelle sizes were limited to less than 150nm, and they varied slightly according to the encapsulated drug amount. Modifying the micellar surface modification with polyethylene glycol diamine successfully inhibited premature drug leakage at a certain level, and it can be expected to prolong the circulation time of the particles in blood. In addition, high-intensity focused ultrasound was introduced to control the release of docetaxel from micelles, to which the release behavior of a drug can be tuned. The in-vitro cell cytotoxicity of docetaxel-loaded micelles was verified against CT-26 and MDA-MB-231 cells. The IC50 values of drug-loaded micelles to CT-26 and MDA-MB-231 cells were 1230.2 and 870.9ng/mL, respectively. However, when exposed to HIFU, the values decreased significantly, to 181.9 and 114.3ng/mL, suggesting that HIFU can enhance cell cytotoxicity by triggering the release of a drug from the micelles. Furthermore, cellular uptake tests were conducted via the quantitative analysis of intracellular drug concentration within CT-26 (CD44 negative), MDA-MB-231 (CD44 positive), and MDA-MB-231 (CD44 blocked), and then imaged with coumarin-6 loaded micelles. The results verified that intracellular drug delivery can be enhanced efficiently via the CD44 receptor-mediated endocytosis of HA micelles. Moreover, HIFU enhanced the cellular uptake behavior by altering the permeability of the cell membrane. It was also able to aid with the extravasation of micelles into the interior of tumors, which will be explained in further research. Therefore, the present study demonstrates that the micelles

  15. Dosimetric evaluation of a moving tumor target in intensity-modulated radiation therapy (IMRT) for lung cancer patients

    Kim, Sung Kyu; Kang, Min Kyu; Yea, Ji Woon; Oh, Se An

    2013-07-01

    Immobilization plays an important role in intensity-modulated radiation therapy (IMRT). The application of IMRT in lung cancer patients is very difficult due to the movement of the tumor target. Patient setup in radiation treatment demands high accuracy because IMRT employs a treatment size of a 1mm pixel unit. Hence, quality assurance of the dose delivered to patients must be at its highest. The radiation dose was evaluated for breathing rates of 9, 14, and 18 breaths per minute (bpm) for tumor targets moving up and down by 1.0 cm and 1.5 cm. The dose of the moving planned target volume (PTV) was measured by using a thermo-luminescent dosimeter (TLD) and Gafchromic™ EBT film. The measurement points were 1.0 cm away from the top, the bottom and the left and the right sides of the PTV center. The evaluated dose differences ranged from 94.2 to 103.8%, from 94.4 to 105.4%, and from 90.7 to 108.5% for 9, 14 and 18 bpm, respectively, for a tumor movement of 1.0 cm. The mean values of the doses were 101.4, 99.9, and 99.5% for 9, 14 and 18 bpm, respectively, for a tumor movement of 1.0 cm. Meanwhile, the evaluated dose differences ranged from 93.6 to 105.8%, from 95.9 to 111.5%, and from 96.2 to 111.7% for 9, 14 and 18 bpm, respectively, for a tumor movement of 1.5 cm. The mean values of the doses were 102.3, 103.4, and 103.1% for 9, 14 and 18 bpm, respectively, for a tumor movement of 1.5 cm. Therefore, we suggest that IMRT can be used in the treatment of lung cancer patients with vertical target movements within the range of 1.0 to 1.5 cm.

  16. Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer

    McGuire, Michael J.; Gray, Bethany Powell; Li, Shunzi; Cupka, Dorothy; Byers, Lauren Averett; Wu, Lei; Rezaie, Shaghayegh; Liu, Ying-Horng; Pattisapu, Naveen; Issac, James; Oyama, Tsukasa; Diao, Lixia; Heymach, John V.; Xie, Xian-Jin; Minna, John D.; Brown, Kathlynn C.

    2014-03-01

    Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071-40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands.

  17. Tumor targeting of the IL-15 superagonist RLI by an anti-GD2 antibody strongly enhances its antitumor potency.

    Vincent, Marie; Bessard, Anne; Cochonneau, Denis; Teppaz, Géraldine; Solé, Véronique; Maillasson, Mike; Birklé, Stéphane; Garrigue-Antar, Laure; Quéméner, Agnès; Jacques, Yannick

    2013-08-01

    Immunocytokines (ICKs) targeting cytokines to the tumor environment using antibodies directed against a tumor-associated antigen often have a higher therapeutic index than the corresponding unconjugated cytokines. Various ICKs displaying significant antitumoral effects in several murine tumor models have already been developed, and some of them, in particular interleukin (IL)-2-based ICKs, are in Phase II clinical trials. Although sharing common biological activities with IL-2 in vitro, IL-15 is now considered as having a better potential in antitumor immunotherapeutical strategies and has been shown to be less toxic than IL-2 in preclinical studies. We previously developed the fusion protein RLI, linking a soluble form of human IL-15Rα-sushi+ domain to human IL-15. RLI showed better biological activities than IL-15 in vitro as well as higher antitumoral effects in vivo in murine and human cancer models. Here, we investigated, in the context of an ICK, the effect of associating RLI with an antibody targeting the GD2 ganglioside, a validated tumoral target expressed on many neurectodermal tumors. Anti-GD2-RLI fully retained the cytokine potential of RLI and the antibody effector functions (antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity). It displayed strong antitumor activities in two syngeneic cancer models in immunocompetent mice (subcutaneous EL4 and metastatic NXS2). Its therapeutic potency was higher than those of RLI and anti-GD2 alone or in combination. We suggest that this is related to its bifunctional (cytokine and antibody) nature. PMID:23354868

  18. Nanoparticles Modified With Tumor-targeting scFv Deliver siRNA and miRNA for Cancer Therapy

    Chen, Yunching; Zhu, Xiaodong; Zhang, Xiaoju; Liu, Bin; Huang, Leaf

    2010-01-01

    Targeted delivery of RNA-based therapeutics for cancer therapy remains a challenge. We have developed a LPH (liposome-polycation-hyaluronic acid) nanoparticle formulation modified with tumor-targeting single-chain antibody fragment (scFv) for systemic delivery of small interfering RNA (siRNA) and microRNA (miRNA) into experimental lung metastasis of murine B16F10 melanoma. The siRNAs delivered by the scFv targeted nanoparticles efficiently downregulated the target genes (c-Myc/MDM2/VEGF) in the lung metastasis. Two daily intravenous injections of the combined siRNAs in the GC4-targeted nanoparticles significantly reduced the tumor load in the lung. miRNA-34a (miR-34a) induced apoptosis, inhibited survivin expression, and downregulated MAPK pathway in B16F10 cells. miR-34a delivered by the GC4-targeted nanoparticles significantly downregulated the survivin expression in the metastatic tumor and reduced tumor load in the lung. When miR-34a and siRNAs were co-formulated in GC4-targeted nanoparticles, an enhanced anticancer effect was observed. PMID:20606648

  19. Breast Tumor Targetable Fe3O4 Embedded Thermo-Responsive Nanoparticles for Radiofrequency Assisted Drug Delivery.

    Rejinold, N Sanoj; Thomas, Reju George; Muthiah, Muthunarayanan; Lee, Hwa Jeongong; Jeong, Yong Yeon; Park, In-kyu; Jayakumar, R

    2016-01-01

    Non-invasive radiofrequency (RF) frequency may be utilized as an energy source to activate thermo-responsive nanoparticles for the controlled local delivery of drugs to cancer cells. Herein, we demonstrate that 180 ± 20 nm sized curcumin encapsulated chitosan-graft-poly(N-vinyl caprolactam) nanoparticles containing iron oxide nanoparticles (Fe3O4-CRC-TRC-NPs) were selectively internalized in cancer cells in vivo. Using an RF treatment at 80 watts for 2 min, Fe3O4-CRC-TRC-NPs, dissipated heat energy of 42 degrees C, which is the lower critical solution temperature (LCST) of the chitosan-graft-poly(N-vinyl caprolactam), causing controlled curcumin release and apoptosis to cultured 4T1 breast cancer cells. Further, the tumor localization studies on orthotopic breast cancer model revealed that Fe3O4-CRC-TRC-NPs selectively accumulated at the primary tumor as confirmed by in vivo live imaging followed by ex vivo tissue imaging and HPLC studies. These initial results strongly support the development of RF assisted drug delivery from nanoparticles for improved tumor targeting for breast cancer treatment. PMID:27301171

  20. Anti-EGFR-iRGD recombinant protein conjugated silk fibroin nanoparticles for enhanced tumor targeting and antitumor efficiency

    Bian, Xinyu; Wu, Puyuan; Sha, Huizi; Qian, Hanqing; Wang, Qing; Cheng, Lei; Yang, Yang; Yang, Mi; Liu, Baorui

    2016-01-01

    In this study, we report a novel kind of targeting with paclitaxel (PTX)-loaded silk fibroin nanoparticles conjugated with iRGD–EGFR nanobody recombinant protein (anti-EGFR-iRGD). The new nanoparticles (called A-PTX-SF-NPs) were prepared using the carbodiimide-mediated coupling procedure and their characteristics were evaluated. The cellular cytotoxicity and cellular uptake of A-PTX-SF-NPs were also investigated. The results in vivo suggested that NPs conjugated with the recombinant protein exhibited more targeting and anti-neoplastic property in cells with high EGFR expression. In the in vivo antitumor efficacy assay, the A-PTX-SF-NPs group showed slower tumor growth and smaller tumor volumes than PTX-SF-NPs in a HeLa xenograft mouse model. A real-time near-infrared fluorescence imaging study showed that A-PTX-SF-NPs could target the tumor more effectively. These results suggest that the anticancer activity and tumor targeting of A-PTX-SF-NPs were superior to those of PTX-SF-NPs and may have the potential to be used for targeted delivery for tumor therapies.

  1. Systemic delivery of siRNA by hyaluronan-functionalized calcium phosphate nanoparticles for tumor-targeted therapy

    Qiu, Chong; Wei, Wei; Sun, Jing; Zhang, Hai-Tao; Ding, Jing-Song; Wang, Jian-Cheng; Zhang, Qiang

    2016-06-01

    In this study, hyaluronan (HA)-functionalized calcium phosphate nanoparticles (CaP-AHA/siRNA NPs) were developed for an injectable and targetable delivery of siRNA, which were prepared by coating the alendronate-hyaluronan graft polymer (AHA) around the surface of calcium phosphate-siRNA co-precipitates. The prepared CaP-AHA/siRNA NPs had a uniform spherical core-shell morphology with an approximate size of 170 nm and zeta potential of -12 mV. The coating of hydrophilic HA improved the physical stability of nanoparticles over one month due to the strong interactions between phosphonate and calcium. In vitro experiments demonstrated that the negatively charged CaP-AHA/siRNA NPs could effectively deliver EGFR-targeted siRNA into A549 cells through CD44-mediated endocytosis and significantly down-regulate the level of EGFR expression. Also, the internalized CaP-AHA/siRNA NPs exhibited a pH-responsive release of siRNA, indicating that the acidification of lysosomes probably facilitated the disassembling of nanoparticles and the resultant ions sharply increased the inner osmotic pressure and thus expedited the release of siRNA from late lysosomes into the cytoplasm. Furthermore, in vivo tumor therapy demonstrated that high accumulation of CaP-AHA/siEGFR NPs in tumor led to a significant tumor growth inhibition with a specific EGFR gene silencing effect after intravenous administration in nude mice xenografted with A549 tumor, along with a negligible body weight loss. These results suggested that the CaP-AHA/siRNA NPs could be an effective and safe systemic siRNA delivery system for a RNAi-based tumor targeted therapy strategy.In this study, hyaluronan (HA)-functionalized calcium phosphate nanoparticles (CaP-AHA/siRNA NPs) were developed for an injectable and targetable delivery of siRNA, which were prepared by coating the alendronate-hyaluronan graft polymer (AHA) around the surface of calcium phosphate-siRNA co-precipitates. The prepared CaP-AHA/siRNA NPs had a uniform

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

    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.

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

    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. PMID:20879980

  4. Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells

    Tran TH

    2015-08-01

    Full Text Available Tuan Hiep Tran,1 Thiruganesh Ramasamy,1 Ju Yeon Choi,1 Hanh Thuy Nguyen,1 Thanh Tung Pham,1 Jee-Heon Jeong,1 Sae Kwang Ku,2 Han-Gon Choi,3 Chul Soon Yong,1 Jong Oh Kim11College of Pharmacy, Yeungnam University, Dae-Dong, 2College of Korean Medicine, Daegu Haany University, Gyeongsan, 3College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South KoreaAbstract: The attachment of polyethylene glycol (PEG increases the circulation time of drug-containing nanoparticles; however, this also negatively affects cellular uptake. To overcome this problem, unique lipid polymer hybrid (LPH nanoparticles were developed with a pH-responsive PEG layer that detached prior to cell uptake. Docetaxel (DTX was incorporated into the lipid core of the nanoparticles, which was then shielded with the pH-responsive block co-polymer polyethylene glycol-b-polyaspartic acid (PEG-b-PAsp using a modified emulsion method. The optimized LPH nanoparticles were ~200 nm and had a narrow size distribution. Drug release from DTX-loaded LPH (DTX-LPH nanoparticles was pH-sensitive, which is beneficial for tumor targeting. More importantly, DTX-LPH nanoparticles were able to effectively induce apoptosis in cancer cells. The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX. The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice. The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment. Thus, the results suggest that this novel LPH system could be an effective new treatment for cancer.Keywords: docetaxel, polyaspartic acid, drug delivery systems, antitumor, pH-sensitive

  5. Oseltamivir-conjugated polymeric micelles prepared by RAFT living radical polymerization as a new active tumor targeting drug delivery platform.

    Kapishon, Vitaliy; Allison, Stephanie; Whitney, Ralph A; Cunningham, Michael F; Szewczuk, Myron R; Neufeld, Ronald J

    2016-02-23

    Targeted drug delivery using polymeric nanostructures has been at the forefront of cancer research, engineered for safer, more efficient and effective use of chemotherapy. Here, we designed a new polymeric micelle delivery system for active tumor targeting followed by micelle-drug internalization via receptor-induced endocytosis. We recently reported that oseltamivir phosphate targets and inhibits Neu1 sialidase activity associated with receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) which are overexpressed in cancer cells. By decorating micelles with oseltamivir, we investigated whether they actively targeted human pancreatic PANC1 cancer cells. Amphiphilic block copolymers with oseltamivir conjugated at the hydrophilic end, oseltamivir-pPEGMEMA-b-pMMA (oseltamivir-poly(polyethylene glycol methyl ether methacrylate)-block-poly(methyl methacrylate), were synthesized using reversible addition-fragmentation chain transfer (RAFT) living radical polymerization. Oseltamivir-conjugated micelles have self-assembling properties to give worm-like micellar structures with molecular weight of 80 000 g mol(-1). Oseltamivir-conjugated water soluble pPEGMEMA, dose dependently, both inhibited sialidase activity associated with Neu1, and reduced viability of PANC1 cells. In addition, oseltamivir-conjugated micelles, labelled with a hydrophobic fluorescent dye within the micelle core, were subsequently internalized by PANC1 cells. Blocking cell surface Neu1 with anti-Neu1 antibody, reduced internalization of oseltamivir-conjugated micelles, demonstrating that Neu1 binding linked to sialidase inhibition were prerequisite steps for subsequent internalization of the micelles. The mechanism of internalization is likely that of receptor-induced endocytosis demonstrating potential as a new nanocarrier system for not only targeting a tumor cell, but also for directly reducing viability through Neu1 inhibition, followed by intracellular delivery of hydrophobic

  6. Nanoprobes for two-photon excitation time-resolved imaging of living animals: In situ analysis of tumor-targeting dynamics of nanocarriers.

    Yang, Wen; Fu, Li-Min; Wen, Xue; Liu, Ying; Tian, Ye; Liu, Yu-Chen; Han, Rong-Cheng; Gao, Zhi-Yue; Wang, Tian-En; Sha, Yin-Lin; Jiang, Yu-Qiang; Wang, Yuan; Zhang, Jian-Ping

    2016-09-01

    Great challenges remain in the noninvasive luminescence imaging analysis of tumor-targeting dynamics of nanocarriers in living animals which is of significance for the development of anti-cancer nanomedicine. In this work, luminescent nanoparticles Eu(tta)3bpt@SMA (dav = 15 nm), which exhibited good water dispersion stability and high yields of red Eu-luminescence under near-infrared two-photon excitation, were prepared by a modified microfluidic mixing method in the absence of surfactants. Tumor-targeting agents, Arg-Gly-Asp-D-Phe-Lys (cRGD) polypeptide or transferrin (Tf), were then anchored on the nanoparticle surfaces to form the desired nanocarriers Eu@SMA-RGD or Eu@SMA-Tf. The tumor-targeting processes of the prepared nanocarriers in intact living mice were analyzed on a home-built two-photon excitation time-resolved (TPE-TR) imaging apparatus having a wide view filed. The TPE-TR strategy could effectively suppress the interference from biological autofluorescence, which allowed the targeted domains to be visualized with a high signal-to-noise ratio. It was found that the tumor-tissue trapping efficacy of Eu@SMA-RGD was much higher than that of Eu@SMA-Tf, and the desorption process from the tumor tissues of Eu@SMA-RGD was slower than that of Eu@SMA-Tf. The methods developed in this work pave a way to investigate the in vivo tumor-targeting dynamics of nanocarriers by noninvasive luminescence imaging of living animals. PMID:27258485

  7. 分子成像与肿瘤靶向治疗%Molecular imaging and tumor targeted therapy

    孙夕林; 韩兆国; 吴泳仪; 申宝忠

    2016-01-01

    肿瘤关键分子靶点的异常表达(表达水平和表达状态)与分子靶向治疗反应、治疗效果及预后密切相关。因此,精准评价肿瘤关键分子表达水平和表达状态,无论在肿瘤分子靶向治疗开展前、过程中以及治疗后均显得尤为关键。分子成像可以无创、实时而全面地对肿瘤关键靶点的表达水平及表达状态进行定性、定量研究,对筛选优势人群、指导治疗、判断预后具有重大意义。本文简述基于不同分子探针的分子成像技术在肿瘤靶向治疗过程中的应用,对比分析分子成像在靶向治疗中的价值,以期有益于新型治疗策略的开发。%The abnormal expression (level and status) of the key molecular targets of tumors is related to molecular targeted therapy response, effect, and prognosis. Therefore, the expression level and status of key molecular targets of tumors must be accurately evalu-ated, regardless of the status before, during, and after receiving targeted therapy. Molecular imaging is a non-invasive method used for qualitative and quantitative research on key molecular targets of tumor in vivo and in real-time. This technique is also employed to screen treatment beneficiaries, guide therapy, and evaluate prognosis. This paper reviews the application progress of molecular imag-ing using various probes in cancer targeted therapy. The clinical value of molecular imaging in tumor targeted therapy is further ana-lyzed to promote the development of novel targeted therapy for tumors.

  8. Photodynamic therapy of a 2-methoxyestradiol tumor-targeting drug delivery system mediated by Asn-Gly-Arg in breast cancer

    Shi J

    2013-04-01

    Full Text Available Jinjin Shi, Zhenzhen Wang, Lei Wang, Honghong Wang, Lulu Li, Xiaoyuan Yu, Jing Zhang, Rou Ma, Zhenzhong ZhangSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People's Republic of ChinaAbstract: Fullerene (C60 has shown great potential in drug delivery. In this study we exploited modified fullerene (diadduct malonic acid-fullerene-Asn-Gly-Arg peptide [DMA-C60-NGR] as an antitumor drug carrier in order to build a new tumor-targeting drug delivery system. We also investigated the synergistic enhancement of cancer therapy using photodynamic therapy (PDT induced by DMA-C60-NGR and 2-methoxyestradiol (2ME. Cytotoxicity tests indicated that DMA-C60-NGR had no obvious toxicity, while our drug delivery system (DMA-C60-2ME-NGR had a high inhibition effect on MCF-7 cells compared to free 2ME. The tumor-targeting drug delivery system could efficiently cross cell membranes, and illumination induced the generation of intracellular reactive oxygen species and DNA damage. Furthermore, DMA-C60-2ME-NGR with irradiation had the highest inhibition effect on MCF-7 cells compared to the other groups. DMA-C60-NGR combined with 2ME showed a good synergistic photosensitization effect for inhibiting the growth of MCF-7 cells, demonstrating that DMA-C60-2ME-NGR may be promising for high treatment efficacy with minimal side effects in future therapy.Keywords: fullerene, drug delivery system, photodynamic therapy, tumor targeting

  9. Efficacy of Tumor-Targeting Salmonella A1-R on a Melanoma Patient-Derived Orthotopic Xenograft (PDOX) Nude-Mouse Model

    Yamamoto, Mako; Zhao, Ming; Hiroshima, Yukihiko; Zhang, Yong; Shurell, Elizabeth; Eilber, Fritz C.; Bouvet, Michael; Noda, Makoto; Hoffman, Robert M.

    2016-01-01

    Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0.021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0.001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer. PMID:27500926

  10. 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

    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

  11. Coupling of a bifunctional peptide R13 to OTMCS-PEI copolymer as a gene vector increases transfection efficiency and tumor targeting

    Lv H

    2014-03-01

    Full Text Available Hui Lv,1,* Qing Zhu,1,* Kewu Liu,2 Manman Zhu,1 Wenfang Zhao,1 Yuan Mao,1 Kehai Liu1 1Department of Biopharmaceutics, College of Food Science and Technology, Shanghai Ocean University, Shanghai, People's Republic of China; 2Heilongjiang Forest By-Product and Speciality Institute, Mudanjiang, People's Republic of China *These authors contributed equally to this work Background: A degradable polyethylenimine (PEI derivative coupled to a bifunctional peptide R13 was developed to solve the transfection efficiency versus cytotoxicity and tumor-targeting problems of PEI when used as a gene vector. Methods: We crossed-linked low molecular weight PEI with N-octyl-N-quaternary chitosan (OTMCS to synthesize a degradable PEI derivative (OTMCS-PEI, and then used a bifunctional peptide, RGDC-Tat (49–57 called R13 to modify OTMCS-PEI so as to prepare a new gene vector, OTMCS-PEI-R13. This new gene vector was characterized by various physicochemical methods. Its cytotoxicity and gene transfection efficiency were also determined both in vitro and in vivo. Results: The vector showed controlled degradation and excellent buffering capacity. The particle size of the OTMCS-PEI-R13/DNA complexes was around 150–250 nm and the zeta potential ranged from 10 mV to 30 mV. The polymer could protect plasmid DNA from being digested by DNase I at a concentration of 23.5 U DNase I/µg DNA. Further, the polymer was resistant to dissociation induced by 50% fetal bovine serum and 400 µg/mL sodium heparin. Compared with PEI 25 kDa, the OTMCS-PEI-R13/DNA complexes showed higher transfection efficiency both in vitro and in vivo. Further, compared with OTMCS-PEI, distribution of OTMCS-PEI-R13 at tumor sites was markedly enhanced, indicating the tumor-targeting specificity of R13. Conclusion: OTMCS-PEI-R13 could be a potential candidate as a safe and efficient gene delivery carrier for gene therapy. Keywords: nonviral gene vector, polyethylenimine, R13, transfection efficiency

  12. Separation of effector cells mediating antibody-dependent cellular cytotoxicity (ADC) to erythrocyte targets from those mediating ADC to tumor targets.

    Pollack, S B; Nelson, K; Grausz, J D

    1976-04-01

    Murine spleen cells mediate antibody-dependent cellular cytotoxicity (ADC) both to erythrocyte targets in a 51Cr release assay and to syngeneic tumor targets in a microcytotoxicity assay. The effector cells active in the two ADC assays can be separated by passage of the spleen cells through columns of Sephadex G-10 at 37 degrees C. Cells mediating ADC to sarcoma cells did not adhere to the G-10 and were recovered in the column effluent. These nonadherent cells were not cytotoxic to antibody-coated chicken red blood cells. Spleen cells which mediated ADC in a 51Cr release assay to the red cell targets adhered to G-10. Adherent effector cells could subsequently be recovered from the columns by elution with 5 X 10(-4) M EDTA. PMID:815438

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

    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. PMID:27135196

  14. Tumor-targeted paclitaxel-loaded folate conjugated poly(ethylene glycol)-poly(L-lactide) microparticles produced by supercritical fluid technology.

    Huang, Xiaobei; Zhang, Yanzhi; Yin, Guangfu; Pu, Ximing; Liao, Xiaoming; Huang, Zhongbing; Chen, Xianchun; Yao, Yadong

    2015-02-01

    The new biodegradable diblock copolymers poly(ethylene glycol)-poly(L-lactide) (PEG-PLLA) were synthesized and were chemically conjugated with folate (FA) in the PEG terminal ends to form FA-PEG-PLLA. Then the hydrophobic drug paclitaxel (PTX) loaded microparticles (PTX/FA-PEG-PLLA) were produced via solution enhanced dispersion by supercritical fluids (SEDS). These microparticles exhibited sphere-like shape by scanning electron microscopy observation and showed narrow hydrodynamic size distributions by dynamic light scattering measurement. Drug loading of PTX loaded microparticles was about 7-9% and the encapsulation efficiency of PTX loaded microparticles was about 18-23%. Flow cytometry and confocal laser scanning microscope analyses revealed that fluorescein isothiocyanate labeled FA conjugated microparticles presented significantly higher cellular uptake than FA-free group due to the FA-receptor-mediated endocytosis. In vitro cytotoxicity evaluation indicated that FA-PEG-PLLA expressed negligible cytotoxicity to mouse fibroblasts L929 cells. Moreover, PTX/FA-PEG-PLLA microparticles exhibited much higher anti-cancer efficacy than PTX/PEG-PLLA microparticles against human ovarian cancer SKOV3 cells. Nude mice xenografted with SKOV3 cells were used in biodistribution studies, the results indicated that an increased amount of PTX was accumulated in the tumor tissue deal with PTX/FA-PEG-PLLA microparticles. These results collectively suggested that PTX/FA-PEG-PLLA microparticles prepared by SEDS would have potential in anti-tumor applications as a tumor-targeted drug delivery formulation. PMID:25649516

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

    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. PMID:24628452

  16. One-pot synthesized aptamer-functionalized CdTe:Zn2+ quantum dots for tumor-targeted fluorescence imaging in vitro and in vivo.

    Zhang, Cuiling; Ji, Xinghu; Zhang, Yuan; Zhou, Guohua; Ke, Xianliang; Wang, Hanzhong; Tinnefeld, Philip; He, Zhike

    2013-06-18

    High quality and facile DNA functionalized quantum dots (QDs) as efficient fluorescence nanomaterials are of great significance for bioimaging both in vitro and in vivo applications. Herein, we offer a strategy to synthesize DNA-functionalized Zn(2+) doped CdTe QDs (DNA-QDs) through a facile one-pot hydrothermal route. DNA is directly attached to the surface of QDs. The as-prepared QDs exhibit small size (3.85 ± 0.53 nm), high quantum yield (up to 80.5%), and excellent photostability. In addition, the toxicity of QDs has dropped considerably because of the Zn-doping and the existence of DNA. Furthermore, DNA has been designed as an aptamer specific for mucin 1 overexpressed in many cancer cells including lung adenocarcinoma. The aptamer-functionalized Zn(2+) doped CdTe QDs (aptamer-QDs) have been successfully applied in active tumor-targeted imaging in vitro and in vivo. A universal design of DNA for synthesis of Zn(2+) doped CdTe QDs could be extended to other target sequences. Owing to the abilities of specific recognition and the simple synthesis route, the applications of QDs will potentially be extended to biosensing and bioimaging. PMID:23682757

  17. Tumor targeting via integrin ligands

    HorstKessler

    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.

  18. Recombinant antibodies and tumor targeting

    Sheikholvaezin, Ali

    2006-01-01

    Different antibody derived constructs are rapidly advancing as putative tools for treatment of malignant diseases. Antibody engineering has added significant new technologies to modify size, affinities, solubility, stability and biodistribution properties for immunoconjugates. In the present thesis, the aim was to increase our knowledge on how new recombinant antibodies could be tailored to optimize localization to experimental tumors in mice. One hybridoma, producing the monoclonal antibody ...

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

    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.

  20. Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5.

    Huynh, Amanda Shanks; Estrella, Veronica; Stark, Valerie E; Cohen, Allison S; Chen, Tingan; Casagni, Todd J; Josan, Jatinder S; Lloyd, Mark C; Johnson, Joseph; Kim, Jongphil; Hruby, Victor J; Vagner, Josef; Morse, David L

    2016-02-01

    Fluorescence molecular imaging can be employed for the development of novel cancer targeting agents. Herein, we investigated the pharmacokinetics (PK) and cellular uptake of Dmt-Tic-Cy5, a delta-opioid receptor (δOR) antagonist-fluorescent dye conjugate, as a tumor-targeting molecular imaging agent. δOR expression is observed normally in the CNS, and pathologically in some tumors, including lung liver and breast cancers. In vitro, in vivo, and ex vivo experiments were conducted to image and quantify the fluorescence signal associated with Dmt-Tic-Cy5 over time using in vitro and intravital fluorescence microscopy and small animal fluorescence imaging of tumor-bearing mice. We observed specific retention of Dmt-Tic-Cy5 in tumors with maximum uptake in δOR-expressing positive tumors at 3 h and observable persistence for >96 h; clearance from δOR nonexpressing negative tumors by 6 h; and systemic clearance from normal organs by 24 h. Live-cell and intravital fluorescence microscopy demonstrated that Dmt-Tic-Cy5 had sustained cell-surface binding lasting at least 24 h with gradual internalization over the initial 6 h following administration. Dmt-Tic-Cy5 is a δOR-targeted agent that exhibits long-lasting and specific signal in δOR-expressing tumors, is rapidly cleared from systemic circulation, and is not retained in non-δOR-expressing tissues. Hence, Dmt-Tic-Cy5 has potential as a fluorescent tumor imaging agent. PMID:26713599

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

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

    2016-01-01

    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. PMID:26641134

  2. An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    Ding Y

    2015-10-01

    Full Text Available Yuan Ding,1,* Dan Sun,1,* Gui-Ling Wang,1 Hong-Ge Yang,1 Hai-Feng Xu,1 Jian-Hua Chen,2 Ying Xie,1,3 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 2School of Medicine, Jianghan University, Wuhan, 3State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 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: Cell-penetrating peptides (CPPs as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into

  3. Novel lactoferrin-conjugated amphiphilic poly(aminoethyl ethylene phosphate/poly(L-lactide copolymer nanobubbles for tumor-targeting ultrasonic imaging

    Luo BH

    2015-09-01

    core inside the NBs. The Lf-PAEEP-PLLA NBs also exhibited good biocompatibility in cytotoxicity and hemolysis studies and good stability during storage. The high cellular uptake of Lf-PAEEP-PLLA NBs in C6 cells (low-density lipoprotein receptor-related protein 1-positive cells at concentrations of 0–20 µg/mL indicated that the Lf provided effective targeting for brain-tumor cells. The in vitro acoustic behavior of Lf-PAEEP-PLLA NBs was evaluated using a B-mode clinical ultrasound imaging system. In vivo ultrasound imaging was performed on tumor-bearing BALB/c nude mice, and compared with SonoVue® microbubbles, a commercial ultrasonic contrast agent. Both in vitro and in vivo ultrasound imaging indicated that the Lf-PAEEP-PLLA NBs possessed strong, long-lasting, and tumor-enhanced ultrasonic contrast ability. Taken together, these results indicate that Lf-PAEEP-PLLA NBs represent a promising nano-sized ultrasonic contrast agent for tumor-targeting ultrasonic imaging.Keywords: PAEEP-PLLA copolymer, in vitro acoustic behavior, in vivo ultrasonic imaging, SonoVue® microbubbles

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

    Hsieh WJ

    2012-06-01

    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.Conclusion: 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-VEGF-NPs have potential for use as a molecular-targeted tumor imaging agent in vivo.Keywords: nanoparticles, vascular endothelial growth factor, colon tumor, magnetic resonance imaging, transmission electron microscopy

  5. Poly(Ethylene Oxide)-Modified Poly(β-Amino Ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs: Part I. In Vitro Evaluations

    Shenoy, Dinesh; Little, Steven; Langer, Robert; Amiji, Mansoor

    2005-01-01

    A representative poly(β-amino ester) (PbAE) with biodegradable and pH-sensitive properties was used to formulate nanoparticle-based dosage form for tumor-targeted paclitaxel delivery. The polymer undergoes rapid dissolution when the pH of the medium is less than 6.5, and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells. PbAE nanoparticles were prepared by solvent displacement method and characterized for particl...

  6. Tumor targeting using liposomal antineoplastic drugs

    Jörg Huwyler; Jürgen Drewe; Stephan Krähenbühl

    2008-01-01

    Jörg Huwyler1, Jürgen Drewe2, Stephan Krähenbühl21University of Applied Sciences Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland; 2Department of Research and Division of Clinical Pharmacology, University Hospital Basel, Basel, SwitzerlandAbstract: During the last years, liposomes (microparticulate phospholipid vesicles) have beenused with growing success as pharmaceutical carriers for antineoplastic drugs. Fields of applicatio...

  7. Process optimization for the preparation of oligomycin-loaded folate-conjugated chitosan nanoparticles as a tumor-targeted drug delivery system using a two-level factorial design method

    Zu Y

    2011-12-01

    Full Text Available Yuangang Zu, Qi Zhao, Xiuhua Zhao, Shuchong Zu, Li MengKey Laboratory of Forest Plant Ecology, Northeast Forestry University, Ministry of Education, Harbin, Heilongjiang, ChinaAbstract: Oligomycin-A (Oli-A, an anticancer drug, was loaded to the folate (FA-conjugated chitosan as a tumor-targeted drug delivery system for the purpose of overcoming the nonspecific targeting characteristics and the hydrophobicity of the compound. The two-level factorial design (2-LFD was applied to modeling the preparation process, which was composed of five independent variables, namely FA-conjugated chitosan (FA-CS concentration, Oli-A concentration, sodium tripolyphosphate (TPP concentration, the mass ratio of FA-CS to TPP, and crosslinking time. The mean particle size (MPS and the drug loading rate (DLR of the resulting Oli-loaded FA-CS nanoparticles (FA-Oli-CSNPs were used as response variables. The interactive effects of the five independent variables on the response variables were studied. The characteristics of the nanoparticles, such as amount of FA conjugation, drug entrapment rate (DER, DLR, surface morphology, and release kinetics properties in vitro were investigated. The FA-Oli-CSNPs with MPS of 182.6 nm, DER of 17.3%, DLR of 58.5%, and zeta potential (ZP of 24.6 mV were obtained under optimum conditions. The amount of FA conjugation was 45.9 mg/g chitosan. The FA-Oli-CSNPs showed sustained-release characteristics for 576 hours in vitro. The results indicated that FA-Oli-CSNPs obtained as a targeted drug delivery system could be effective in the therapy of leukemia in the future.Keywords: oligomycin-A, chitosan, folate, targeted drug delivery system, nanoparticles, two-level factorial design

  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

    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 18×18cm2, 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 both

  9. LNA aptamer based multi-modal, Fe3O4-saturated lactoferrin (Fe3O4-bLf) nanocarriers for triple positive (EpCAM, CD133, CD44) colon tumor targeting and NIR, MRI and CT imaging.

    Roy, Kislay; Kanwar, Rupinder K; Kanwar, Jagat R

    2015-12-01

    , survivin splice variant (survivin 2B) and other anti-apoptotic proteins Bad, Bcl-2 and XIAP. Apart from the promising anti-cancer efficacy and the exceptional tumor targeting ability observed by multimodal imaging using near-infrared (NIR) imaging, magnetic resonance imaging (MRI) and computerized tomographic (CT) techniques, these NCs also maintained the immunomodulatory benefits of bLf as they were able to increase the RBC, hemoglobin, iron calcium and zinc levels in mice. PMID:26318819

  10. 3,2'-Dimethyl-4-aminobiphenyl-DNA adduct formation in tumor target and nontarget organs of rapid and slow acetylator Syrian hamsters cogenic at the NAT2 locus.

    Feng, Y; Jiang, W; Deitz, A C; Hein, D W

    1996-10-01

    DNA adduct formation is an important step in initiation of the carcinogenic process. 3,2'-Dimethyl-4-aminobiphenyl (DMABP) is a well-documented multiorgan carcinogenic aromatic amine in rodents. In the present study, DMABP-DNA adduct levels were measured in rapid (Bio. 82.73/H-Pat(r)) and slow (Bio. 82.73/H-Pat(s)) acetylator Syrian hamsters congenic at the NAT2 locus following a single injection of 33 or 100 mg/kg body wt DMABP. Two DNA adducts, N-(deoxyguanosin-8-yl)-DMABP and 5-(deoxyguanosin-N2-yl)-DMABP, were identified and quantitated by 32P-postlabeling assay. After injection of 33 mg/kg, DMABP-DNA adducts were detected in urinary bladder at 6, 18, 24, and 48 hr with adduct levels increasing up to 48 hr postinjection. DMABP-DNA adducts were not detected in liver, colon, and heart. After injection of 100 mg/kg, DMABP-DNA adducts were detected in urinary bladder, liver, prostate, colon, and heart at 48 hr postinjection. DMABP-DNA adduct levels were significantly higher in urinary bladder (primary tumor target organ) than in the other organs of both rapid and slow acetylator congenic hamsters. N-(deoxyguanosin-8-yl)-DMABP levels were significantly higher in liver and prostate than in colon and heart of rapid and slow acetylator congenic hamsters, whereas 5-(deoxyguanosin-N2-yl)-DMABP levels were significantly higher in prostate than in colon and heart of rapid and slow acetylator congenic hamsters. DMABP-DNA adduct levels in each tissue examined did not differ significantly between rapid and slow acetylator hamsters following either 33 or 100 mg/kg injection. The tissue-dependent differences in DMABP-DNA adduct levels observed in the Syrian hamster differ from those reported in the rat and are consistent with previous studies that show DMABP induces primarily urinary bladder tumors in the Syrian hamster. PMID:8887447

  11. CT/MRI融合图像在盆腔肿瘤放疗靶区勾画中的应用%Application of CT/MRI Image Fusion in the Delineating of the Gross Tumor Target Volumes in the Radiotherapy for Pelvic Cavity Tumor

    张海南; 汤日杰; 张书旭; 蔡霜

    2011-01-01

    Objective To study the value of application of CT/MRI image fusion in the delineating of the gross tumor target volumes in the radiotherapy for pelvic tumor in the middle-aged and elderly patients. Methods Nineteen patients suffering from pelvic tumor underwent CT and MRI examination within one week.All CT and MRI images were manually transported to the Nucletron PLATO Radiation Treatment Planning System(V 8.0, Philips medical corporation), and CT/MRI images were processed for image fusion.The experienced radiotherapeutic physicians delineated and analyzed the target volume of CT and MRI images, and gross tumor target volume of the CT/MR image fusion. Results The gross tumor target volume of the CT/MR image fusion relative the target volume of CT increased 6.29%,and relative MRI raised 11.84%,CT/MRI image fusion is superior to single CT and MRI image in the delineation of the gross tumor target volume, which was verified by test. Conclusion The technology of CT/MR image fusion can help to confirm target volume for pelvic tumor which will improve the accuracy in demarcating of the gross tumor target volume of pelvic cavity tumor, and promote the diagnosis and treatment of pelvic cavity tumor.%目的 探讨CT/MRI融合图像在中老年盆腔肿瘤放疗靶区(GTV)勾画中的应用价值.方法 19例盆腔肿瘤患者均在1周内分别进行CT、MRI异机非同步扫描.全部CT和MRI图像手工配准后传送至飞利浦公司的PINNACLE V8.0放射治疗计划系统,并进行图像融合.由有经验的放疗科医师对CT靶区、MRI靶区及CT与MR融合图像肿瘤靶区(GTV)进行勾画及评价分析.结果 GTVFUSION相对GTVCT提高了6.29%、相对GTVMRI提高了11.84%,融合图像对GTV的勾画明显优于单独CT图像或MRI图像.结论 CT/MRI图像融合技术有利于盆腔肿瘤靶区的确定,提高了临床对盆腔肿瘤靶区(GTV)勾画的准确率,利于患者的诊治.

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

    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.

  13. Phenylalanine-coupled solid lipid nanoparticles for brain tumor targeting

    The purpose of this study is to investigate the targeting potential of amino acid (phenylalanine)-coupled solid lipid nanoparticles (SLN) loaded with ionically complexed doxorubicin HCl (Dox). Ionic complexation was used to enhance the loading efficiency and release characteristics of water soluble form of Dox. l-Type amino acid transporters (LAT1) are highly expressed on blood brain barrier as well as on many brain cancer cells, thus targeting LAT1 using phenylalanine improved anticancer activity of prepared nanocarrier. The phenylalanine-coupled SLN were characterized by fourier transform infrared spectroscopy, scanning electron microscope, transmission electron microscopy, particle size, zeta potential, entrapment efficiency and in vitro release. The particle size of the resulting SLN was found to be in the range of 163.3 ± 5.2 to 113.0 ± 2.6 nm, with a slightly negative surface charge. In ex vivo study on C6 glioma cell lines, the cellular cytotoxicity of the SLN was highly increased when coupled with phenylalanine. In addition, stealthing sheath of PEG present on the surface of the SLN enhanced the cellular uptake of the SLN on C6 glioma cell line. Results of biodistribution and fluorescence studies clearly revealed that phenylalanine-coupled SLN could deliver high amount of drug into the brain tumor cells and showed the brain-targeting potential

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

    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 Fe2+ 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.

  15. Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy.

    Luderer, Micah John; de la Puente, Pilar; Azab, Abdel Kareem

    2015-09-01

    Boron neutron capture therapy (BNCT) is a promising cancer therapy modality that utilizes the nuclear capture reaction of epithermal neutrons by boron-10 resulting in a localized nuclear fission reaction and subsequent cell death. Since cellular destruction is limited to approximately the diameter of a single cell, primarily only cells in the neutron field with significant boron accumulation will be damaged. However, the emergence of BNCT as a prominent therapy has in large part been hindered by a paucity of tumor selective boron containing agents. While L-boronophenylalanine and sodium borocaptate are the most commonly investigated clinical agents, new agents are desperately needed due to their suboptimal tumor selectivity. This review will highlight the various strategies to improve tumor boron delivery including: nucleoside and carbohydrate analogs, unnatural amino acids, porphyrins, antibody-dendrimer conjugates, cationic polymers, cell-membrane penetrating peptides, liposomes and nanoparticles. PMID:26033767

  16. Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

    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.

  17. The development of somatostatin analogues mediated tumor targeting and therapy

    Radionuclide labelled somatostatin analogues have been widely used in the detection of neuro-endocrine tumors. Till now, most of somatostatin analogues only have high affinity to somatostatin receptor 2 (SSTR2), further clinical applications was limitted. A new generation of somatostatin analogues such as 1, 4, 7, 10-tetraazacyclodocecane-N, N', N'', N''' -tetaraacetic acid-Na 13- octertide (DOTA-NOC) etc, binding to somatostatin receptors not only SSTR2 but other subtypes has been used mainly in preclinical study. In this review, we discussed these new somatostatin analogues, chelating agent, and their new labelled compounds, these new radionuclide labelled somatostatin analogues may hold great promise for the receptor-mediated tumor imaging and treatments. (authors)

  18. Synthesis and Evaluation of GnRHa-paclitaxel Tumor-targeting Conjugates%促性腺激素释放激素类似物-紫杉醇靶向抗肿瘤缀合物的合成及评价

    马永涛; 冯思良; 王晨宏; 周宁; 刘克良

    2014-01-01

    Tumor targeting can be achieved by combining a chemotherapeutic agent with a targeting moiety, which recognizes tumor-specific or highly expressed receptors on cancer cells. GnRH receptor is over-ex-pressed on various tumor cells but is barely expressed in healthy visceral organs which makes it possible to use GnRH analogues( GnRHa) as the targeting moieties to deliver cytotoxic agents. Two conjugates were synthe-sized by incorporating paclitaxel( PTX) into GnRH analogue which was synthesized in the solid phase, the conjugation of PTX with GnRH analogs was performed by thio-ether bond and disulfide bond as a linker. The purity of the conjugates was analyzed by high performance liquid chromatography( HPLC) and the structures of the conjugates were confirmed by high resolution mass spectrum ( HRMS ) . The resulting conjugates 1 and 2 both preserved the cytotoxic activity of PTX and also retained the high binding affinity of the peptide hormone portion of the conjugates. The high affinity indicated that the conjugates might be specifically delivered to tumor tissues or cells via endocytosis mediated by GnRH receptor. The results showed that more than 50%prototypes of conjugate 1 remained with incubating in human serum for 24 h which indicating a favorable sta-bility.%以促性腺激素释放激素类似物( GnRHa)为靶向配体,以紫杉醇为抗癌因子,分别以硫醚键和二硫键为连接臂,设计合成了2个靶向抗肿瘤缀合物。研究了缀合物的肿瘤细胞增殖抑制活性和GnRH受体结合活性,结果表明,2个缀合物均具有较强的抗肿瘤活性和GnRH受体亲和力;另外,血浆稳定性实验结果显示,以硫醚键偶联的缀合物1在血浆中孵育24 h,原型保留仍在50%以上,具有较高的稳定性。

  19. The Blazing Horror of Now

    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....

  20. Photodynamic therapy and imaging based on tumor-targeted nanoprobe, polymer-conjugated zinc protoporphyrin

    Fang, J.; Liao, L.; Yin, H.; Nakamura, H.; Šubr, Vladimír; Ulbrich, Karel; Maeda, H.

    2015-01-01

    Roč. 2015, č. 4 (2015), s. 1-13. ISSN 2056-5623 R&D Projects: GA ČR(CZ) GAP301/12/1254 Grant ostatní: AV ČR(CZ) Praemium Academiae Institutional support: RVO:61389013 Keywords : fluorescent nanoprobe * photodynamic therapy * theranostic nanomedicine Subject RIV: CD - Macromolecular Chemistry

  1. Biodistribution in sarcoma 180-bearing mice of N-succinyl-chitosan nanoparticles for tumor targeting

    Cheng, Yan; Yan, Chengyun; Gu, Jiwei; Wang, Xi; Huang, Zhan; Chen, Dawei

    2011-01-01

    In the present study, we sought to systemically evaluate the biodistribution and the tumor-accumulation of N-succinyl-chitosan nanoparticles (Suc-Chi-NPs, 200 nm in diameter) in model tumor-bearing mice and also the binding of Suc-Chi-NPs to k562 cells was evaluated by flow cytometry. In vitro studies showed that all Suc-Chi-NPs displayed high affinity to k562 cells. After intravenous injection of Suc- Chi-NPs via the tail vein, a small amount of Suc-Chi-NPs was found in liver and spleen for ...

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

    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.

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

    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.

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

    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 malign

  5. Tumor-targeted boron-containing amino acids and their related compounds. Synthesis and biological activity

    In a series of our synthetic studies on boron-containing amino acids and their related compounds for BNCT (Boron Neutron Capture Therapy), p-boronophenylalanine (BPA), p-boronophenylserine (BPS), o-carboranylmethyl-3-hydroxytyrosine (CMHT) and their derivatives were designed and synthesized by using of isocyano compounds as a starting material. Two water-soluble amino alcohols, BPA-OH and BPS-OH, were prepared by the reduction of the corresponding N-formyl amino esters. On the other hand, CMHTA, an amide derivative of CMHT, was synthesized by an aldol-type condensation of isocyanoacetamide with 4-(o-carboranylmethyloxy)benz aldehyde as a key reaction. The relative tumor cell (human glioma T98G) killing effect of nBPS-OH, nBPA-OH and CMHTA against 10BPA was 0.7, 1.0 and 4.9, respectively. The uptake of CMHTA by the tumor cell increased with increasing cultivation time. (J.P.N.)

  6. Tumor targeting and imaging with dual-peptide conjugated multifunctional liposomal nanoparticles

    Rangger C; Helbok A; Sosabowski J; Kremser C; Koehler G; Prassl R; Andreae F; Virgolini IJ; von Guggenberg E; Decristoforo C

    2013-01-01

    Christine Rangger,1 Anna Helbok,1 Jane Sosabowski,2 Christian Kremser,3 Gottfried Koehler,4 Ruth Prassl,5,6 Fritz Andreae,7 Irene J Virgolini,1 Elisabeth von Guggenberg,1 Clemens Decristoforo11Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria; 2Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK; 3Department of Radiology, Innsbruck Medical University, Innsbruck, 4Department of Computational and Structural Biology, M...

  7. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

    John C. Leach

    2016-03-01

    Full Text Available The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA, was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.

  8. Galactoxyloglucan-modified nanocarriers of doxorubicin for improved tumor-targeted drug delivery with minimal toxicity.

    Joseph, Manu M; Aravind, S R; George, Suraj K; Pillai, K Raveendran; Mini, S; Sreelekha, T T

    2014-11-01

    Doxorubicin (Dox) is commonly used to treat human malignancies, and the efficacy of Dox can be maximized by limiting toxicity when combined with nanoparticles. PST-Dox nanoparticles were prepared via conjugation of doxorubicin to galactoxyloglucan polysaccharide (PST001) isolated from Tamarindus indica (Ti), and by ionic gelation with tripolyphosphate (TPP). This formulation possessed superior therapeutic efficiency because of the small size and increased surface-to-volume ratio. The PST-Dox nanoparticles exhibited a pH-responsive Dox release in the acidic pH of 4.5, favoring as high as 90% Dox release in a sustainable manner. PST-Dox was characterized and evaluated for its in vitro and in vivo anticancer effects. Surprisingly, this nanoparticle formulation retained the cytotoxic effects of PST001 even at lower concentrations. In vitro studies confirmed the selective cytotoxicity of PST-Dox in cancer cells through the induction of apoptosis. In vivo toxicity studies demonstrated a lower LD50 for Dox and a higher LD50 for the PST-Dox. Evaluation of the biochemical, hematological and histopathological parameters in mice supported the safety and efficacy of this formulation compared to Dox. Biodistribution data substantiated the tumor-specific delivery of these particles. Although prospective studies are warranted, in a complex disease such as cancer, cell-selective and pH-sensitive nanoparticle-based targeted drug delivery systems should be used as an effective choice over standard agents, such as doxorubicin. PMID:26000385

  9. MRI-visible liposome nanovehicles for potential tumor-targeted delivery of multimodal therapies

    Ren, Lili; Chen, Shizhen; Li, Haidong; Zhang, Zhiying; Ye, Chaohui; Liu, Maili; Zhou, Xin

    2015-07-01

    Real-time diagnosis and monitoring of disease development, and therapeutic responses to treatment, are possible by theranostic magnetic resonance imaging (MRI). Here we report the synthesis of a multifunctional liposome, which contains Gd-DOTA (an MRI probe), paclitaxel and c(RGDyk) (a targeted peptide). This nanoparticle overcame the insolubility of paclitaxel, reduced the side effects of FDA-approved formulation of PTX-Cre (Taxol®) and improved drug delivery efficiency to the tumor. c(RGDyk) modification greatly enhanced the cytotoxicity of the drug in tumor cells A549. The T1 relaxivity in tumor cells treated with the targeted liposome formulation was increased 16-fold when compared with the non-targeted group. In vivo, the tumors in mice were visualized using T1-weighted imaging after administration of the liposome. Also the tumor growth could be inhibited well after the treatment. Fluorescence images in vitro and ex vivo also showed the targeting effect of this liposome in tumor cells, indicating that this nanovehicle could limit the off-target side effects of anticancer drugs and contrast agents. These findings lay the foundation for further tumor inhibition study and application of this delivery vehicle in cancer therapy settings.

  10. Magnetic tumor targeting of β-glucosidase immobilized iron oxide nanoparticles

    Directed enzyme/prodrug therapy (DEPT) has promising application for cancer therapy. However, most current DEPT strategies face shortcomings such as the loss of enzyme activity during preparation, low delivery and transduction efficiency in vivo and difficultly of monitoring. In this study, a novel magnetic directed enzyme/prodrug therapy (MDEPT) was set up by conjugating β-glucosidase (β-Glu) to aminated, starch-coated, iron oxide magnetic iron oxide nanoparticles (MNPs), abbreviated as β-Glu–MNP, using glutaraldehyde as the crosslinker. This β-Glu–MNP was then characterized in detail by size distribution, zeta potential, FTIR spectra, TEM, SQUID and magnetophoretic mobility analysis. Compared to free enzyme, the conjugated β-Glu on MNPs retained 85.54% ± 6.9% relative activity and showed much better temperature stability. The animal study results showed that β-Glu–MNP displays preferable pharmacokinetics characteristics in relation to MNPs. With an adscititious magnetic field on the surface of a tumor, a significant quantity of β-Glu–MNP was selectively delivered into a subcutaneous tumor of a glioma-bearing mouse. Remarkably, the enzyme activity of the delivered β-Glu in tumor lesions showed as high as 20.123±5.022 mU g−1 tissue with 2.14 of tumor/non-tumor β-Glu activity. (paper)

  11. Tumor targeting of humanized fragment antibody secreted from transgenic rice cell suspension culture

    Hong, Shin-Young; Lee, Tae-Sup; Kim, Ju; Jung, Jae-Ho; Choi, Chang-Woon; Kim, Tae-Geum; Kwon, Tae-Ho; Jang, Yong-Suk; Yang, Moon-Sik

    The tumor-associated glycoprotein 72 (TAG 72) has been shown to be expressed in the majority of human adenocarcinomas. In an effort to develop a technique for the safe and inexpensive production of large quantities of anti-TAG 72 humanized antibody fragments (hzAb) as a future source of clinical......-grade proteins, we developed a transgenic rice cell suspension culture system. The in vivo assembly and secretion of hzAb were achieved in a transgenic rice cell culture under the control of the rice alpha amylase 3D (RAmy 3D) expression system, and the biological activities of plant-derived hzAb were determined...

  12. Image-guided and tumor-targeted drug delivery with radiolabeled unimolecular micelles

    Guo, Jintang; Hong, Hao; Chen, Guojun; Shi, Sixiang; Zheng, Qifeng; Zhang, Yin; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo; Gong, Shaoqin

    2013-01-01

    Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)–poly(l-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N’, N-triacetic acid (NOTA, a macrocyclic chelator for 64Cu) (abbreviated as PAMAM–PLA-b-PEG–TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti-cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physic...

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

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

    2009-01-01

    alpha-carboxylic acid. The cytotoxicity of the gamma-alkylated compound towards KATO III (IC50 = 55 nM) and HT-29 (IC50 = 400 nM) cell lines, Was unaffected by the alkylation, whereas the additional benzyl group on the alpha-carboxyl group made the Compound nontoxic. The gamma-derivative with promising......Two lipophilic methotrexate analogues have been synthesized and evaluated for cytotoxicity against KATO III and HT-29 human colon cancer cells. Both analogues contained a C-16-alkyl chain attached to the gamma-carboxylic acid and one of the analogues had an additional benzyl group attached to the...

  14. Anti-tumor targeted drug delivery systems mediated by aminopeptidase N/CD13

    Xun Wang

    2011-08-01

    Full Text Available Aminopeptidase N (APN/CD13 is a transmembrane glycoprotein, which is overexpressed on tumor neovascular endothelial cells and most tumor cells, where it plays an important role in tumor angiogenesis. Peptides containing the Asn-Gly-Arg (NGR motif can specifically recognize APN/CD13 allowing them to act as tumor-homing peptides for the targeted delivery of anti-tumor drugs to tumor neovascular endothelial cells and tumor cells. This article reviews the literature and recent developments related to APN/CD13, its role in tumor growth and some anti-tumor drug delivery systems containing NGR peptides designed to target APN/CD13.

  15. In vivo tumor targeting by a NGR decorated micelle of a recombinant diblock copolypeptide

    Simnick, Andrew J.; Amiram, Miriam; Liu, Wenge; Hanna, Gabi; Mark W. Dewhirst; Kontos, Christopher D.; Chilkoti, Ashutosh

    2011-01-01

    Antivascular targeting is a promising strategy for tumor therapy. This strategy has the potential to overcome many of the transport barriers associated with targeting tumor cells in solid tumors, because the tumor vasculature is directly accessible to targeting vehicles in systemic circulation. We report a novel nanoscale delivery system consisting of multivalent polymer micelles to target receptors that are preferentially upregulated in the tumor vasculature and perivascular cells, specifica...

  16. Anti-tumor targeted drug delivery systems mediated by aminopeptidase N/CD13

    Xun Wang; Bin Wang; Qiang Zhang

    2011-01-01

    Aminopeptidase N (APN)/CD13 is a transmembrane glycoprotein, which is overexpressed on tumor neovascular endothelial cells and most tumor cells, where it plays an important role in tumor angiogenesis. Peptides containing the Asn-Gly-Arg (NGR) motif can specifically recognize APN/CD13 allowing them to act as tumor-homing peptides for the targeted delivery of anti-tumor drugs to tumor neovascular endothelial cells and tumor cells. This article reviews the literature and recent developments rela...

  17. Structural and Enzymatic Analysis of Tumor-Targeted Antifolates That Inhibit Glycinamide Ribonucleotide Formyltransferase.

    Deis, Siobhan M; Doshi, Arpit; Hou, Zhanjun; Matherly, Larry H; Gangjee, Aleem; Dann, Charles E

    2016-08-16

    Pemetrexed and methotrexate are antifolates used for cancer chemotherapy and inflammatory diseases. These agents have toxic side effects resulting, in part, from nonspecific cellular transport by the reduced folate carrier (RFC), a ubiquitously expressed facilitative transporter. We previously described 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine antifolates with modifications of the side chain linker and aromatic ring that are poor substrates for RFC but are efficiently transported via folate receptors (FRs) and the proton-coupled folate transporter (PCFT). These targeted antifolates are cytotoxic in vitro toward FR- and PCFT-expressing tumor cells and in vivo with human tumor xenografts in immune-compromised mice, reflecting selective cellular uptake. Antitumor efficacy is due to inhibition of glycinamide ribonucleotide (GAR) formyltransferase (GARFTase) activity in de novo synthesis of purine nucleotides. This study used purified human GARFTase (formyltransferase domain) to assess in vitro inhibition by eight novel thieno- and pyrrolo[2,3-d]pyrimidine antifolates. Seven analogues (AGF23, AGF71, AGF94, AGF117, AGF118, AGF145, and AGF147) inhibited GARFTase with Ki values in the low- to mid-nanomolar concentration range, whereas AGF50 inhibited GARFTase with micromolar potency similar to that of PMX. On the basis of crystal structures of ternary complexes with GARFTase, β-GAR, and the monoglutamyl antifolates, differences in inhibitory potencies correlated well with antifolate binding and the positions of the terminal carboxylates. Our data provide a mechanistic basis for differences in inhibitory potencies between these novel antifolates and a framework for future structure-based drug design. These analogues could be more efficacious than clinically used antifolates, reflecting their selective cellular uptake by FRs and PCFT and potent GARFTase inhibition. PMID:27439469

  18. Development of radiolabeled radachlorin complex as a possible tumor targeting agent

    Developing radiolabeled tetrahydropyrrole complexes for ultimate dual-purpose imaging as well as dual-therapeutic modalities was of our interests. [67Ga] labeled radachlorin was prepared followed by stability tests, partition coefficient determination as well as biodistribution studies in wild type rodents using scarification and SPECT imaging. However, the results showed high and prolonged uptake of the labeled compound in many organs that the potential of the labeled compound for diagnostic proposal is weak. (author)

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

    Kunjachan, S.; Pola, Robert; Gremse, F.; Theek, B.; Ehling, J.; Moeckel, D.; Hermanns-Sachweh, B.; Pechar, Michal; Ulbrich, Karel; Hennink, W. E.; Storm, G.; Lederle, W.; Kiessling, F.; Lammers, T.

    2014-01-01

    Roč. 14, č. 2 (2014), s. 972-981. ISSN 1530-6984 R&D Projects: GA ČR GCP207/12/J030 Institutional support: RVO:61389013 Keywords : nanomedicine * drug targeting * EPR Subject RIV: CD - Macromolecular Chemistry Impact factor: 13.592, year: 2014

  20. Passive tumor targeting and imaging by using mercaptosuccinic acid-coated near-infrared quantum dots

    Lin, Guimiao

    2015-01-01

    Guimiao Lin,1 Xiaomei Wang,1 Feng Yin,2 Ken-Tye Yong2 1The Engineering Lab of Synthetic Biology and Research Institute of Uropoiesis and Reproduction, School of Medicine, Shenzhen University, Shenzhen, People’s Republic of China; 2School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore, Singapore Abstract: In this paper, we demonstrate the preparation of monodispersed quantum dots (QDs) as near-infrared (NIR) optical probes for in vivo pancreati...

  1. Smart linkers in polymer-drug conjugates for tumor-targeted delivery.

    Chang, Minglu; Zhang, Fang; Wei, Ting; Zuo, Tiantian; Guan, Yuanyuan; Lin, Guimei; Shao, Wei

    2016-07-01

    To achieve effective chemotherapy, many types of drug delivery systems have been developed for the specific environments in tumor tissues. Polymer-drug conjugates are increasingly used in tumor therapy due to several significant advantages over traditional delivery systems. In the fabrication of polymer-drug conjugates, a smart linker is an important component that joins two fragments or molecules together and can be cleared by a specific stimulus, which results in targeted drug delivery and controlled release. By regulating the conjugation between the drug and the nanocarriers, stimulus-sensitive systems based on smart linkers can offer high payloads, certified stability, controlled release and targeted delivery. In this review, we summarize the current state of smart linkers (e.g. disulfide, hydrazone, peptide, azo) used recently in various polymer-drug conjugate-based delivery systems with a primary focus on their sophisticated design principles and drug delivery mechanisms as well as in vivo processes. PMID:26560242

  2. Biodegradable Inorganic Nanovector: Passive versus Active Tumor Targeting in siRNA Transportation.

    Park, Dae-Hwan; Cho, Jaeyong; Kwon, Oh-Joon; Yun, Chae-Ok; Choy, Jin-Ho

    2016-03-24

    The biodegradable inorganic nanovector based on a layered double hydroxide (LDH) holds great promise for gene and drug delivery systems. However, in vivo targeted delivery of genes through LDH still remains a key challenge in the development of RNA interference therapeutics. Here, we describe in vivo and in vitro delivery system for Survivin siRNA (siSurvivin) assembled with passive LDH with a particle size of 100 nm or active LDH conjugated with a cancer overexpressing receptor targeting ligand, folic acid (LDHFA), conferring them an ability to target the tumor by either EPR-based clathrin-mediated or folate receptor-mediated endocytosis. When not only transfected into KB cells but also injected into xenograft mice, LDHFA/siSurvivin induced potent gene silencing at mRNA and protein levels in vitro, and consequently achieved a 3.0-fold higher suppression of tumor volume than LDH/siSurvivin in vivo. This anti-tumor effect was attributed to a selectively 1.2-fold higher accumulation of siSurvivin in tumor tissue compared with other organs. Targeting to the tumor with inorganic nanovector can guide and accelerate an evolution of next-generation theranosis system. PMID:26879376

  3. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

    Leach, John C.; Andrew Wang; Kaiming Ye; Sha Jin

    2016-01-01

    The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antig...

  4. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

    Leach, John C.; Wang, Andrew; Ye, Kaiming; Jin, Sha

    2016-01-01

    The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox) was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells. PMID:26985893

  5. Baicalin loaded in folate-PEG modified liposomes for enhanced stability and tumor targeting

    Chen, Y.; Minh, L. V.; Liu, J.; Angelov, Borislav; Drechsler, M.; Garamus, V. M.; Willumeit-Römer, R.; Zou, A.

    2016-01-01

    Roč. 140, 1 April (2016), s. 74-82. ISSN 0927-7765 R&D Projects: GA ČR(CZ) GC15-10527J Institutional support: RVO:61389013 Keywords : baicalin * liposomes * folate receptor Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 4.152, year: 2014

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

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

    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...

  7. Polymer nanostructures synthesized by controlled living polymerization for tumor-targeted drug delivery.

    Wang, Christine E; Stayton, Patrick S; Pun, Suzie H; Convertine, Anthony J

    2015-12-10

    The development of drug delivery systems based on well-defined polymer nanostructures could lead to significant improvements in the treatment of cancer. The design of these therapeutic nanosystems must account for numerous systemic and circulation obstacles as well as the specific pathophysiology of the tumor. Nanoparticle size and surface charge must also be carefully selected in order to maintain long circulation times, allow tumor penetration, and avoid clearance by the reticuloendothelial system (RES). Targeting ligands such as vitamins, peptides, and antibodies can improve the accumulation of nanoparticle-based therapies in tumor tissue but must be optimized to allow for intratumoral penetration. In this review, we will highlight factors influencing the design of nanoparticle therapies as well as the development of modern controlled "living" polymerization techniques (e.g. ATRP, RAFT, ROMP) that are leading to the creation of sophisticated new polymer architectures with discrete spatially-defined functional modules. These innovative materials (e.g. star polymers, polymer brushes, macrocyclic polymers, and hyperbranched polymers) combine many of the desirable properties of traditional nanoparticle therapies while substantially reducing or eliminating the need for complex formulations. PMID:26342661

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

    Bachran, Christopher; Abdelazim, Suzanne; Fattah, Rasem J; Liu, Shihui; Leppla, Stephen H

    2013-01-01

    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 (TGFα). 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 TGFα). 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. PMID:23200832

  9. Recombinant Expression and Purification of a Tumor-Targeted Toxin in Bacillus anthracis

    Bachran, Christopher; Abdelazim, Suzanne; Fattah, Rasem J.; Liu, Shihui; Leppla, Stephen H.

    2012-01-01

    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 pr...

  10. Tumor-Targeting Co-Delivery of Drug and Gene from Temperature-Triggered Micelles.

    Seo, Seog-Jin; Lee, Seon-Young; Choi, Seong-Jun; Kim, Hae-Won

    2015-09-01

    Co-delivery strategy using multifunctional nanocarriers is an attractive option for the synergistic and enhanced effects in cancer treatment, but one system integrating multiple functions for controlled release at the target is still challenging. Herein, this study shows the synthesis and characterization of our stimulus-responsive co-delivery system for the controlled release into tumors, which is composed of polyethylenimine (PEI)-linked Pluronic F127 (PF127) and folic acid (FA), called PF127-PEI-FA. PF127-PEI-FA system facilitated drug loading and gene complex formation, and showed controlled release behaviors in response to hitting temperature to hyperthermia. PF127-PEI-FA system was demonstrated to be biocompatible and showed receptor-mediated gene delivery. The results of our multifunctional nanocarrier system that enabled co-delivery suggest a promising potential for controlled drug release at targeted areas. However, further in-depth studies on the use of therapeutic drugs and genes in multiple cell types and the animal response are required. PMID:25990042

  11. Long circulating reduced graphene oxide-iron oxide nanoparticles for efficient tumor targeting and multimodality imaging.

    Xu, Cheng; Shi, Sixiang; Feng, Liangzhu; Chen, Feng; Graves, Stephen A; Ehlerding, Emily B; Goel, Shreya; Sun, Haiyan; England, Christopher G; Nickles, Robert J; Liu, Zhuang; Wang, Taihong; Cai, Weibo

    2016-07-01

    Polyethylene glycol (PEG) surface modification is one of the most widely used approaches to improve the solubility of inorganic nanoparticles, prevent their aggregation and prolong their in vivo blood circulation half-life. Herein, we developed double-PEGylated biocompatible reduced graphene oxide nanosheets anchored with iron oxide nanoparticles (RGO-IONP-(1st)PEG-(2nd)PEG). The nanoconjugates exhibited a prolonged blood circulation half-life (∼27.7 h) and remarkable tumor accumulation (>11 %ID g(-1)) via an enhanced permeability and retention (EPR) effect. Due to the strong near-infrared absorbance and superparamagnetism of RGO-IONP-(1st)PEG-(2nd)PEG, multimodality imaging combining positron emission tomography (PET) imaging with magnetic resonance imaging (MRI) and photoacoustic (PA) imaging was successfully achieved. The promising results suggest the great potential of these nanoconjugates for multi-dimensional and more accurate tumor diagnosis and therapy in the future. PMID:27109431

  12. Use of novel metalloporphyrins as imageable tumor-targeting agents for radiation therapy

    Miura, Michiko; Slatkin, Daniel N.

    2005-10-04

    The present invention covers halogenated derivatives of boronated phorphyrins containing multiple carborane cages having the formula ##STR1## which selectively accumulate in neoplastic tissue within the irradiation volume and thus can be used in cancer therapies including, but not limited to, boron neutron-capture therapy and photodynamic therapy. The present invention also covers methods for using these halogenated derivatives of boronated porphyrins in tumor imaging and cancer treatment.

  13. RGD-modified poly(D,L-lactic acid) nanoparticles enhance tumor targeting of oridonin

    Xu J; Zhao JH; Liu Y.; Feng NP; Zhang YT

    2012-01-01

    Jie Xu, Ji-Hui Zhao, Ying Liu, Nian-Ping Feng, Yong-Tai ZhangSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of ChinaObjective: The purpose of this study was to develop an active targeting strategy to improve the therapeutic antitumor efficacy of oridonin (ORI), the main active ingredient in the medicinal herb Rabdosia rubescens.Methods: A modified spontaneous emulsification solvent diffusion method was used to prepare the ORI-loade...

  14. System for recovery of daughter isotopes from a source material

    Tranter, Troy J [Idaho Falls, ID; Todd, Terry A [Aberdeen, ID; Lewis, Leroy C [Idaho Falls, ID; Henscheid, Joseph P [Idaho Falls, ID

    2009-08-04

    A method of separating isotopes from a mixture containing at least two isotopes in a solution is disclosed. A first isotope is precipitated and is collected from the solution. A daughter isotope is generated and collected from the first isotope. The invention includes a method of producing an actinium-225/bismuth-213 product from a material containing thorium-229 and thorium-232. A solution is formed containing nitric acid and the material containing thorium-229 and thorium-232, and iodate is added to form a thorium iodate precipitate. A supernatant is separated from the thorium iodate precipitate and a second volume of nitric acid is added to the thorium iodate precipitate. The thorium iodate precipitate is stored and a decay product comprising actinium-225 and bismuth-213 is generated in the second volume of nitric acid, which is then separated from the thorium iodate precipitate, filtered, and treated using at least one chromatographic procedure. A system for producing an actinium-225/bismuth-213 product is also disclosed.

  15. Teenage Suicide in Zimbabwe.

    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)

  16. A novel combination of TRAIL and doxorubicin enhances antitumor effect based on passive tumor-targeting of liposomes

    Guo Liangran; Fan Li; Ren Jinfeng; Pang Zhiqing; Ren Yulong; Li Jingwei; Jiang Xinguo [Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai (China); Wen Ziyi, E-mail: xgjiang@shmu.edu.cn [Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang (China)

    2011-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel anticancer agent for non-small cell lung cancer (NSCLC). However, approximately half of NSCLC cell lines are highly resistant to TRAIL. Doxorubicin (DOX) can sensitize NSCLC cells to TRAIL-induced apoptosis, indicating the possibility of combination therapy. Unfortunately, the therapeutic effect of a DOX and TRAIL combination is limited by multiple factors including the short serum half-life of TRAIL, poor compliance and application difficulty in the clinic, chronic DOX-induced cardiac toxicity, and the multidrug resistance (MDR) property of NSCLC cells. To solve such problems, we developed the combination of TRAIL liposomes (TRAIL-LP) and DOX liposomes (DOX-LP). An in vitro cytotoxicity study indicated that DOX-LP sensitized the NSCLC cell line A-549 to TRAIL-LP-induced apoptosis. Furthermore, this combination therapy of TRAIL-LP and DOX-LP displayed a stronger antitumor effect on NSCLC in xenografted mice when compared with free drugs or liposomal drugs alone. Therefore, the TRAIL-LP and DOX-LP combination therapy has excellent potential to become a new therapeutic approach for patients with advanced NSCLC.

  17. Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells

    Kim, Jong Oh

    2015-01-01

    Tuan Hiep Tran,1 Thiruganesh Ramasamy,1 Ju Yeon Choi,1 Hanh Thuy Nguyen,1 Thanh Tung Pham,1 Jee-Heon Jeong,1 Sae Kwang Ku,2 Han-Gon Choi,3 Chul Soon Yong,1 Jong Oh Kim11College of Pharmacy, Yeungnam University, Dae-Dong, 2College of Korean Medicine, Daegu Haany University, Gyeongsan, 3College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South KoreaAbstract: The attachment of polyethylene glycol (PEG) increases the circulation time of drug-containing nanoparti...

  18. Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells

    Tran TH; Ramasamy T; Choi JY; Nguyen HT; Pham TT; Jeong JH; SK Ku; Choi HG; Yong CS; Kim JO

    2015-01-01

    Tuan Hiep Tran,1 Thiruganesh Ramasamy,1 Ju Yeon Choi,1 Hanh Thuy Nguyen,1 Thanh Tung Pham,1 Jee-Heon Jeong,1 Sae Kwang Ku,2 Han-Gon Choi,3 Chul Soon Yong,1 Jong Oh Kim11College of Pharmacy, Yeungnam University, Dae-Dong, 2College of Korean Medicine, Daegu Haany University, Gyeongsan, 3College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South KoreaAbstract: The attachment of polyethylene glycol (PEG) increases the circulation time of drug-containing nanoparticles...

  19. Coupling Gd‑DTPA with a bispecific, recombinant protein anti‑EGFR‑iRGD complex improves tumor targeting in MRI.

    Xin, Xiaoyan; Sha, Huizi; Shen, Jingtao; Zhang, Bing; Zhu, Bin; Liu, Baorui

    2016-06-01

    Recombinant anti‑epidermal growth factor receptor‑internalizing arginine‑glycine‑aspartic acid (anti‑EGFR single‑domain antibody fused with iRGD peptide) protein efficiently targets the EGFR extracellular domain and integrin αvβ/β5, and shows a high penetration into cells. Thus, this protein may improve penetration of conjugated drugs into the deep zone of gastric cancer multicellular 3D spheroids. In the present study, a novel tumor‑targeting contrast agent for magnetic resonance imaging (MRI) was developed, by coupling gadolinium‑diethylene triamine pentaacetate (Gd‑DTPA) with the bispecific recombinant anti‑EGFR‑iRGD protein. The anti‑EGFR‑iRGD protein was extracted from Escherichia coli and Gd was loaded onto the recombinant protein by chelation using DTPA anhydride. Single‑targeting agent anti‑EGFR‑DTPA‑Gd, which served as the control, was also prepared. The results of the present study showed that anti‑EGFR‑iRGD‑DTPA‑Gd exhibited no significant cyto-toxicity to human gastric carcinoma cells (BGC‑823) under the experimental conditions used. Compared with a conventional contrast agent (Magnevist), anti‑EGFR‑iRGD‑DTPA‑Gd showed higher T1 relaxivity (10.157/mM/sec at 3T) and better tumor‑targeting ability. In addition, the signal intensity and the area under curve for the enhanced signal time in tumor, in vivo, were stronger than Gd‑DTPA alone or the anti‑EGFR‑Gd control. Thus, Gd‑labelled anti‑EGFR‑iRGD has potential as a tumor‑targeting contrast agent for improved MRI. PMID:27035336

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

    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.

  1. Breast tumor targeting with {sup 99m}Tc-HYNIC-PR81 complex as a new biologic radiopharmaceutical

    Salouti, Mojtaba [Department of Medical Physics, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Rajabi, Hossein [Department of Medical Physics, Tarbiat Modares University, Tehran (Iran, Islamic Republic of)], E-mail: hrajabi@modares.ac.ir; Babaei, Mohammad Hossein [Department of Radioisotope, Atomic Energy Organization of Iran, Tehran (Iran, Islamic Republic of); Rasaee, Mohammad Javad [Department of Medical Biotechnology, School of Medical Sciences, Tarbiat Modares University, Tehran (Iran, Islamic Republic of)

    2008-10-15

    Human epithelial mucin, MUC1, is commonly overexpressed in adenocarcinoma that includes more than 80% of breast cancers. The PR81 is a murine anti-MUC1 monoclonal antibody (MAb) that was prepared against the human breast cancer. We developed an indirect method for labeling of this antibody with {sup 99m}Tc in order to use the new preparation in immunoscintigraphy studies of BALB/c mice bearing breast tumors. The {sup 99m}Tc-PR81 complex was prepared using the HYNIC as a chelator and tricine as a coligand. The labeling efficiency determined by instant thin-layer chromatography (ITLC) was 89.2%{+-}4.7%, and radiocolloides measured by cellulose nitrate electrophoresis were 3.4%{+-}0.9%. The in vitro stability of labeled product was determined at room temperature by ITLC and in human serum by gel filtration chromatography - 88.3%{+-}4.6% and 79.8%{+-}5.7% over 24 h, respectively. The integrity of labeled MAb was checked by means of sodium dodecyl sulfate polyacrylamide gel electrophoresis, and no significant fragmentation was seen. The results of cell binding studies showed that both labeled and unlabeled PR81 were able to compete for binding to MCF 7 cells. Biodistribution studies performed in female BALB/c mice with breast tumor xenografts at 4, 16 and 24 h after the {sup 99m}Tc-HYNIC-PR81 injection demonstrated a specific localization of the compound at the site of tumors and minimum accumulation in non target organs. The tumor imaging was performed in BALB/c mice with breast xenograft tumors at 4, 8, 12, 16, 20, 24, 28, 32 and 36 h after the complex injection. The tumors were visualized with high sensitivity after 8 h. The findings showed that the new radiopharmaceutical is a promising candidate for radioimmunoscintigraphy of the human breast cancer.

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

    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.

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

    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.

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

    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

  5. Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10. Therapeutic efficacy largely depends on radiosensitivity

    Frizzled homolog 10 (FZD10) is expressed at high levels on the cell surface of almost all synovial sarcoma tissues, but is absent in most normal organs. In a previous study, yttrium-90 (90Y)-labeled anti-FZD10 antibody (MAb 92-13) showed considerable therapeutic efficacy in synovial sarcoma cell-bearing mice. The purpose of the present study was to elucidate the factors associated with this therapeutic efficacy of 90Y-MAb 92-13. FZD10 expression levels of SYO-1 (FZD10-overexpressing synovial sarcoma cell line) and DLD-1/FZD10 (FZD10-transfected DLD-1 cell) were determined by the cell binding assay, and their radiosensitivity was evaluated by incubation with 90Y-MAb 92-13 in vitro. Biodistribution study of indium-111 (111In)-MAb 92-13 was performed in SYO-1 and DLD-1/FZD10 tumor-bearing mice. For therapeutic studies, SYO-1 and DLD-1/FZD10 tumor-bearing mice were treated with 90Y-MAb 92-13 (100, 150, and 200 μCi), after which the change in tumor volume was measured. Immunohistochemical staining was performed on the excised tumor. Expression level of FZD10 on DLD-1/FZD10 was much greater than that on SYO-1. The accumulation of 111In-MAb 92-13 was much higher in DLD-1/FZD10 tumor-bearing mice than in SYO-1 tumor-bearing mice (49.0±4.2 and 22.0±4.5% ID/g, respectively, at 48 h after administration). In SYO-1 tumor, substantial tumor size reduction was observed in all mice treated with 90Y-MAb 92-13 (tumor volume decreased to less than 0.1 cm3 at 11 days after treatment) and tumor regrowth was not observed in most of them. In contrast, only slow progression was observed in DLD-1/FZD10 tumor. When incubated with 90Y-MAb 92-13, high radioactivity was needed to damage DLD-1/FZD10. Immunohistochemical study indicated apoptosis of SYO-1 tumor. The therapeutic efficacy of radioimmunotherapy (RIT) seems to largely depend on the tumor radiosensitivity. (author)

  6. Synthesis and characterization of superparamagnetic CoFe2O4/MWCNT hybrids for tumor-targeted therapy.

    Sun, Chuanyu; Liu, Yong; Ding, Weihong; Gou, Yuancheng; Xu, Ke; Xia, Guowei; Ding, Qiang

    2013-01-01

    Owing to their great potentialities of carbon nanotubes (CNTs)-based magnetic nano-composites, numerous applications of them have been found in nanotechnology, integrated functional system, and in medicine. Herein, nearly monodisperse CoFe2O4 nanoparticles have been deposited on multi-walled carbon nanotubes (MWCNTs) by high-temperature hydrolysis and inorganic polymerization of ionic Co(II) and Fe(III) salts and MWCNTs in a polyol solution. X-ray diffraction, energy-dispersive X-ray spectrometry and transmission electron microscopy were used to characterize the final products. The average size of CoFe2O4 nanoparticles and their coverage density on MWCNTs can be adjusted to some extent by altering the reaction parameters. A proposed formation mechanism of the magnetic hybrids is presented. Magnetic measurements showed that the hybrids were superparamagnetic at room temperature and their saturation magnetization could be fine tuned by changing the loading of CoFe2O4 nanoparticles on the MWCNTs. PMID:23646722

  7. Tumor targeting using 67Ga-DOTA-Bz-folate - investigations of methods to improve the tissue distribution of radiofolates

    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 [67Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-(γ)-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with 67GaCl3 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: 67Ga-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 (67Ga-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 67Ga-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 [68Ga]-gallium radionuclide.

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

    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.

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

    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 IC50 of 0.79 µg ml−1. Tumor cell-killing potency was enhanced when MIT/HA-GO were combined with NIR irradiation, and the IC50 of MIT/HA-GO plus laser irradiation was 0.38 µg ml−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

  10. Polyethylene glycol-conjugated chondroitin sulfate A derivative nanoparticles for tumor-targeted delivery of anticancer drugs.

    Lee, Jae-Young; Park, Ju-Hwan; Lee, Jeong-Jun; Lee, Song Yi; Chung, Suk-Jae; Cho, Hyun-Jong; Kim, Dae-Duk

    2016-10-20

    Polyethylene glycol (PEG)-decorated chondroitin sulfate A-deoxycholic acid (CSD) nanoparticles (NPs) were fabricated for the selective delivery of doxorubicin (DOX) to ovarian cancer. CSD-PEG was synthesized via amide bond formation between the NH2 group of methoxypolyethylene glycol amine and the COOH group of CSD. CSD-PEG/DOX NPs with a 247nm mean diameter, negative zeta potential, and >90% drug encapsulation efficiency were prepared. Sustained and pH-dependent DOX release profiles from CSD-PEG NPs were observed in dissolution tests. Endocytosis of NPs by SKOV-3 cells (CD44 receptor-positive human ovarian cancer cells), based on the CSA-CD44 receptor interaction, was determined by flow cytometry and confocal laser scanning microscopy (CLSM) studies. PEGylation of NPs also resulted in reduced drug clearance (CL) in vivo and improved relative bioavailability, compared to non-PEGylated NPs, as determined by the pharmacokinetic study performed after intravenous administration in rats. Developed CSD-PEG NPs can be a promising delivery vehicle for the therapy of CD44 receptor-expressing ovarian cancers. PMID:27474544

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

    Ullman, Christopher; Mathonet, Pascale; Oleksy, Arkadiusz; Diamandakis, Agata; Tomei, Licia; Demartis, Anna; Nardi, Chiara; Sambucini, Sonia; Missineo, Antonino; Alt, Karen; Hagemeyer, Christoph E.; Harris, Matt; Hedt, Amos; Weis, Roland; Gehlsen, Kurt R.

    2015-01-01

    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. PMID:26313909

  12. Antiepidermal growth factor variant III scFv fragment: effect of radioiodination method on tumor targeting and normal tissue clearance

    Shankar, Sriram [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States); Vaidyanathan, Ganesan [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States); Kuan, C.-T. [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Bigner, Darell D. [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Zalutsky, Michael R. [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States) and Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States) and Department of Biomedical Engineering, Duke University, Durham, NC 27708 (United States)]. E-mail: zalut001@duke.edu

    2006-01-15

    Introduction: MR1-1 is a single-chain Fv (scFv) fragment that binds with high affinity to epidermal growth factor receptor variant III, which is overexpressed on gliomas and other tumors but is not present on normal tissues. The objective of this study was to evaluate four different methods for labeling MR1-1 scFv that had been previously investigated for the radioiodinating of an intact anti-epidermal growth factor receptor variant III (anti-EGFRvIII) monoclonal antibody (mAb) L8A4. Methods: The MR1-1 scFv was labeled with {sup 125}I/{sup 131}I using the Iodogen method, and was also radiohalogenated with acylation agents bearing substituents that were positively charged-N-succinimidyl-3-[*I]iodo-5-pyridine carboxylate and N-succinimidyl-4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB)-and negatively charged-N-succinimidyl-3-[*I]iodo-4-phosphonomethylbenzoate ([*I]SIPMB). In vitro internalization assays were performed with the U87MG{delta}EGFR cell line, and the tissue distribution of the radioiodinated scFv fragments was evaluated in athymic mice bearing subcutaneous U87MG{delta}EGFR xenografts. Results and Conclusion: As seen previously with the anti-EGFRvIII IgG mAb, retention of radioiodine activity in U87MG{delta}EGFR cells in the internalization assay was labeling method dependent, with SGMIB and SIPMB yielding the most prolonged retention. However, unlike the case with the intact mAb, the results of the internalization assays were not predictive of in vivo tumor localization capacity of the labeled scFv. Renal activity was dependent on the nature of the labeling method. With MR1-1 labeled using SIPMB, kidney uptake was highest and most prolonged; catabolism studies indicated that this uptake primarily was in the form of {epsilon}-N-3-[*I]iodo-4-phosphonomethylbenzoyl lysine.

  13. Lysine-directed conjugation of ethidium homodimer to B72.3 antibody: retention of immunoreactivity but altered tumor targeting

    Ethidium homodimer (EHD) was conjugated to B72.3 monoclonal antibody using a method whereby 85-90% of the conjugated EHD remains available for DNA intercalation. Antibody was thiopropionylated by reaction with N-succinimidyl 3-(2-pyridyldithio)propionate and reduction of pyridyldithio groups with dithiothreitol. EHD was maleimido-functionalized with succinimidyl-4-(N-maleimidoethyl)cyclohexane-1-carboxylate and treated with thiopropionylated antibody to obtain a conjugate containing ∼3.4 EHD per antibody molecule. For biologic studies, 14C-labeled EHD was synthesized by reductive amination and conjugated as above. In vitro the conjugate maintained chemical integrity and immunoreactivity, while in vivo its targeting of LS174T tumors was reduced compared with that of iodinated antibody. A decrease in isoelectric point of the immunoconjugate was also observed

  14. Synthesis and Preliminary Biological Evaluation of High-drug Load Paclitaxel-Antibody Conjugates for Tumor-targeted Chemotherapy1

    Quiles, Sherly; Raisch, Kevin P.; Sanford, Leisa L.; Bonner, James A.; Safavy, Ahmad

    2010-01-01

    The goal of this study was to design paclitaxel (PTX)-monoclonal antibody (MAb) prodrug conjugates (PTXMAbs) with the ability to deliver therapeutically significant doses of the drug to the tumor while avoiding the previously observed solubility limitations of conjugates with PTX : MAb molar ratios of >3. New PTX conjugates were synthesized using the discrete poly(ethylene glycol) (dPEG) as linkers. These compounds, PTX-L-Lys[(dPEG12)3-dPEG4]-dPEG6-NHS (9a and 9b, for L=GL or SX, respectively...

  15. Multiple cues on the physiochemical, mesenchymal, and intracellular trafficking interactions with nanocarriers to maximize tumor target efficiency

    Kim SW; Khang D

    2015-01-01

    Sang-Woo Kim, Dongwoo Khang Nanomedicine Laboratory, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, South Korea Abstract: Over the past 60 years, numerous medical strategies have been employed to overcome neoplasms. In fact, with the exception of lung, bronchial, and pancreatic cancers, the 5-year survival rate of most cancers currently exceeds 70%. However, the quality of life of patients during chemotherapy remains unsatisfactory despite the increase in ...

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

    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.

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

    Thayyath Sreenivasan Anirudhan; Sylaja Raveendran Rejeena

    2014-01-01

    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...

  18. Novel multifunctional pH-sensitive nanoparticles loaded into microbubbles as drug delivery vehicles for enhanced tumor targeting.

    Lv, Yongjiu; Hao, Lan; Hu, Wenjing; Ran, Ya; Bai, Yan; Zhang, Liangke

    2016-01-01

    This study fabricated novel multifunctional pH-sensitive nanoparticles loaded into microbubbles (PNP-MB) with the combined advantages of two excellent drug delivery vehicles, namely, pH-sensitive nanoparticles and microbubbles. As an antitumor drug, resveratrol (RES) was loaded into acetylated β-cyclodextrin nanoparticles (RES-PNP). The drug-loaded nanoparticles were then encapsulated into the internal space of the microbubbles. The characterization and morphology of this vehicle were investigated through dynamic light scattering and confocal laser scanning microscopy, respectively. In vitro drug release was performed to investigate the pH sensitivity of RES-PNP. The antitumor property of RES-loaded PNP-MB (RES-PNP-MB) was also analyzed in vivo to evaluate the antitumor effect of RES-PNP-MB. Results suggested that PNP exhibited pH sensitivity, and was successfully encapsulated into the microbubbles. RES-PNP-MB exhibit effective tumor growth suppressing in vivo. Therefore, such drug delivery vehicle should be of great attention in tumor therapy. PMID:27378018

  19. Development of peritoneal tumor-targeting vector by in vivo screening with a random peptide-displaying adenovirus library.

    Takeshi Nishimoto

    Full Text Available The targeting of gene transfer at the cell-entry level is one of the most attractive challenges in vector development. However, attempts to redirect adenovirus vectors to alternative receptors by engineering the capsid-coding region have shown limited success, because the proper targeting ligands on the cells of interest are generally unknown. To overcome this limitation, we have constructed a random peptide library displayed on the adenoviral fiber knob, and have successfully selected targeted vectors by screening the library on cancer cell lines in vitro. The infection of targeted vectors was considered to be mediated by specific receptors on target cells. However, the expression levels and kinds of cell surface receptors may be substantially different between in vitro culture and in vivo tumor tissue. Here, we screened the peptide display-adenovirus library in the peritoneal dissemination model of AsPC-1 pancreatic cancer cells. The vector displaying a selected peptide (PFWSGAV showed higher infectivity in the AsPC-1 peritoneal tumors but not in organs and other peritoneal tumors as compared with a non-targeted vector. Furthermore, the infectivity of the PFWSGAV-displaying vector for AsPC-1 peritoneal tumors was significantly higher than that of a vector displaying a peptide selected by in vitro screening, indicating the usefulness of in vivo screening in exploring the targeting vectors. This vector-screening system can facilitate the development of targeted adenovirus vectors for a variety of applications in medicine.

  20. Theranostic Tumor Targeted Nanoparticles Combining Drug Delivery with Dual Near Infrared and (19)F Magnetic Resonance Imaging Modalities

    Vu-Quang, Hieu; Vinding, Mads Sloth; Nielsen, Thomas;

    2016-01-01

    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 (19)F MRI and NIR, respectively, using folate-receptor-targeted nanoparticles compared with non-targeted...

  1. Co-Encapsulation of Doxorubicin With Galactoxyloglucan Nanoparticles for Intracellular Tumor-Targeted Delivery in Murine Ascites and Solid Tumors

    Manu M. Joseph

    2014-10-01

    Full Text Available Doxorubicin (Dox treatment is limited by severe toxicity and frequent episodes of treatment failure. To minimize adverse events and improve drug delivery efficiently and specifically in cancer cells, encapsulation of Dox with naturally obtained galactoxyloglucan polysaccharide (PST001, isolated from Tamarindus indica was attempted. Thus formed PST-Dox nanoparticles induced apoptosis and exhibited significant cytotoxicity in murine ascites cell lines, Dalton’s lymphoma ascites and Ehrlich’s ascites carcinoma. The mechanism contributing to the augmented cytotoxicity of nanoconjugates at lower doses was validated by measuring the Dox intracellular uptake in human colon, leukemic and breast cancer cell lines. PST-Dox nanoparticles showed rapid internalization of Dox into cancer cells within a short period of incubation. Further, in vivo efficacy was tested in comparison to the parent counterparts - PST001 and Dox, in ascites and solid tumor syngraft mice models. Treatment of ascites tumors with PST-Dox nanoparticles significantly reduced the tumor volume, viable tumor cell count, and increased survival and percentage life span in the early, established and prophylactic phases of the disease. Administration of nanoparticles through intratumoral route delivered more robust antitumor response than the intraperitoneal route in solid malignancies. Thus, the results indicate that PST-Dox nanoparticles have greater potential compared to the Dox as targeted drug delivery nanocarriers for loco regional cancer chemotherapy applications.

  2. After the Arab Spring: power shift in the Middle East?: from the ‘Arab Awakening’ to the Arab Spring; the post-colonial state in the Middle East

    Dodge, Toby

    2012-01-01

    The consequences of the political turmoil that swept across the Middle East in 2011 support the claim that those twelve months have been the most politically significant in the region for over fifty years. The tragic self-immolation of Mohamed Bouazizi in the Tunisian town of Sidi Bouzid on December 17, 2010 was not just the final desperate act of an individual ground down by state corruption, repression and incompetence. His suicide gave rise to a region-wide wave of sympathy,...

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

    Touraj Ahmadijouybari

    2014-01-01

    Full Text Available 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

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

    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 124I-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 124I-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.)

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

    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.

  6. Clinical-scale laser-based scanning and processing of live cells: selective photothermal killing of fluorescent tumor targets for autologous stem cell transplantation

    Koller, Manfred R.; Hanania, Elie G.; Eisfeld, Timothy; O'Neal, Robert A.; Khovananth, Kevin M.; Palsson, Bernhard O.

    2001-04-01

    High-dose chemotherapy, followed by autologous hematopoietic stem cell (HSC) transplantation, is widely used for the treatment of cancer. However, contaminating tumor cells within HSC harvests continue to be of major concern since re-infused tumor cells have proven to contribute to disease relapse. Many tumor purging methods have been evaluated, but all leave detectable tumor cells in the transplant and result in significant loss of HSCs. These shortcomings cause engraftment delays and compromise the therapeutic value of purging. A novel approach integrating automated scanning cytometry, image analysis, and selective laser-induced killing of labeled cells within a cell mixture is described here. Non-Hodgkin's lymphoma (NHL) cells were spiked into cell mixtures, and fluorochrome-conjugated antibodies were used to label tumor cells within the mixture. Cells were then allowed to settle on a surface, and as the surface was scanned with a fluorescence excitation source, a laser pulse was fired at every detected tumor cell using high-speed beam steering mirrors. Tumor cells were selectively killed with little effect on adjacent non-target cells, demonstrating the feasibility of this automated cell processing approach. This technology has many potential research and clinical applications, one example of which is tumor cell purging for autologous HSC transplantation.

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

    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.)

  8. Sortase-catalyzed in vitro functionalization of a HER2-specific recombinant Fab for tumor targeting of the plant cytotoxin gelonin

    Kornberger, Petra; Skerra, Arne

    2013-01-01

    We report on the preparation of a new type of immunotoxin via in vitro ligation of the αHer2 antigen binding fragment (Fab) of the clinically-validated antibody trastuzumab to the plant toxin gelonin, employing catalysis by the bacterial enzyme sortase A (SrtA). The αHer2 Fab was fused with the extended SrtA recognition motif LPET↓GLEH6 at the C-terminus of its heavy chain, thereby preventing interference with antigen binding, while the toxin was equipped with a Gly2 sequence at its N-terminu...

  9. Sortase-catalyzed in vitro functionalization of a HER2-specific recombinant Fab for tumor targeting of the plant cytotoxin gelonin

    Kornberger, Petra; Skerra, Arne

    2014-01-01

    We report on the preparation of a new type of immunotoxin via in vitro ligation of the αHer2 antigen binding fragment (Fab) of the clinically-validated antibody trastuzumab to the plant toxin gelonin, employing catalysis by the bacterial enzyme sortase A (SrtA). The αHer2 Fab was fused with the extended SrtA recognition motif LPET↓GLEH6 at the C-terminus of its heavy chain, thereby preventing interference with antigen binding, while the toxin was equipped with a Gly2 sequence at its N-terminus, distant to the catalytically active site in the C-terminal region. Site-specific in vitro transpeptidation led to a novel antibody-toxin conjugate wherein gelonin had effectively replaced the Fc region of a conventional (monomerized) immunoglobulin. After optimization of reaction conditions and incubation time, the resulting Fab-Gelonin ligation product was purified to homogeneity in a two-step procedure by means of Strep-Tactin affinity chromatography—utilizing the Strep-tag II appended to gelonin—and size exclusion chromatography. Binding activity of the immunotoxin for the Her2 ectodomain was indistinguishable from the unligated Fab as measured by real-time surface plasmon resonance spectroscopy. Specific cytotoxic potency of Fab-Gelonin was demonstrated against two Her2-positive cell lines, resulting in EC50 values of ~1 nM or lower, indicating a 1000-fold enhanced cell-killing activity compared with gelonin itself. Thus, our strategy provides a convenient route to the modular construction of functional immunotoxins from Fabs of established tumor-specific antibodies with gelonin or related proteotoxins, also avoiding the elevated biosafety levels that would be mandatory for the direct biotechnological preparation of corresponding fusion proteins. PMID:24492291

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

    Highlights: → We compared lipofection with magnetofection about difference of transfection efficiency on delivery a therapeutic gene in vitro and in vivo. → 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. → 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. → 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.

  11. Radiolabeled gastrins in CCK2R-positive tumor targeting: Toward improved diagnostic efficacy via in situ enzyme-inhibition approaches

    Kaloudi, Katerina

    2016-01-01

    markdownabstractIn this thesis, several novel radiolabeled gastrin analogs were developed preclinically in vitro as well as in vivo in animal models. In addition, the effect of in situ enzyme inhibition on metabolic stability and tumor uptake of the same gastrin radioligands was investigated.

  12. Dosimetric impact of inter-observer variability for 3D conformal radiotherapy and volumetric modulated arc therapy: the rectal tumor target definition case

    To assess the dosimetric effect induced by inter-observer variability in target definition for 3D-conformal RT (3DCRT) and volumetric modulated arc therapy by RapidArc (RA) techniques for rectal cancer treatment. Ten patients with rectal cancer subjected to neo-adjuvant RT were randomly selected from the internal database. Four radiation oncologists independently contoured the clinical target volume (CTV) in blind mode. Planning target volume (PTV) was defined as CTV + 7 mm in the three directions. Afterwards, shared guidelines between radiation oncologists were introduced to give general criteria for the contouring of rectal target and the four radiation oncologists defined new CTV following the guidelines. For each patient, six intersections (I) and unions (U) volumes were calculated coupling the contours of the various oncologists. This was repeated for the contours drawn after the guidelines. Agreement Index (AI = I/U) was calculated pre and post guidelines. Two RT plans (one with 3DCRT technique using 3–4 fields and one with RA using a single modulated arc) were optimized on each radiation oncologist’s PTV. For each plan the PTV volume receiving at least 95% of the prescribed dose (PTV V95%) was calculated for both target and non-target PTVs. The inter-operator AI pre-guidelines was 0.57 and was increased up to 0.69 post-guidelines. The maximum volume difference between the various CTV couples, drawn for each patient, passed from 380 ± 147 cm3 to 137 ± 83 cm3 after the introduction of guidelines. The mean percentage for the non-target PTV V95% was 93.7 ± 9.2% before and 96.6 ± 4.9%after the introduction of guidelines for the 3DCRT, for RA the increase was more relevant, passing from 86.5 ± 13.8% (pre) to 94.5 ± 7.5% (post). The OARs were maximally spared with VMAT technique while the variability between pre and post guidelines was not relevant in both techniques. The contouring inter-observer variability has dosimetric effects in the PTV coverage. The introduction of guidelines increases the dosimetric consistency for both techniques, with greater improvements for RA technique

  13. Theranostic Unimolecular Micelles Based on Brush-Shaped Amphiphilic Block Copolymers for Tumor-Targeted Drug Delivery and Positron Emission Tomography Imaging

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

    2014-01-01

    Brush-shaped amphiphilic block copolymers were conjugated with a monoclonal antibody against CD105 (i.e., TRC105) and a macrocyclic chelator for 64Cu-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...

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

    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. PMID:26855572

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

    Filippov, Sergey K.; Chytil, Petr; Konarev, P. V.; Dyakonova, M.; Papadakis, C. M.; Zhigunov, Alexander; Pleštil, Josef; Štěpánek, Petr; Etrych, Tomáš; Ulbrich, Karel; Svergun, D. I.

    2012-01-01

    Roč. 13, č. 8 (2012), s. 2594-2604. ISSN 1525-7797 R&D Projects: GA MŠk ME09059; GA AV ČR IAAX00500803; GA ČR GAP108/12/0640 Institutional research plan: CEZ:AV0Z40500505 Institutional support: RVO:61389013 Keywords : HPMA * cholesterol * SAXS Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.371, year: 2012

  16. Mixed PEG-PE/Vitamin E Tumor-Targeted Immunomicelles as Carriers for Poorly Soluble Anti-Cancer Drugs: Improved Drug Solubilization and Enhanced In Vitro Cytotoxicity

    Sawant, Rupa R.; Sawant, Rishikesh M.; Torchilin, Vladimir P.

    2008-01-01

    Two poorly soluble, potent anticancer drugs, paclitaxel and camptothecin, were successfully solubilized by mixed micelles of polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) and vitamin E. Drug containing micelles were additionally modified with anti-nucleosome monoclonal antibody 2C5 (mAb 2C5), which can specifically bring micelles to tumor cells in vitro. The optimized micelles had an average size of about 13-to-22 nm and the immuno-modification of micelles did not significantly chang...

  17. Systemic and tumor-targeted delivery of siRNA by cyclic NGR and isoDGR motif-containing peptides.

    Huang, Yuanyu; Cheng, Qiang; Jin, Xingyu; Ji, Jia-Li; Guo, Shutao; Zheng, Shuquan; Wang, Xiaoxia; Cao, Huiqing; Gao, Shan; Liang, Xing-Jie; Du, Quan; Liang, Zicai

    2016-02-23

    The drug development of siRNA has been seriously hindered by the lack of an effective, safe and clinically applicable delivery system. The cyclic NGR motif and its isomerization product isoDGR recruit CD13 and integrin as their specific receptors, both of which are overexpressed by tumor and neovascular cells. In this study, a bi-functional peptide, named NGR-10R, was designed and tested for siRNA delivery in vitro and in vivo. Through the formation of peptide/siRNA nanoparticles, RNase resistance was greatly enhanced for the siRNAs. Both FACS and confocal assays revealed that the peptide/siRNA complexes were effectively internalized by MDA-MB-231 cells. Gene silencing assays indicated that anti-Lamin A/C siRNA delivered by NGR-10R robustly repressed gene expression in MDA-MB-231 and HUVEC (a CD13(+)/αvβ3(+) cell). Importantly, the siRNAs were efficiently delivered into tumor tissues and localized around the nuclei, as revealed by in vivo imaging and cryosection examination. In summary, NGR-10R not only efficiently delivered siRNAs into MDA-MB-231 cells in vitro but also delivered siRNAs into tumor cells in vivo, taking advantage of its specific binding to CD13 (neovascular) or αvβ3 (MDA-MB-231). Therefore, the NGR-10R peptide provides a promising siRNA delivery reagent that could be used for drug development, particularly for anti-tumor therapeutics. PMID:26783563

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

    Choi G

    2016-01-01

    Full Text Available Goeun Choi,1 Huiyan Piao,1 Zeid A Alothman,2 Ajayan Vinu,3 Chae-Ok Yun,4 Jin-Ho Choy1 1Center for Intelligent Nano-Bio Materials, Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Korea; 2Advanced Materials Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia; 3Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia; 4Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea Abstract: 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. Keywords: anionic clay, biodistribution, cervical cancer, colloidal stability, layered double hydroxide, methotrexate 

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

    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.

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

    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.

  1. Dual fluorescent HPMA copolymers for passive tumor targeting with pH-sensitive drug release II: impact of release rate on biodistribution

    Chytil, Petr; Hoffmann, S.; Schindler, Lucie; Kostka, Libor; Ulbrich, Karel; Caysa, H.; Mueller, T.; Mäder, K.; Etrych, Tomáš

    2013-01-01

    Roč. 172, č. 2 (2013), s. 504-512. ISSN 0168-3659. [International Symposium on Recent Advances in Drug Delivery Systems /16./. Salt Lake City, 03.02.2013-06.02.2013] R&D Projects: GA ČR GCP207/12/J030; GA MŠk EE2.3.30.0029 Institutional support: RVO:61389013 Keywords : HPMA copolymers * pH-responsive drug release * tumor accumulation Subject RIV: CD - Macromolecular Chemistry Impact factor: 7.261, year: 2013

  2. Synthesis of Zn-Cu-In-S/ZnS Core/Shell Quantum Dots with Inhibited Blue-Shift Photoluminescence and Applications for Tumor Targeted Bioimaging

    Weisheng Guo, Na chen, Yu Tu, Chunhong Dong, Bingbo Zhang, Chunhong Hu, Jin Chang

    2013-01-01

    Full Text Available A facile strategy is reported here for synthesis of Zn-Cu-In-S/ZnS (ZCIS/ZnS core/shell QDs to address the synthetic issues that the unexpected blue-shift of CuInS2-based nanocrystals. In this strategy, Zn2+ ions are intentionally employed for the synthesis of alloyed ZCIS core QDs before ZnS shell coating, which contributes to the reduced blue-shift in photoluminescence (PL emission. The experimental results demonstrate this elaborate facile strategy is effective for the reduction of blue-shift during shell growth. Particularly, a hypothesis is proposed and proved for explanation of this effective strategy. Namely, both cation exchange inhibition and ions accumulation are involved during the synthesis of ZCIS/ZnS QDs. Furthermore, the obtained near infrared (NIR ZCIS/ZnS QDs are transferred into aqueous phase by a polymer coating technique and coupled with cyclic Arg-Gly-Asp peptide (cRGD peptides. After confirmation of biocompability by cytotoxicity test on normal 3T3 cells, these QDs are injected via tail vein into nude mice bearing U87 MG tumor. The result indicates that the signals detected in the tumor region are much more distinguishing injected with ZCIS/ZnS-cRGD QDs than that injected with ZCIS/ZnS QDs.

  3. Synthesis of Zn-Cu-In-S/ZnS Core/Shell Quantum Dots with Inhibited Blue-Shift Photoluminescence and Applications for Tumor Targeted Bioimaging

    Weisheng Guo, Na chen, Yu Tu, Chunhong Dong, Bingbo Zhang, Chunhong Hu, Jin Chang

    2013-01-01

    A facile strategy is reported here for synthesis of Zn-Cu-In-S/ZnS (ZCIS/ZnS) core/shell QDs to address the synthetic issues that the unexpected blue-shift of CuInS2-based nanocrystals. In this strategy, Zn2+ ions are intentionally employed for the synthesis of alloyed ZCIS core QDs before ZnS shell coating, which contributes to the reduced blue-shift in photoluminescence (PL) emission. The experimental results demonstrate this elaborate facile strategy is effective for the reduction of blue-...

  4. 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

    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

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

    Hsieh WJ; Liang CJ; Chieh JJ; SH Wang; Lai IR; Chen JH; Chang FH; Tseng WK; Yang SY; Wu CC; Chen YL

    2012-01-01

    Wan-Ju Hsieh,1 Chan-Jung Liang,1 Jen-Jie Chieh,4 Shu-Huei Wang,1 I-Rue Lai,1 Jyh-Horng Chen,2 Fu-Hsiung Chang,3 Wei-Kung Tseng,4–6 Shieh-Yueh Yang,4 Chau-Chung Wu,7 Yuh-Lien Chen11Institute of Anatomy and Cell Biology, College of Medicine, 2Department of Electrical Engineering, 3Institute of Biochemistry and Molecular Biology, National Taiwan University, Taipei, Taiwan; 4Institute of Electro-Optical Science and Technology, National Taiwan Normal University, Taipei, Taiwan; 5Division...

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

    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. PMID:26855572

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

    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. PMID:26855027

  8. Triggered Drug Release from an Antibody-Drug Conjugate Using Fast "Click-to-Release" Chemistry in Mice.

    Rossin, Raffaella; van Duijnhoven, Sander M J; Ten Hoeve, Wolter; Janssen, Henk M; Kleijn, Laurens H J; Hoeben, Freek J M; Versteegen, Ron M; Robillard, Marc S

    2016-07-20

    The use of a bioorthogonal reaction for the selective cleavage of tumor-bound antibody-drug conjugates (ADCs) would represent a powerful new tool for ADC therapy, as it would not rely on the currently used intracellular biological activation mechanisms, thereby expanding the scope to noninternalizing cancer targets. Here we report that the recently developed inverse-electron-demand Diels-Alder pyridazine elimination reaction can provoke rapid and self-immolative release of doxorubicin from an ADC in vitro and in tumor-bearing mice. PMID:27306828

  9. Paediatric suicidal burns: A growing concern.

    Segu, Smitha; Tataria, Rachana

    2016-06-01

    An alarming rise in rates of paediatric population committing self-immolation acts is a growing social and medical problem. In recent times there seems to be a rising concern in paediatric population. A study was conducted at a government tertiary care burn centre over 5 years in paediatric age group of peer pressure leaving them vulnerable. A multidisciplinary care involving medical, psychological and social support is required. Identifying children at risk and proper counselling and support can form an important strategy at prevention rather than cure. PMID:26803366

  10. Tumor-targeted delivery of IL-2 by NKG2D leads to accumulation of antigen-specific CD8+ T cells in the tumor loci and enhanced anti-tumor effects.

    Tae Heung Kang

    Full Text Available Interleukin-2 (IL-2 has been shown to promote tumor-specific T-cell proliferation and differentiation but systemic administration of IL-2 results in significant toxicity. Therefore, a strategy that can specifically deliver IL-2 to the tumor location may alleviate concerns of toxicity. Because NKG2D ligands have been shown to be highly expressed in many cancer cells but not in healthy cells, we reason that a chimeric protein consisting of NKG2D linked to IL-2 will lead to the specific targeting of IL-2 to the tumor location. Therefore, we created chimeric proteins consisting of NKG2D linked to Gaussia luciferase (GLuc; a marker protein or IL-2 to form NKG2D-Fc-GLuc and NKG2D-Fc-IL2, respectively. We demonstrated that NKG2D linked to GLuc was able to deliver GLuc to the tumor location in vivo. Furthermore, we showed that TC-1 tumor-bearing mice intramuscularly injected with DNA encoding NKG2D-Fc-IL2, followed by electroporation, exhibited an increased number of luciferase-expressing E7-specific CD8+ T cells at the tumor location. More importantly, treatment with the DNA construct encoding NKG2D-Fc-IL2 significantly enhanced the therapeutic anti-tumor effects generated by intradermal vaccination with therapeutic HPV DNA in tumor-bearing mice. Therefore, by linking NKG2D to IL2, we are able to specifically deliver IL-2 to the tumor location, enhancing antigen-specific T-cell immune response and controlling tumor growth. Our approach represents a platform technology to specifically deliver proteins of interest to tumor loci.

  11. Synthesis and biological evaluation of a novel (177)Lu-DOTA-[Gly(3)-cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]α-MSH(3-13) analogue for melanocortin-1 receptor-positive tumor targeting.

    Lim, Jae Cheong; Hong, Young Don; Kim, Jin Ju; Choi, Sang Mu; Baek, Hye Suk; Choi, Sun-Ju

    2012-10-01

    In this study, a novel α-melanocyte stimulating hormone (α-MSH) analogue 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled [Gly(3)-cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]α-MSH(3-13) (DOTA-GMSH) for melanocortin-1 receptor (MC-1R) targeting was newly synthesized, radiolabeled with (177)Lu, and in vitro and in vivo characterized. (177)Lu-labeled peptides were prepared with a high radiolabeling yield (>98%), and its Log p value was -2.89. No degradation was observed not only by serum incubation at 37°C for 7 days but also by an HPLC analysis of radioactive metabolites in urine. A cell binding assay revealed that an inhibitory concentration of 50% (IC(50)) of the peptide was 3.80 nM. The tumor-to-blood ratio, which was 14.27 at 2 hours p.i., was increased to 56.37 at 24 hours p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and was rapidly cleared from the blood pool. We, therefore, conclude that (177)Lu-DOTA-GMSH has promising characteristics for application in nuclear medicine, namely for the diagnosis of MC-1R over-expressing tumors. PMID:22831553

  12. 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

    Jensen, Benjamin Anderschou Holbech; Pedersen, Sara R; Christensen, Jan P; Thomsen, Allan Randrup

    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 of dif...

  13. Research Progress in Polymeric Micelles with Tumor-Targeting in Chemotherapy%聚合物胶束结合靶向在肿瘤化疗中的研究进展

    王晓君; 丁辉; 刘新利; 张松

    2012-01-01

    肿瘤研究的一个主要方向是开发高效无毒副作用的药物载体系统。聚合物胶束由内部可装载难溶性药物的疏水内核,外部能提高体内运输作用的亲水外壳组成,粒径一般为10~100nm左右。这种粒径范围的载药体系既能逃脱肾脏的排泄清除,又能躲避内皮网状系统的吞噬,延长药物在血液中的循环时间。聚合物胶束结合肿瘤靶向在化疗方面的应用,能够有效改善化疗药物的水溶性,提高化疗药物的利用率和抗肿瘤活性,降低对机体正常细胞组织的毒副作用,克服多药耐药性问题,进而极大地提高了肿瘤化疗效果和促进了肿瘤化疗的发展进步。本文着重综述聚合物胶束在化疗药物载药与靶向策略方面的研究现状与进展。%A major field in cancer research is to develop carriers that can deliver drugs into targeted region effectively without side effects. Polymeric micelles (PMs) are core-shell structure with diameters of 10-100nm (suitable size with a narrow distribution could avoid rapid renal excretion and entrapment by the reticuloendothelial system), which are self-assembled with good biodegradable and biocompatible polymer to form hydrophobic core and hydrophilic shell in an aqueous media. The preparation of PMs with stimuli-responsive block copolymers and modification of target molecules on PMs' surface could significantly improve the performance of the drug-loaded, enhance drug utilization and anti-tumor activity, reduce the normal tissue toxicity and solve the problem of multi-drug resistance, and thus contribute significantly to the development and progress of chemotherapy. Here we review some of the promising analog of targeting strategies that are under development for drug delivery. This review describes the preparation of polymeric micelles and the targeted modification which greatly enhance the effect of chemotherapy.

  14. Biological evaluation of 177Lu-labeled DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 for gastrin-releasing peptide receptor-positive prostate tumor targeting

    Bombesin binds with selectivity and high affinity to a Gastrin-releasing peptide receptor (GRPR), which is highly overexpressed in prostate cancer cells. The present study describes the in vitro and in vivo biological characteristics of DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 (DOTA-sBBNA), an antagonist analogue of bombesin peptide for the targeting of GRPR. DOTA-sBBNA was synthesized and labeled with 177Lu as previously published. A saturation assay on PC-3 human prostate cancer cells revealed that the Kd value of the radiolabeled peptide was 1.88 nM with a maximum binding capacity (Bmax) of 289.3 fmol/106 cells. The radio-peptide slowly internalized, and 24.4 ± 0.5% of the total binding was internalized in 4 hr. Biodistribution studies were conducted in healthy and PC-3 xenografted balb/c mice, which showed high uptake and retention of tumor-associated radioactivity in PC-3 xenografted mice. The tumor-to-blood ratio was 126.02 ± 9.36 at 1.5 hr p.i., and was increased to 216.33 ± 61.58 at 24 hr p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and rapidly cleared from the blood pool. The GRPR is also over-expressed in Korean prostate cancer patients. These results suggest that this 177Lu-labeled peptide has promising characteristics for application in nuclear medicine, namely for the diagnosis and treatment of GRPR over-expressing prostate tumors

  15. Preparation, in vitro and in vivo evaluation of polymeric nanoparticles based on hyaluronic acid-poly(butyl cyanoacrylate and D-alpha-tocopheryl polyethylene glycol 1000 succinate for tumor-targeted delivery of morin hydrate

    Abbad S

    2015-01-01

    Full Text Available Sarra Abbad,1,2 Cheng Wang,1 Ayman Yahia Waddad,1 Huixia Lv,1 Jianping Zhou11Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Department of Pharmacy, Abou Bekr Belkaid University, Tlemcen, AlgeriaAbstract: Herein, we describe the preparation of a targeted cellular delivery system for morin hydrate (MH, based on a low-molecular-weight hyaluronic acid-poly(butyl cyanoacrylate (HA-PBCA block copolymer. In order to enhance the therapeutic effect of MH, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS was mixed with HA-PBCA during the preparation process. The MH-loaded HA-PBCA “plain” nanoparticle (MH-PNs and HA-PBCA/TPGS “mixed” nanoparticles (MH-MNs were concomitantly characterized in terms of loading efficiency, particle size, zeta potential, critical aggregation concentration, and morphology. The obtained MH-PNs and MH-MNs exhibited a spherical morphology with a negative zeta potential and a particle size less than 200 nm, favorable for drug targeting. Remarkably, the addition of TPGS resulted in about 1.6-fold increase in drug-loading. The in vitro cell viability experiment revealed that MH-MNs enhanced the cytotoxicity of MH in A549 cells compared with MH solution and MH-PNs. Furthermore, blank MNs containing TPGS exhibited selective cytotoxic effects against cancer cells without diminishing the viability of normal cells. In addition, the cellular uptake study indicated that MNs resulted in 2.28-fold higher cellular uptake than that of PNs, in A549 cells. The CD44 receptor competitive inhibition and the internalization pathway studies suggested that the internalization mechanism of the nanoparticles was mediated mainly by the CD44 receptors through a clathrin-dependent endocytic pathway. More importantly, MH-MNs exhibited a higher in vivo antitumor potency and induced more tumor cell apoptosis than did MH-PNs, following intravenous administration to S180 tumor-bearing mice. Overall, the results imply that the developed nanoparticles are promising vehicles for the targeted delivery of lipophilic anticancer drugs.Keywords: anti-tumor effect, hyaluronic acid, TPGS, morin hydrate, nanoparticles

  16. Consumption of vitamin B6 reduces colonic damage and protein expression of HSP70 and HO-1, the anti-tumor targets, in rats exposed to 1,2-dimethylhydrazine

    KAYASHIMA, TOMOKO; Tanaka, Kenta; OKAZAKI, YUKAKO; Matsubara, Kiminori; Yanaka, Noriyuki; Kato, Norihisa

    2011-01-01

    Mounting evidence indicates that vitamin B6 is a protective factor for colon cancer. Elevations in colonic damage, cell proliferation and heat shock proteins (HSPs, molecular chaperones) have been suggested to be associated with colon carcinogenesis. This study was performed to examine the effect of dietary levels of vitamin B6 (1, 7 or 35 mg pyridoxine HCl/kg diet) for 22 weeks on colon damage, epithelial cell proliferation and expression of HSPs in rats exposed to 1,2-dimethylhydrazine (DMH...

  17. 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

    Hoffmann, S.; Vystrčilová, Lucie; Ulbrich, Karel; Etrych, Tomáš; Caysa, H.; Mueller, T.; Mäder, K.

    2012-01-01

    Roč. 13, č. 3 (2012), s. 652-663. ISSN 1525-7797 R&D Projects: GA AV ČR IAAX00500803; GA ČR GAP301/11/0325 Institutional research plan: CEZ:AV0Z40500505 Keywords : fluorescence dyes * star-like HPMA polymer carriers * diagnostics of tumors Subject RIV: EC - Immunology Impact factor: 5.371, year: 2012

  18. Synthesis and anti-HIV evaluation of hybrid-type prodrugs conjugating HIV integrase inhibitors with d4t by self-cleavable spacers containing an amino acid residue.

    Fossey, Christine; Huynh, Ngoc-Trinh; Vu, Anh-Hoang; Vidu, Anamaria; Zarafu, Irina; Laduree, Daniel; Schmidt, Sylvie; Laumond, Geraldine; Aubertin, Anne-Marie

    2007-10-01

    In an attempt to combine the anti-HIV inhibitory capacity of reverse transcriptase (RT) inhibitors (NRTIs) and integrase (IN) inhibitors (INIs), several heterodimer analogues of the previously reported [d4T]-PABC-[INI] and [d4T]-OABC-[INI] prototypes have been prepared. In these novel series, we wished to extend our results to conjugates which incorporated an enzymatically labile aminoacid unit (L-alanine) connected to d4T through a self-immolative para- or ortho-aminobenzyl carbonate (PABC or OABC) spacer. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable to that of the [L-708,906]-PABC-[d4T] Heterodimer A prototype. However, although the compounds proved inhibitory to HIV-1, they were less potent than the parent compounds from which they were derived. PMID:18035829

  19. Hydrogen peroxide detection with high specificity in living cells and inflamed tissues.

    Rong, Lei; Zhang, Chi; Lei, Qi; Hu, Ming-Ming; Feng, Jun; Shu, Hong-Bing; Liu, Yi; Zhang, Xian-Zheng

    2016-12-01

    Hydrogen peroxide (H2O2) detection in biological systems is of significant importance, which act as critical second messenger in fundamental biological processes. Here, we report on a chemoselective fluorescent naphthylimide peroxide probe (NPP) for the H2O2 detection in vitro and in vivo. NPP is a phenylboronic acid-caged chromophore that selectively responds to H2O2 through a self-immolate mechanism. NPP exhibited high sensitivity and selectivity to H2O2 with distinctive fluorescence change due to the excellent two-photon excitation property, which permits the facile detection of inflammation produced H2O2 and offers chance to monitor the inflammatory stages in diseased cells. PMID:27482463

  20. Hydrogen peroxide detection with high specificity in living cells and inflamed tissues

    Rong, Lei; Zhang, Chi; Lei, Qi; Hu, Ming-Ming; Feng, Jun; Shu, Hong-Bing; Liu, Yi; Zhang, Xian-Zheng

    2016-01-01

    Hydrogen peroxide (H2O2) detection in biological systems is of significant importance, which act as critical second messenger in fundamental biological processes. Here, we report on a chemoselective fluorescent naphthylimide peroxide probe (NPP) for the H2O2 detection in vitro and in vivo. NPP is a phenylboronic acid-caged chromophore that selectively responds to H2O2 through a self-immolate mechanism. NPP exhibited high sensitivity and selectivity to H2O2 with distinctive fluorescence change due to the excellent two-photon excitation property, which permits the facile detection of inflammation produced H2O2 and offers chance to monitor the inflammatory stages in diseased cells.

  1. Tumor immunotargeting using innovative radionuclides.

    Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Mathieu, Cédric; Guérard, François; Frampas, Eric; Carlier, Thomas; Chouin, Nicolas; Haddad, Ferid; Chatal, Jean-François; Faivre-Chauvet, Alain; Chérel, Michel; Barbet, Jacques

    2015-01-01

    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. PMID:25679452

  2. Tumor Immunotargeting Using Innovative Radionuclides

    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.

  3. Spectroscopic and computational investigation of actinium coordination chemistry.

    Ferrier, Maryline G; Batista, Enrique R; Berg, John M; Birnbaum, Eva R; Cross, Justin N; Engle, Jonathan W; La Pierre, Henry S; Kozimor, Stosh A; Lezama Pacheco, Juan S; Stein, Benjamin W; Stieber, S Chantal E; Wilson, Justin J

    2016-01-01

    Actinium-225 is a promising isotope for targeted-α therapy. Unfortunately, progress in developing chelators for medicinal applications has been hindered by a limited understanding of actinium chemistry. This knowledge gap is primarily associated with handling actinium, as it is highly radioactive and in short supply. Hence, Ac(III) reactivity is often inferred from the lanthanides and minor actinides (that is, Am, Cm), with limited success. Here we overcome these challenges and characterize actinium in HCl solutions using X-ray absorption spectroscopy and molecular dynamics density functional theory. The Ac-Cl and Ac-OH2O distances are measured to be 2.95(3) and 2.59(3) Å, respectively. The X-ray absorption spectroscopy comparisons between Ac(III) and Am(III) in HCl solutions indicate Ac(III) coordinates more inner-sphere Cl(1-) ligands (3.2±1.1) than Am(III) (0.8±0.3). These results imply diverse reactivity for the +3 actinides and highlight the unexpected and unique Ac(III) chemical behaviour. PMID:27531582

  4. 靶向治疗用Fe3O4及其白蛋白包被磁性纳米粒子的制备%Preparation Fe3O4 Nanoparticles and HAS-Coated Magnetite Nanoparticals for Tumor Target Therapy

    谭家驹; 张春富; 冯彦林; 曹金全; 曹本洪; 尹端; 汪勇先

    2003-01-01

    目的制备用于肿瘤靶向治疗的Fe3O4及其白蛋白包被的磁性纳米粒子.方法采用部分还原法制备Fe3O4纳米粒子,通过微乳化方法制备了白蛋白包被的Fe3O4磁性纳米颗粒.结果Fe3O4粒径为10nm左右,X-射线粉末衍射分析显示Fe3O4纳米磁性微粒是典型的尖晶石构型;白蛋白包被的磁性纳米粒子直径在200nm左右.结论Fe3O4及其白蛋白包被的磁性纳米粒子适于用于肿瘤靶向治疗的进一步研究.%Objective:To prepare Fe3O4 magnetite nanoparticles and HSA- coated magnetite particles for the purpose of regional target therapy. Methods: To adopt partial reduction method to prepare the Fe3O4 nanoparticles:100 ml 0.01 mol/L Na2SO3 was added dropwise into 100 ml 0.06 mol/LFeCl3 solution under nitrogen gas flow.10%(V%) ammonia was added dropwise with rapid stirring until pH of the reaction solution reach 8. Heated at 70℃ with water bath for 15 min. Preparation of HAS- coated magnetite particles:To use microemulsion approach,with oleic acid as oil phase, mixture of HSA and magnetite solution as water phase and sp- 85 as emulsion agent.Results: Fe3O4 magnetite particles with about 10 nm in diameter and X - ray power diffraction show that the nanoparticles is γ- Fe2O3. HAS- coated Fe3O4 magnetite nanoparticles is characterized by TEM with diameter no more than 200 nm. Conclusions: Fe3O4 magnetite nanoparticles and HSA - coated magnetite particles is suitable for researching of regional target therapy.

  5. 叶酸偶联牛血清白蛋白负载卡铂和紫杉醇肿瘤靶向纳米粒制备、表征及体外释放性能评价%Preparation, Characterization and Evaluation of in vitro Release of Folate-Conjugated Carboplatin and Paclitaxel-loaded Bovine Serum Albumin Tumor-targeting Nanoparticles

    单常; 祖元刚; 赵修华; 桑梅

    2013-01-01

    Paclitaxel under the trade name Taxol,is a natural compounds isolated and purified from the trees of the Taxus (Taxaceae L.) belonging to taxus (Taxus L.).Paclitaxel and carboplatin are anti-cancer drugs currently with high clinical utility rates,which often used in combination on the clinical treatment of different types of cancer.Coupling folic acid in bovine serum albumin as a drug carrier,surface coating using nanoparticle and solvent technology,folate-targeted carboplatin-paclitaxel albumin nanoparticles were prepared,and the in vitro release properties of targeted drug were studied.Research results are as follows:the mean grain size of carboplatin-paclitaxel albumin nanoparticles was 199.4 nm,the zeta electric potential was-30.90 mV; the envelope rates were 91.4% for carboplatin and 56.1% for paclitaxel,respectively; the drug loading capacity was 21%.It was proven that within 12 h a good stability was maintained through the reconstitution of the facarboplatin-paclitaxel albumin nanoparticles.In addition,the folic acid-carboplatin-paclitaxel albumin nanoparticles showed an evident slow-release effect as compared with the carboplatin and paclitaxel original powder,the in vitro release time was up to 120 h.%紫杉醇(Paclitaxel,商品名Taxol)是一种在红豆杉科(Taxaceae L.)红豆杉属(Taxus L.)生长缓慢的常绿乔木中分离提取的天然化合物.卡铂和紫杉醇均是目前临床上使用率很高的抗肿瘤药物,并在临床上经常配伍使用治疗不同的癌症.本研究以叶酸偶联的牛血清白蛋白作为药物载体,采用去溶剂技术制备了叶酸靶向卡铂—紫杉醇的白蛋白纳米粒,并研究了靶向制剂体外释放性质.研究结果表明:卡铂—紫杉醇白蛋白纳米粒平均粒径为199.4 nm,Zeta电位为-30.90 mV.卡铂包封率为91.4%;紫杉醇包封率为56.1%,药物总载药量为21%.其冻干粉复溶12h后各项数据未发生较大变化,说明其具有良好的稳定性.体外释放结果表明叶酸—卡铂—紫杉醇白蛋白纳米粒与卡铂和紫杉醇原粉比较具有明显的缓释效果,体外释药时间可达120 h.

  6. Astatine-211 Pathway from Radiochemistry to Clinical Investigation

    Particularly in clinical settings where tumour burden is low and cancers are located in close proximity to essential normal tissue structures, α-particle emitting radionuclides can offer significant advantages for targeted radionuclide therapy. One of the first alpha emitters to be evaluated for this purpose is the 7.2-h half-life radiohalogen Astatine-211 (211At). From a commercialization-potential perspective 211At, is less appealing than the longer half-life alpha particle emitters Radium-223, Actinium-225 and Thorium-227, which have become the focus of many laboratories. However, if methods for providing a better supply of 211At could be developed, this alpha emitter would be the radionuclide of choice for many potential therapeutic applications. With regard to the production of 211At, this can be readily be accomplished by bombarding natural bismuth targets with 28−29.5 MeV alpha particles via the 209Bi(α,2n)211At reaction. The goal is to utilize an alpha particle beam energy that provides the required balance for maximizing 211At production while minimizing creation of 210At, which is problematic because of its 138.4-day half life alpha-particle emitting daughter, 210Po. For most intended clinical applications, alpha particle beam energy of about 29 MeV offers the best compromise between maximizing yield and providing 211At with sufficient radionuclidic purity for clinical use. Clinically relevant levels of 211At have been produced at several institutions using both internal and external cyclotron targets

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

    Jaspreet Singh Jaggi

    Full Text Available BACKGROUND: 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. METHODOLOGY AND PRINCIPAL FINDINGS: 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. CONCLUSIONS: The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy.

  8. Alpha Emitting Radionuclides and Radiopharmaceuticals for Therapy

    Today, cancer treatments mainly rely on surgery or external beam radiation to remove or destroy bulky tumors. Chemotherapy is given when tumours cannot be removed or when dissemination is suspected. However, these approaches cannot permanently treat all cancers and relapse occurs in up to 50% of the patients’ population. Radioimmunotherapy (RIT) and peptide receptor radionuclide therapy (PRRT) are effective against some disseminated and metastatic diseases, although they are rarely curative. Most preclinical and clinical developments in this field have involved electron-emitting radionuclides, particularly iodine-131, yttrium-90 and lutetium-177. The large range of the electrons emitted by these radionuclides reduces their efficacy against very small tumour cell clusters or isolated tumour cells present in residual disease and in many haematological tumours (leukaemia, myeloma). The range of alpha particles in biological tissues is very short, less than 0.1 mm, which makes alpha emitters theoretically ideal for treatment of such isolated tumour cells or micro-clusters of malignant cells. Thus, over the last decade, a growing interest for the use of alpha-emitting radionuclides has emerged. Research on targeted alpha therapy (TAT) began years ago in Nantes through cooperation between Subatech, a nuclear physics laboratory, CRCNA, a cancer research centre with a nuclear oncology team and ITU (Karlsruhe, Germany). CD138 was demonstrated as a potential target antigen for Multiple Myeloma, which is a target of huge clinical interest particularly suited for TAT because of the disseminated nature of the disease consisting primarily of isolated cells and small clusters of tumour cells mainly localized in the bone marrow. Thus anti-CD138 antibodies were labelled with bismuth-213 from actinium-225/bismuth-213 generators provided by ITU and used to target multiple myeloma cells. In vitro studies showed cell cycle arrest, synergism with chemotherapy and very little induction

  9. The Arab Spring: A Simple Compartmental Model for the Dynamics of a Revolution

    Lang, John

    2012-01-01

    The self-immolation of Mohamed Bouazizi on December 17, 2011 in the small Tunisian city of Sidi Bouzid, set off a sequence of events culminating in the revolutions of the Arab Spring. It is widely believed that the Internet and social media played a critical role in the growth and success of protests that led to the downfall of the regimes in Egypt and Tunisia. However, the precise mechanisms by which these new media affected the course of events remain unclear. We introduce a simple compartmental model for the dynamics of a revolution in a dictatorial regime such as Tunisia or Egypt which takes into account the role of the Internet and social media. An elementary mathematical analysis of the model identifies four main parameter regions: stable police state, meta-stable police state, unstable police state, and failed state. We illustrate how these regions capture, at least qualitatively, a wide range of scenarios observed in the context of revolutionary movements by considering the revolutions in Tunisia and ...

  10. Design and synthesis of peptide conjugates of phosphoramide mustard as prodrugs activated by prostate-specific antigen.

    Wu, Xinghua; Hu, Longqin

    2016-06-15

    A series of Glutaryl-Hyp-Ala-Ser-Chg-Gln-4-aminobenzyl phosphoramide mustard conjugates (1a-e) was designed and synthesized as potential prodrugs for site-specific activation by PSA in prostate cancer cells. All conjugates were found to be substrates of PSA with cleavage occurring between Gln and the para-aminobenzyl (PAB) linker. Structure-activity relationship studies on these conjugates indicated that introduction of electron-withdrawing fluorine(s) on the phenyl ring in the PAB linker uniformly improved the chemical stability of the conjugates while the position of substitution affected differently the self-immolative process of conjugates upon proteolysis. Introduction of a fluorine at ortho position to benzylic phosphoramide as in 1b results in better stability of the conjugate prior to activation while maintaining its antiproliferative activity upon activation by PSA. The conjugate 1b with 2-fluoro substitution was identified as a promising lead for further evaluation and optimization in the development of prostate cancer-targeted prodrugs. PMID:27156193

  11. Estimate the prevalence of physical methods used in attempted suicides in Iran: A systematic review and meta-analysis

    Milad Nazarzadeh

    2013-01-01

    Full Text Available Background and Aim: One of the most important subjects in the study of suicide is the methods used to it. There are not accurate statistics relating to employed physical methods for suicide in our country. Studies conducted in different provinces provided different results. This study aimed to estimate the prevalence of physical methods used in attempted suicides in Iran.Materials and Methods: All national scientific databases searched with the term “Suicide”. A search strategy was also done using keywords of “Suicide AND Iran” in PubMed and Science direct databases. The conducted database searches was limited to the past twenty years and updated by May 21, 2012. Overall, 1229 articles were retrieved through the initial search. Finally 95 studies included for the analysis. Random effect model of Mantel-Haenzel employed for estimation of pooled prevalence and Q-Cochran test to assess the cause of heterogeneity among the selected studies.Results: The pooled prevalence of suicide methods estimated as hanging with prevalence 17 %( CI 95%: 12 to 21%, self-immolation with prevalence 13% (CI 95%: 9 to 17% and use of gun 3% (CI 95%: 1 to 4%.Conclusion: The most common physical methods used in suicide were hanging. We proposed more serious mental health programs in primary health care and special treatments for patients with depression and other mental illnesses.

  12. A multifunctional DNA origami as carrier of metal complexes to achieve enhanced tumoral delivery and nullified systemic toxicity.

    Huang, Yanyu; Huang, Wei; Chan, Leung; Zhou, Binwei; Chen, Tianfeng

    2016-10-01

    The use of metal complexes in cancer treatment is hampered by the insufficient accumulation in tumor regions and observable systemic toxicity due to their nonspecificity in vivo. Herein we present a cancer-targeted DNA origami as biocompatible nanocarrier of metal complexes to achieve advanced antitumor effect. The formation of unique tetrahedral nanostructure of DNA cages effectively enhances the interaction between ruthenium polypyridyl complexes (RuPOP) and the cages, thus increasing the drug loading efficacy. Conjugation of biotin to the DNA-based nanosystem (Bio-cage@Ru) enhances its specific cellular uptake, drug retention and cytotoxicity against HepG2 cells. Different from free RuPOP and the cage itself, Bio-cage@Ru translocates to cell nucleus after internalization, where it undergoes self-immolative cleavage in response to DNases, leading to triggered drug release and induction of ROS-mediated cell apoptosis. Moreover, in the nude mice model, the nanosystem specifically accumulates in tumor sites, thus exhibits satisfactory in vivo antitumor efficacy, and alleviates the damage of liver, kidney, lung and heart function of nude mice induced by RuPOP and tumor xenografts. Collectively, this study demonstrates a strategy for construction of biocompatible and cancer-targeted DNA origami with enhanced anticancer efficacy and reduced toxicity for next-generation cancer therapy. PMID:27388944

  13. Adsorption of Cathepsin B-sensitive peptide conjugated DOX on nanodiamonds

    Drug delivery mediated by nanodiamonds (NDs) has shown great promise in controlled drug release field. In present study, dipeptide (Phe-Lys) conjugated antitumor drug doxorubicin hydrochloride (DOX) with self-immolative p-aminobenzylcarbonyl (PABC) spacer was non-covalently bound to carboxylated NDs via the electrostatic interactions. HIV-1 trans-activating transcriptor peptide (TAT) was additionally integrated to this ND-based delivery system in order to enhance the transmembrane efficiency. Fourier transforms infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and zeta potentials were applied to characterize the DOX and TAT loaded ND delivery platform. The adsorption equilibrium, kinetics and thermodynamics for the adsorption of peptide conjugated DOX onto NDs were investigated. It was found that the adsorption fitted well with the Freundlich model and conformed to pseudo-second order kinetics. It also showed that the adsorption was a spontaneous and exothermic process. Therefore, our work offered a facile way to formulate a ND-based drug delivery platform with multifunctionality in a layer by layer adsorption fashion.

  14. Trends of Suicidal Poisoning In Ahmedabad (Retrospective Study

    Kartik Prajapati

    2012-07-01

    Full Text Available 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. Physical and mental illness, disturbed interpersonal relationships and economic difficulties were the major reasons for suicide. The vulnerable population was found to be women, students, farmers etc. A social and public health response in addition to a mental health response is crucial to prevent suicidal behaviour in India.The present study was undertaken in the department of Forensic Medicine & Toxicology of Smt NHL MMC at Ahmedabad (Gujarat to know the pattern of Suicidal poisoning. Total 130 cases of death due to Suicidal poisoning were selected for this Retrospective study, which were brought to us for postmortem examination during the span of two year (From May 2007 to April 2009. Our study revealed that most of the victims of fatal poisoning were Hindus, married males of middle socio-economic status who died due to self ingestion of some poison

  15. Aromatizing unzipping polyester for EUV photoresist

    Matsuzawa, Kensuke; Mesch, Ryan; Olah, Mike; Wang, Wade; Phillips, Scott T.; Willson, C. Grant

    2015-03-01

    New "self-immolating" or "unzipping" polymers, materials that depolymerize in response to irradiation, were designed and prepared successfully. We studied several candidate polymers and ultimately chose two of them for further development. One is a polyester that aromatizes upon depolymerization. The unzipping reaction initiated by UV exposure in solution was confirmed. The polymer was then studied in thin films to assess its potential for use in formulating photoresists. The neat polymer was tested as a blend with novolac resin. The effect of unzipping polyester loading in novolac on the rate of dissolution of films in TMAH was studied. Inhibition occurs at 20-30% loading. The films were exposed with DUV light and patterning was observed. The sensitivity of the unzipping polyester formulation is low in part due to the low absorption of the polymer for UV light. However, the polymer showed higher sensitivity with EUV exposure and first contrast curves show sensitivity in the range of 20-25mJ/cm2.

  16. Enzyme-Responsive Polymeric Vesicles for Bacterial-Strain-Selective Delivery of Antimicrobial Agents.

    Li, Yamin; Liu, Guhuan; Wang, Xiaorui; Hu, Jinming; Liu, Shiyong

    2016-01-01

    Antimicrobial resistance poses serious public health concerns and antibiotic misuse/abuse further complicates the situation; thus, it remains a considerable challenge to optimize/improve the usage of currently available drugs. We report a general strategy to construct a bacterial strain-selective delivery system for antibiotics based on responsive polymeric vesicles. In response to enzymes including penicillin G amidase (PGA) and β-lactamase (Bla), which are closely associated with drug-resistant bacterial strains, antibiotic-loaded polymeric vesicles undergo self-immolative structural rearrangement and morphological transitions, leading to sustained release of antibiotics. Enhanced stability, reduced side effects, and bacterial strain-selective drug release were achieved. Considering that Bla is the main cause of bacterial resistance to β-lactam antibiotic drugs, as a further validation, we demonstrate methicillin-resistant S. aureus (MRSA)-triggered release of antibiotics from Bla-degradable polymeric vesicles, in vitro inhibition of MRSA growth, and enhanced wound healing in an in vivo murine model. PMID:26694087

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

    AnkitaKothari

    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

  18. Suicide Methods in Asia: Implications in Suicide Prevention

    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.

  19. Engineering Intracellular Delivery Nanocarriers and Nanoreactors from Oxidation-Responsive Polymersomes via Synchronized Bilayer Cross-Linking and Permeabilizing Inside Live Cells.

    Deng, Zhengyu; Qian, Yinfeng; Yu, Yongqiang; Liu, Guhuan; Hu, Jinming; Zhang, Guoying; Liu, Shiyong

    2016-08-24

    Reactive oxygen species (ROS) and oxidative stress are implicated in various physiological and pathological processes, and this feature provides a vital biochemical basis for designing novel therapeutic and diagnostic nanomedicines. Among them, oxidation-responsive micelles and vesicles (polymersomes) of amphiphilic block copolymers have been extensively explored; however, in previous works, oxidation by ROS including H2O2 exclusively leads to microstructural destruction of polymeric assemblies. For oxidation-responsive polymersomes, fast release of encapsulated hydrophilic drugs and bioactive macromolecules will occur upon microstructural disintegration. Under certain application circumstances, this does not meet design requirements for sustained-release drug nanocarriers and long-acting in vivo nanoreactors. Also note that conventional polymersomes possess thick hydrophobic bilayers and compromised membrane permeability, rendering them as ineffective nanocarriers and nanoreactors. We herein report the fabrication of oxidation-responsive multifunctional polymersomes exhibiting intracellular milieu-triggered vesicle bilayer cross-linking, permeability switching, and enhanced imaging/drug release features. Mitochondria-targeted H2O2 reactive polymersomes were obtained through the self-assembly of amphiphilic block copolymers containing arylboronate ester-capped self-immolative side linkages in the hydrophobic block, followed by surface functionalization with targeting peptides. Upon cellular uptake, intracellular H2O2 triggers cascade decaging reactions and generates primary amine moieties; prominent amidation reaction then occurs within hydrophobic bilayer membranes, resulting in concurrent cross-linking and hydrophobic-to-hydrophilic transition of polymersome bilayers inside live cells. This process was further utilized to achieve integrated functions such as sustained drug release, (combination) chemotherapy monitored by fluorescence and magnetic resonance (MR

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

    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

  1. Termination of Safeguards on ULWBR Material

    Ivan R. Thomas; Ernest L. Laible

    2008-07-01

    The Department of Energy (DOE), Office of Environmental Management, has approved the disposition of 31 metric tons of Unirradiated Light Water Breeder Reactor (ULWBR) material in canisters stored within dry wells of the Underground Fuel Storage Facility at the Idaho Nuclear Technology and Engineering Center (INTEC). This unirradiated material consists primarily of ceramic pellets of thorium oxide in stainless steel cladding, but it also contains 300 kilograms of uranium that is 98 wt% U-233. The ULWBR material was not processed at the INTEC because it was incompatible with prior chemical separation schemes. Other economical recovery options have not been identified, and expressions of interest for consolidating the material with existing projects at other DOE sites have not been received. The U-233 could be used for producing the medical isotope Actinium-225, but the proof-of-principle demonstration and follow-on pilot program have not been developed to the point of requiring production quantities of U-233. Consequently, the selected disposition of the ULWBR material was burial as Low Level Waste at the Nevada Test Site (NTS), which required terminating safeguards controls for the contained Category II quantity of Attractiveness Level D special nuclear material (SNM). The requested termination followed the twelve point evaluation criteria of the Historical Defense Program Discard Guidance and included a security analysis for evaluating the risks of theft, diversion, and radiological sabotage associated with the material. Continuity of knowledge in the book inventory was assured by documenting that the original shipper’s measurements accurately reflected the quantities of materials received and that the ULWBR materials had remained under adequate physical protection and had been subject to periodic physical inventories. The method selected for substantiating the book values as the basis for terminating safeguards was the nondestructive assay used during physical

  2. Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes

    Alessandro Ruggiero

    2010-09-01

    imaging. Near-infrared three-dimensional fluorescent-mediated tomography was used to image the LS174T tumor model, collect antibody-alone PK data, and calculate the number of copies of VE-cad epitope per cell. All of these studies were performed as a single administration of construct and were found to be safe and well tolerated by the murine model. These data have implications that support further imaging and radiotherapy studies using a SWCNT-based platform and focusing on the tumor vessels as the target.Keywords: actinium-225 (225Ac, zirconium-89 (89Zr, angiogenesis, vascular endothelial-cadherin, radioimmunotherapy (RIT, radioimmunoPET

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

    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

  4. 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.

    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

  5. Applications of High Intensity Proton Accelerators

    Raja, Rajendran; Mishra, Shekhar

    2010-06-01

    collider and neutrino factory - summary of working group 2 / J. Galambos, R. Garoby and S. Geer -- Prospects for a very high power CW SRF linac / R. A. Rimmer -- Indian accelerator program for ADS applications / V. C. Sahni and P. Singh -- Ion accelerator activities at VECC (particularly, operating at low temperature) / R. K. Bhandari -- Chinese efforts in high intensity proton accelerators / S. Fu, J. Wang and S. Fang -- ADSR activity in the UK / R. J. Barlow -- ADS development in Japan / K. Kikuchi -- Project-X, SRF, and very large power stations / C. M. Ankenbrandt, R. P. Johnson and M. Popovic -- Power production and ADS / R. Raja -- Experimental neutron source facility based on accelerator driven system / Y. Gohar -- Transmutation mission / W. S. Yang -- Safety performance and issues / J. E. Cahalan -- Spallation target design for accelerator-driven systems / Y. Gohar -- Design considerations for accelerator transmutation of waste system / W. S. Yang -- Japan ADS program / T. Sasa -- Overview of members states' and IAEA activities in the field of Accelerator Driven Systems (ADS) / A. Stanculescu -- Linac for ADS applications - accelerator technologies / R. W. Garnett and R. L. Sheffield -- SRF linacs and accelerator driven sub-critical systems - summary working groups 3 & 4 / J. Delayen -- Production of Actinium-225 via high energy proton induced spallation of Thorium-232 / J. Harvey ... [et al.] -- Search for the electric dipole moment of Radium-225 / R. J. Holt, Z.-T. Lu and R. Mueller -- SRF linac and material science and medicine - summary of working group 5 / J. Nolen, E. Pitcher and H. Kirk.

  6. Employment of Salmonella in Cancer Gene Therapy.

    Lee, Che-Hsin

    2016-01-01

    One of the primary limitations of cancer gene therapy is lack of selectivity of the therapeutic gene to tumor cells. Current efforts are focused on discovering and developing tumor-targeting vectors that selectively target only cancer cells but spare normal cells to improve the therapeutic index. The use of preferentially tumor-targeting bacteria as vectors is one of the innovative approaches for the treatment of cancer. This is based on the observation that some obligate or facultative-anaerobic bacteria are capable of multiplying selectively in tumors and inhibiting their growth. In this study, we exploited attenuated Salmonella as a tumoricidal agent and a vector to deliver genes for tumor-targeted gene therapy. Attenuated Salmonella, carrying a eukaryotic expression plasmid encoding an anti-angiogenic gene, was used to evaluate its' ability for tumor targeting and gene delivery in murine tumor models. We also investigated the use of a polymer to modify or shield Salmonella from the pre-existing immune response in the host in order to improve gene delivery to the tumor. These results suggest that tumor-targeted gene therapy using Salmonella carrying a therapeutic gene, which exerts tumoricidal and anti-angiogenic activities, represents a promising strategy for the treatment of tumors. PMID:26846804

  7. Media Mobilization, Demolition-Resistant Families, and Contentious Politics.Reanalysis of the Event of Yihuang%媒介动员、钉子户与抗争政治 宜黄事件再分析

    吕德文

    2012-01-01

    宜黄事件具有某种标志性意义,它颠覆了当代中国抗争政治的刻板印象,创造了一个新的抗争政治类型。宜黄事件原本是一个普通的钉子户抗争事件,在进入媒体的视野之前,它只是底层政治的一部分,当事人采用的基本上属于"弱者的武器"的方式,并且是地方性的、特殊的和双轨的,显著性和协同性都不高。由于媒介动员将政策的内在张力呈现于公众视野,钉子户利用这一政治机遇结构,不断创新了抗争表演,从而使宜黄事件发生了规模转变和极化,最终使事件发展成为一场要求保护弱势群体利益,发动制度变革的专业化社会运动的一部分,宜黄事件也就具有了普适性的、模式化的和自主的特征。宜黄事件的遣散是因为钉子户和媒体的抗争目标出现了竞争,而并非明确的适度制度化所致,这是当代中国国家建设中"反体制"的体制重建的一部分。%The contention event of Yihuang in September, 2010 is of great significance because it has changed the contention routine in contemporary China by adopting a new type of contentious politics. Before it became the media focus, Yihuang event was just another ordinary occurrence of residents resisting demolition of their houses, a part of the subaltern politics. The main contention strategies taken by the families under the order to move typically including negotiation with the local government in charge of demolition, intercepting visits to appeal, and seeking media attention. These are "weapons of the weak", parochial, local-specific, and bifurcated~ therefore, of low salience and poor coordination, usually unsuccessful to achieve contention objectives. This time, the Zhong family adopted an extreme contention means of self-immolation. Since the occurrence of this event, the large-scale involvement of the media has presented the inherent tension of policies to the public, and the demolition

  8. In Vivo Targeting and Positron Emission Tomography Imaging of Tumor Vasculature with 66Ga-Labeled Nano-Graphene

    Hong, Hao; Zhang, Yin; Engle, Jonathan W.; Nayak, Tapas R.; Theuer, Charles P.; Robert J. Nickles; Barnhart, Todd E.; Cai, Weibo

    2012-01-01

    The goal of this study was to employ nano-graphene for tumor targeting in an animal tumor model, and quantitatively evaluate the pharmacokinetics and tumor targeting efficacy through positron emission tomography (PET) imaging using 66Ga as the radiolabel. Nano-graphene oxide (GO) sheets with covalently linked, amino group-terminated six-arm branched polyethylene glycol (PEG; 10 kDa) chains were conjugated to NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid, for 66Ga-labeling) and TRC105 (an...

  9. Mechanism for Clastogenic Activity of Naphthalene

    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.

  10. Mechanism for Clastogenic Activity of Naphthalene

    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.

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

    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.

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

    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,

  13. Radionuclide therapy in children: An overview

    Radionuclide therapy in children has advanced significantly over the past few decades. Literature is replete with reports from investigators on the cytotoxic effects of tumor targeting radionuclides and radiopharmaceuticals. The collective experiences gained through numerous clinical trials has led to fairly well established treatment strategies in some tumours and paved the way for exploration of treatment alternatives in many others

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

    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.

  15. Serum-stable quantum dot--protein hybrid nanocapsules for optical bio-imaging

    We introduce shell cross-linked protein/quantum dot (QD) hybrid nanocapsules as a serum-stable systemic delivery nanocarrier for tumor-targeted in vivo bio-imaging applications. Highly luminescent, heavy-metal-free Cu0.3InS2/ZnS (CIS/ZnS) core-shell QDs are synthesized and mixed with amine-reactive six-armed poly(ethylene glycol) (PEG) in dichloromethane. Emulsification in an aqueous solution containing human serum albumin (HSA) results in shell cross-linked nanocapsules incorporating CIS/ZnS QDs, exhibiting high luminescence and excellent dispersion stability in a serum-containing medium. Folic acid is introduced as a tumor-targeting ligand. The feasibility of tumor-targeted in vivo bio-imaging is demonstrated by measuring the fluorescence intensity of several major organs and tumor tissue after an intravenous tail vein injection of the nanocapsules into nude mice. The cytotoxicity of the QD-loaded HSA-PEG nanocapsules is also examined in several types of cells. Our results show that the cellular uptake of the QDs is critical for cytotoxicity. Moreover, a significantly lower level of cell death is observed in the CIS/ZnS QDs compared to nanocapsules loaded with cadmium-based QDs. This study suggests that the systemic tumor targeting of heavy-metal-free QDs using shell cross-linked HSA-PEG hybrid nanocapsules is a promising route for in vivo tumor diagnosis with reduced non-specific toxicity. (papers)

  16. Effect of radiotherapy and hyperthermia on the tumor accumulation of HPMA copolymer-based drug delivery systems

    Lammers, T.; Peschke, P.; Kühnlein, R.; Šubr, Vladimír; Ulbrich, Karel; Debus, J.; Huber, P. E.; Hennink, W. E.; Storm, G.

    2007-01-01

    Roč. 117, č. 3 (2007), s. 333-341. ISSN 0168-3659 R&D Projects: GA ČR GA204/05/2255 Institutional research plan: CEZ:AV0Z40500505 Keywords : HPMA * drug delivery * tumor targeting Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.756, year: 2007

  17. Strains, Mechanism, and Perspective: Salmonella-Based Cancer Therapy

    Wang, Cheng-Zhi; Kazmierczak, Robert A.; Eisenstark, Abraham

    2016-01-01

    Recently, investigation of bacterial-based tumor therapy has regained focus due to progress in molecular, cellular, and microbial biology. Many bacteria such as Salmonella, Listeria, Escherichia, and Clostridium have proved to have tumor targeting and in some cases even tumor-destroying phenotypes. Furthermore, bacterial clinical treatments for cancer have been improved by combination with other therapeutic methods such as chemotherapeutic drugs and radioactive agents. Synthetic biology techniques have also driven the development of new bacterial-based cancer therapies. However, basic questions about the mechanisms of bacterial-mediated tumor targeting and destruction are still being elucidated. In this review, we focus on three tumor-therapeutic Salmonella models, the most intensively studied bacterial genus in this field. One of these Salmonella models is our Salmonella enterica serovar Typhimurium LT2 derived strain CRC2631, engineered to minimize toxicity but maximize tumor-targeting and destruction effects. The other two are VNP20009 and A1-R. We compare the means by which these therapeutic candidate strain models were selected for study, their tumor targeting and tumor destruction phenotypes in vitro and in vivo, and what is currently known about the mechanisms by which they target and destroy tumors.

  18. Investigating photoexcitation-induced mitochondrial damage by chemotherapeutic corroles using multimode optical imaging

    Hwang, Jae Youn; Lubow, David J.; Sims, Jessica D.; Gray, Harry B.; Mahammed, Atif; Gross, Zeev; Medina-Kauwe, Lali K.; Farkas, Daniel L.

    2012-01-01

    We recently reported that a targeted, brightly fluorescent gallium corrole (HerGa) is highly effective for breast tumor detection and treatment. Unlike structurally similar porphryins, HerGa exhibits tumor-targeted toxicity without the need for photoexcitation. We have now examined whether photoexcitation further modulates HerGa toxicity, using multimode optical imaging of live cells, including two-photon excited fluorescence, differential interference contrast (DIC), spectral, and lifetime imaging. Using two-photon excited fluorescence imaging, we observed that light at specific wavelengths augments the HerGa-mediated mitochondrial membrane potential disruption of breast cancer cells in situ. In addition, DIC, spectral, and fluorescence lifetime imaging enabled us to both validate cell damage by HerGa photoexcitation and investigate HerGa internalization, thus allowing optimization of light dose and timing. Our demonstration of HerGa phototoxicity opens the way for development of new methods of cancer intervention using tumor-targeted corroles.

  19. Biosystems Engineering of Prokaryotes with Tumor-Killing Capacities.

    Kalyoncu, Ebuzer; Olmez, Tolga T; Ozkan, Alper D; Sarioglu, Omer F

    2016-01-01

    Certain bacteria selectively attack tumor tissues and trigger tumor shrinkage by producing toxins and modulating the local immune system, but their clinical utility is limited because of the dangers posed by systemic infection. Genetic engineering can be used to minimize the risks associated with tumor-targeting pathogens, as well as to increase their efficiency in killing tumor cells. Advances in genetic circuit design have led to the development of bacterial strains with enhanced tumor-targeting capacities and the ability to secrete therapeutics, cytotoxic proteins and prodrug-cleaving enzymes, which allows their safe and effective use for cancer treatment. The present review details the recent advances in the design and application of these modified bacterial strains. PMID:26654438

  20. T1-Weighted MR imaging of liver tumor by gadolinium-encapsulated glycol chitosan nanoparticles without non-specific toxicity in normal tissues

    Na, Jin Hee; Lee, Sangmin; Koo, Heebeom; Han, Hyounkoo; Lee, Kyung Eun; Han, Seung Jin; Choi, Seung Hong; Kim, Hyuncheol; Lee, Seulki; Kwon, Ick Chan; Choi, Kuiwon; Kim, Kwangmeyung

    2016-05-01

    Herein, we have synthesized Gd(iii)-encapsulated glycol chitosan nanoparticles (Gd(iii)-CNPs) for tumor-targeted T1-weighted magnetic resonance (MR) imaging. The T1 contrast agent, Gd(iii), was successfully encapsulated into 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-modified CNPs to form stable Gd(iii)-encapsulated CNPs (Gd(iii)-CNPs) with an average particle size of approximately 280 nm. The stable nanoparticle structure of Gd(iii)-CNPs is beneficial for liver tumor accumulation by the enhanced permeation and retention (EPR) effect. Moreover, the amine groups on the surface of Gd(iii)-CNPs could be protonated and could induce fast cellular uptake at acidic pH in tumor tissue. To assay the tumor-targeting ability of Cy5.5-labeled Gd(iii)-CNPs, near-infrared fluorescence (NIRF) imaging and MR imaging were used in a liver tumor model as well as a subcutaneous tumor model. Cy5.5-labeled Gd(iii)-CNPs generated highly intense fluorescence and T1 MR signals in tumor tissues after intravenous injection, while DOTAREM®, the commercialized control MR contrast agent, showed very low tumor-targeting efficiency on MR images. Furthermore, damaged tissues were found in the livers and kidneys of mice injected with DOTAREM®, but there were no obvious adverse effects with Gd(iii)-CNPs. Taken together, these results demonstrate the superiority of Gd(iii)-CNPs as a tumor-targeting T1 MR agent.Herein, we have synthesized Gd(iii)-encapsulated glycol chitosan nanoparticles (Gd(iii)-CNPs) for tumor-targeted T1-weighted magnetic resonance (MR) imaging. The T1 contrast agent, Gd(iii), was successfully encapsulated into 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-modified CNPs to form stable Gd(iii)-encapsulated CNPs (Gd(iii)-CNPs) with an average particle size of approximately 280 nm. The stable nanoparticle structure of Gd(iii)-CNPs is beneficial for liver tumor accumulation by the enhanced permeation and retention (EPR) effect. Moreover, the

  1. Activated Charge-Reversal Polymeric Nano-System: The Promising Strategy in Drug Delivery for Cancer Therapy

    Yichen Hu; Xiao Gong; Jinming Zhang; Fengqian Chen; Chaomei Fu; Peng Li; Liang Zou; Gang Zhao

    2016-01-01

    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 impor...

  2. Drug delivery with carbon nanotubes for in vivo cancer treatment

    Liu, Zhuang; Chen, Kai; Davis, Corrine; Sherlock, Sarah; Cao, Qizhen; Chen, Xiaoyuan; Dai, Hongjie

    2008-01-01

    Chemically functionalized single-walled carbon nanotubes (SWNTs) have shown promise in tumor targeted accumulation in mice and exhibit biocompatibility, excretion and little toxicity. Here, we demonstrate in-vivo SWNT drug delivery for tumor suppression in mice. We conjugate paclitaxel (PTX), a widely used cancer chemotherapy drug to branched polyethylene-glycol (PEG) chains on SWNTs via a cleavable ester bond to obtain a water soluble SWNT-paclitaxel conjugate (SWNT-PTX). SWNT-PTX affords hi...

  3. Escherichia coli Nissle 1917 Targets and Restrains Mouse B16 Melanoma and 4T1 Breast Tumors through Expression of Azurin Protein

    Zhang, Yunlei; Zhang, Youming; Xia, Liqiu; Zhang, XiangLi; Ding, Xuezhi; Yan, Fu; Wu, Feng

    2012-01-01

    Many studies have demonstrated that intravenously administered bacteria can target and proliferate in solid tumors and then quickly be released from other organs. Here, we employed the tumor-targeting property of Escherichia coli Nissle 1917 to inhibit mouse B16 melanoma and 4T1 breast tumors through the expression of azurin protein. For this purpose, recombinant azurin-expressing E. coli Nissle 1917 was developed. The levels of in vitro and in vivo azurin secretion in the engineered bacteriu...

  4. Computer modelling of response of the Modelo-2 gamma probe used in intraoperative localisation of tumors

    During the last decade hand-held gamma probes have been introduced into both tumor localisation and surgery. The technique, labelled RIGA (radioimmuno-guided endoscopy), proved to be of help in various stages of the patient treatment preoperational (localisation, as accurate, as possible of even small-size tumor targets), intraoperational (an on-line assessment of the efficiency of the radical surgery) and postoperational, identification of possible local recurrence and metastases

  5. Targeted focal therapy for prostate cancer: a review of the literature

    Sullivan, Kathryn F.; Crawford, E. David

    2009-01-01

    Improvements in prostate cancer diagnosis and treatment have resulted in a decreasing age-adjusted death rate. But improved diagnostic tools have not delivered a proportionate decrease in mortality, primarily because physicians now are diagnosing – and treating – more clinically insignificant tumors. Targeted focal therapy (TFT) uses three dimensional (3D) mapping biopsies to guide cryotherapy so that it targets lesions themselves while sparing surrounding healthy tissues, thereby avoiding si...

  6. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors

    Ginj, Mihaela; Zhang, Hanwen; Waser, Beatrice; Cescato, Renzo; Wild, Damian; Wang, Xuejuan; Erchegyi, Judit; Rivier, Jean; Mäcke, Helmut R.; Reubi, Jean Claude

    2006-01-01

    Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin...

  7. In Vivo Tumor Vasculature Targeting of CuS@MSN Based Theranostic Nanomedicine

    Chen, Feng; Hong, Hao; Goel, Shreya; Graves, Stephen A.; Orbay, Hakan; Ehlerding, Emily B.; Shi, Sixiang; Theuer, Charles P.; Robert J. Nickles; 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 nano...

  8. Engineering of Hollow Mesoporous Silica Nanoparticles for Remarkably Enhanced Tumor Active Targeting Efficacy

    Chen, Feng; Hong, Hao; Shi, Sixiang; Goel, Shreya; Valdovinos, Hector F.; Hernandez, Reinier; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo

    2014-01-01

    Hollow mesoporous silica nanoparticle (HMSN) has recently gained increasing interests due to their tremendous potential as an attractive nano-platform for cancer imaging and therapy. However, possibly due to the lack of efficient in vivo targeting strategy and well-developed surface engineering techniques, engineering of HMSN for in vivo active tumor targeting, quantitative tumor uptake assessment, multimodality imaging, biodistribution and enhanced drug delivery have not been achieved to dat...

  9. In Vivo Targeting and Imaging of Tumor Vasculature with Radiolabeled, Antibody-Conjugated Nano-Graphene

    Hong, Hao; Yang, Kai; Zhang, Yin; Engle, Jonathan W.; Feng, Liangzhu; Yang, Yunan; Nayak, Tapas R.; Goel, Shreya; Bean, Jero; Theuer, Charles P.; Barnhart, Todd E.; Liu, Zhuang; Cai, Weibo

    2012-01-01

    Herein we demonstrate that nano-graphene can be specifically directed to the tumor neovasculature in vivo through targeting of CD105 (i.e. endoglin), a vascular marker for tumor angiogenesis. The covalently functionalized nano-graphene oxide (GO) exhibited excellent stability and target specificity. Pharmacokinetics and tumor targeting efficacy of the GO conjugates were investigated with serial non-invasive positron emission tomography (PET) imaging and biodistribution studies, which were val...

  10. Efficient Rejoining of DNA Double-Strand Breaks despite Increased Cell-Killing Effectiveness following Spread-Out Bragg Peak Carbon-Ion Irradiation

    Averbeck, Nicole B.; Topsch, Jana; Scholz, Michael; Kraft-Weyrather, Wilma; Durante, Marco; Taucher-Scholz, Gisela

    2016-01-01

    Radiotherapy of solid tumors with charged particles holds several advantages in comparison to photon therapy; among them conformal dose distribution in the tumor, improved sparing of tumor-surrounding healthy tissue, and an increased relative biological effectiveness (RBE) in the tumor target volume in the case of ions heavier than protons. A crucial factor of the biological effects is DNA damage, of which DNA double-strand breaks (DSBs) are the most deleterious. The reparability of these les...

  11. T1-Weighted MR imaging of liver tumor by gadolinium-encapsulated glycol chitosan nanoparticles without non-specific toxicity in normal tissues.

    Na, Jin Hee; Lee, Sangmin; Koo, Heebeom; Han, Hyounkoo; Lee, Kyung Eun; Han, Seung Jin; Choi, Seung Hong; Kim, Hyuncheol; Lee, Seulki; Kwon, Ick Chan; Choi, Kuiwon; Kim, Kwangmeyung

    2016-05-01

    Herein, we have synthesized Gd(iii)-encapsulated glycol chitosan nanoparticles (Gd(iii)-CNPs) for tumor-targeted T1-weighted magnetic resonance (MR) imaging. The T1 contrast agent, Gd(iii), was successfully encapsulated into 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-modified CNPs to form stable Gd(iii)-encapsulated CNPs (Gd(iii)-CNPs) with an average particle size of approximately 280 nm. The stable nanoparticle structure of Gd(iii)-CNPs is beneficial for liver tumor accumulation by the enhanced permeation and retention (EPR) effect. Moreover, the amine groups on the surface of Gd(iii)-CNPs could be protonated and could induce fast cellular uptake at acidic pH in tumor tissue. To assay the tumor-targeting ability of Cy5.5-labeled Gd(iii)-CNPs, near-infrared fluorescence (NIRF) imaging and MR imaging were used in a liver tumor model as well as a subcutaneous tumor model. Cy5.5-labeled Gd(iii)-CNPs generated highly intense fluorescence and T1 MR signals in tumor tissues after intravenous injection, while DOTAREM®, the commercialized control MR contrast agent, showed very low tumor-targeting efficiency on MR images. Furthermore, damaged tissues were found in the livers and kidneys of mice injected with DOTAREM®, but there were no obvious adverse effects with Gd(iii)-CNPs. Taken together, these results demonstrate the superiority of Gd(iii)-CNPs as a tumor-targeting T1 MR agent. PMID:27113247

  12. Solubilization of Poorly Soluble PDT Agent, Meso-tetraphenylporphin, in Plain or Immunotargeted PEG-PE Micelles Results in Dramatically Improved Cancer Cell Killing in Vitro

    Roby, Aruna; Erdogan, Suna; Torchilin, Vladimir P.

    2005-01-01

    Poorly soluble photodynamic therapy (PDT) agent, meso-tetratphenylporphine (TPP), was effectively solubilized using non-targeted and tumor-targeted polymeric micelles prepared of polyethylene glycol/phosphatidyl ethanolamine conjugate (PEG-PE). Encapsulation of TPP into PEG-PE-based micelles and immunomicelles (bearing an anti-cancer monoclonal 2C5 antibody) resulted in significantly improved anticancer effects of the drug at PDT conditions against murine (LLC, B16) and human (MCF-7, BT20) ca...

  13. Paclitaxel-loaded PEG-PE-based micellar nanopreparations targeted with tumor specific landscape phage fusion protein enhance apoptosis and efficiently reduce tumors

    Tao WANG; Yang, Shenghong; Mei, Leslie A.; Parmar, Chirag K.; Gillespie, James W.; Praveen, Kulkarni P.; Petrenko, Valery A.; Torchilin, Vladimir P.

    2014-01-01

    In an effort to improve the therapeutic index of cancer chemotherapy, we developed an advanced nanopreparation based on the combination of landscape phage display to obtain new targeting ligands with micellar nanoparticles for tumor targeting of water insoluble neoplastic agents. With paclitaxel as a drug, this self-assembled nanopreparation composed of MCF-7-specific phage protein and polyethylene glycol phosphatidyl ethanolamine (PEG- PE) micelles showed selective toxicity to target cancer ...

  14. Application of phage display technology in targeted therapy of breast cancer

    Mian Kong; Junye Wang; Baojiang Li

    2013-01-01

    Phage display is a technology of gene expression and screening, it is widely used in the fields of defining antigenepitopes, signal transduction, genetic treatment, parasites research and tumor targeted therapy. Breast cancer is the mostcommon cancer in women, we can obtain peptides specially associated with breast cancer by using phage display technology,and this method has great potential in early diagnosis of breast cancer and development new targeted drugs.

  15. Thiol antioxidant-functionalized CdSe/ZnS quantum dots: Synthesis, Characterization, Cytotoxicity

    Zheng, Hong; Mortensen, Luke J.; DeLouise, Lisa A.

    2013-01-01

    Nanotechnology is a growing industry with wide ranging applications in consumer product and technology development. In the biomedical field, nanoparticles are finding increasing use as imaging agents for biomolecular labeling and tumor targeting. The nanoparticle physiochemical properties must be tailored for the specific application but chemical and physical stability in the biological milieu (no oxidation, aggregation, agglomeration or toxicity) are often required. Nanoparticles used for bi...

  16. Carrier-based radiochemotherapy

    Lammers, T.; Šubr, Vladimír; Ulbrich, Karel; Peschke, P.; Kiessling, F.; Huber, P. E.; Hennink, W. E.; Storm, G.

    Noordwijk aan Zee : University of Twente, 2008 - (Sam, A.), s. 248-250 ISBN 978-90-365-2653-1. [European Symposium on Controlled Drug Delivery /10./. Noordwijk aan Zee (NL), 02.04.2008-04.04.2008] R&D Projects: GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z40500505 Keywords : radiochemotherapy * tumor-targeted * drug targeting Subject RIV: CD - Macromolecular Chemistry

  17. Quantum dot-NanoLuc bioluminescence resonance energy transfer enables tumor imaging and lymph node mapping in vivo.

    Kamkaew, Anyanee; Sun, Haiyan; England, Christopher G; Cheng, Liang; Liu, Zhuang; Cai, Weibo

    2016-05-19

    A small luciferase protein (Nluc) was conjugated to QDs as a bioluminescence resonance energy transfer (BRET) pair. The conjugate showed 76% BRET efficiency and lymph node mapping was successfully performed. The cRGD peptide was conjugated to QD-Nluc for tumor targeting. The self-illuminating QD-Nluc showed excellent energy transfer in a living system and offered an optimal tumor-to-background ratio (>85). PMID:27157466

  18. Strategy for accurate liver intervention by an optical tracking system

    Lin, Qinyong; Yang, Rongqian; Cai, Ken; Guan, Peifeng; Xiao, Weihu; Wu, Xiaoming

    2015-01-01

    Image-guided navigation for radiofrequency ablation of liver tumors requires the accurate guidance of needle insertion into a tumor target. The main challenge of image-guided navigation for radiofrequency ablation of liver tumors is the occurrence of liver deformations caused by respiratory motion. This study reports a strategy of real-time automatic registration to track custom fiducial markers glued onto the surface of a patient’s abdomen to find the respiratory phase, in which the static p...

  19. Cellular Uptake of Drug Nanocrystals

    Seybold, Alexandra R; Li, Tonglei; Chen, Yan

    2014-01-01

    Systemic toxicity and poor solubility of existing chemotherapeutic drugs piqued an interest in the use of nanocrystals for chemotherapy. To increase cytotoxicity, surface coating of nanocrystals is of interest to enhance tumor targeting and reduce treatment toxicity. As such, we tested in this project various coated paclitaxel nanocrystals on cancer cells for determining the efficacy of surface coating. An IC50 assay was chosen to determine the cytotoxicity of surface-coated paclitaxel nanocr...

  20. Myeloid-derived suppressor cells as a Trojan horse

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

    2013-01-01

    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.

  1. The efects of low-dose ionizing radiation on angiogenesis

    Oliveira, Inês Sofia Batista Vala Silva de, 1981-

    2011-01-01

    Tese de doutoramento, Biologia (Biologia Celular), Universidade de Lisboa, Faculdade de Ciências, 2011 Angiogenesis is the formation of new blood vessels from pre‐existing ones. This process is regulated by a balance between pro‐ and anti‐angiogenic molecules and is derailed in various diseases, such as cancer. Radiotherapy is a commonly‐used treatment for cancer. However, recent studies suggest that ionizing radiation (IR) doses delivered inside the tumor target volume during fractionated...

  2. Preparation of 10-hydroxycamptothecin-loaded glycyrrhizic acid-conjugated bovine serum albumin nanoparticles for hepatocellular carcinoma-targeted drug delivery

    Zu Y; Meng L; Zhao X; Ge Y.; Yu X.; Zhang Y; Deng Y

    2013-01-01

    Yuangang Zu, Li Meng, Xiuhua Zhao, Yunlong Ge, Xinyang Yu, Yin Zhang, Yiping Deng Key Laboratory of Forest Plant Ecology, Northeast Forestry University, Ministry of Education, Harbin, People’s Republic of China Introduction: The livertaxis of glycyrrhizic acid-conjugated bovine serum albumin (GL-BSA) has been reported in the literature. Now, in this paper, we describe a novel type of drug-targeted delivery system containing 10-hydroxycamptothecin (HCPT) with liver tumor targeting. ...

  3. Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts

    Gerber, David E.; Hao, Guiyang; Watkins, Linda; Jason H. Stafford; Anderson, Jon; Holbein, Blair; Öz, Orhan K.; Mathews, Dana; Thorpe, Philip E; Hassan, Gedaa; Kumar, Amit; Brekken, Rolf A.; Sun, Xiankai

    2015-01-01

    Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when...

  4. Radiolabelled phage display peptide derivatives inhibiting matrix metalloproteinases target xenografted tumors in mice

    Background: A phage display peptide has been characterized, which inhibits matrix metalloproteinase activity, and cell migration. This cyclic decapeptide Cys-Thr-Thr-His-Trp-Gly-Phe-Thr-Leu-Cys is known to inhibit tumor growth both in preincubated cells with peptide and also in vivo. Cell killing has been demonstrated in vitro utilizing peptidoliposome construct which contained adriamycin. Furthermore, tumor targeting using direct labelling with Tc-99m has demonstrated. Materials and Methods: Now wide variety of peptide derivatives of this CTTHWGFTLC peptide has been constructed and they alter by lipophilicity. The biodistribution of labelled peptides containing AAY and GRENYCH residues in the amino terminus has been studied in normal and tumor bearing mice. Labeling method for In-111 has been cDTPA and for iodination direct labelling and indirect ATE method. Results: Direct labeling retained the lipofilicity of the peptide. Indirect labeled peptides were more hydrophobic and their distribution were different compared to direct labeled peptides. These radiolabelled peptides both with In-111 and I-125 retained in vitro inhibitory activity. The biostribution data demonstrated liver uptake with the lipophilic and more kidney uptake with the more hydrophilic constructs. Tumor targeting was demonstrated in nude mice. Conclusion: Because of excellent in vitro characteristics in tumor targeting, and inhibition of the endothelium of tumor vasculature, and inhibition of tumor growth with the cold peptide, these radiolabelled peptides have potential for further development. This tumor targeting peptidoliposomes as drug carrier may be used cancer treatment utilizing multi potential approach: radionuclide therapy, invasion inhibition and cell killing

  5. Engineering of hollow mesoporous silica nanoparticles for remarkably enhanced tumor active targeting efficacy.

    Chen, Feng; Hong, Hao; Shi, Sixiang; Goel, Shreya; Valdovinos, Hector F; Hernandez, Reinier; Theuer, Charles P; Barnhart, Todd E; Cai, Weibo

    2014-01-01

    Hollow mesoporous silica nanoparticle (HMSN) has recently gained increasing interests due to their tremendous potential as an attractive nano-platform for cancer imaging and therapy. However, possibly due to the lack of efficient in vivo targeting strategy and well-developed surface engineering techniques, engineering of HMSN for in vivo active tumor targeting, quantitative tumor uptake assessment, multimodality imaging, biodistribution and enhanced drug delivery have not been achieved to date. Here, we report the in vivo tumor targeted positron emission tomography (PET)/near-infrared fluorescence (NIRF) dual-modality imaging and enhanced drug delivery of HMSN using a generally applicable surface engineering technique. Systematic in vitro and in vivo studies have been performed to investigate the stability, tumor targeting efficacy and specificity, biodistribution and drug delivery capability of well-functionalized HMSN nano-conjugates. The highest uptake of TRC105 (which binds to CD105 on tumor neovasculature) conjugated HMSN in the 4T1 murine breast cancer model was ~10%ID/g, 3 times higher than that of the non-targeted group, making surface engineered HMSN a highly attractive drug delivery nano-platform for future cancer theranostics. PMID:24875656

  6. Targeting multiple types of tumors using NKG2D-coated iron oxide nanoparticles

    Iron oxide nanoparticles (IONPs) hold great potential for cancer therapy. Actively targeting IONPs to tumor cells can further increase therapeutic efficacy and decrease off-target side effects. To target tumor cells, a natural killer (NK) cell activating receptor, NKG2D, was utilized to develop pan-tumor targeting IONPs. NKG2D ligands are expressed on many tumor types and its ligands are not found on most normal tissues under steady state conditions. The data showed that mouse and human fragment crystallizable (Fc)-fusion NKG2D (Fc-NKG2D) coated IONPs (NKG2D/NPs) can target multiple NKG2D ligand positive tumor types in vitro in a dose dependent manner by magnetic cell sorting. Tumor targeting effect was robust even under a very low tumor cell to normal cell ratio and targeting efficiency correlated with NKG2D ligand expression level on tumor cells. Furthermore, the magnetic separation platform utilized to test NKG2D/NP specificity has the potential to be developed into high throughput screening strategies to identify ideal fusion proteins or antibodies for targeting IONPs. In conclusion, NKG2D/NPs can be used to target multiple tumor types and magnetic separation platform can facilitate the proof-of-concept phase of tumor targeting IONP development. (paper)

  7. Dual delivery systems based on polyamine analog BENSpm as prodrug and gene delivery vectors

    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

  8. ImmunoPET imaging of B-cell lymphoma using 124I-anti-CD20 scFv dimers (diabodies).

    Olafsen, Tove; Sirk, Shannon J; Betting, David J; Kenanova, Vania E; Bauer, Karl B; Ladno, Waldemar; Raubitschek, Andrew A; Timmerman, John M; Wu, Anna M

    2010-04-01

    Rapid clearing engineered antibody fragments for immunoPET promise high sensitivity at early time points. Here, tumor targeting of anti-CD20 diabodies (scFv dimers) for detection of low-grade B-cell lymphomas were evaluated. In addition, the effect of linker length on oligomerization of the diabody was investigated. Four rituximab scFv variants in the V(L)-V(H) orientation with different linker lengths between the V domains (scFv-1, scFv-3, scFv-5, scFv-8), plus the scFv-5 with a C-terminal cysteine (Cys-Db) for site-specific modification were generated. The scFv-8 and Cys-Db were radioiodinated with (124)I for PET imaging, and biodistribution of (131)I-Cys-Db was carried out at 2, 4 10 and 20 h. The five anti-CD20 scFv variants were expressed as fully functional dimers. Shortening the linker to three or one residue did not produce higher order of multimers. Both (124)I-labeled scFv-8 and Cys-Db exhibited similar tumor targeting at 8 h post injection, with significantly higher uptakes than in control tumors (P < 0.05). At 20 h, less than 1% ID/g of (131)I-labeled Cys-Db was present in tumors and tissues. Specific tumor targeting and high contrast images were achieved with the anti-CD20 diabodies. These agents extend the repertoire of reagents that can potentially be used to improve detection of low-grade lymphomas. PMID:20053640

  9. In vivo targeting and positron emission tomography imaging of tumor vasculature with (66)Ga-labeled nano-graphene.

    Hong, Hao; Zhang, Yin; Engle, Jonathan W; Nayak, Tapas R; Theuer, Charles P; Nickles, Robert J; Barnhart, Todd E; Cai, Weibo

    2012-06-01

    The goal of this study was to employ nano-graphene for tumor targeting in an animal tumor model, and quantitatively evaluate the pharmacokinetics and tumor targeting efficacy through positron emission tomography (PET) imaging using (66)Ga as the radiolabel. Nano-graphene oxide (GO) sheets with covalently linked, amino group-terminated six-arm branched polyethylene glycol (PEG; 10 kDa) chains were conjugated to NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid, for (66)Ga-labeling) and TRC105 (an antibody that binds to CD105). Flow cytometry analyses, size measurements, and serum stability studies were performed to characterize the GO conjugates before in vivo investigations in 4T1 murine breast tumor-bearing mice, which were further validated by histology. TRC105-conjugated GO was specific for CD105 in cell culture. (66)Ga-NOTA-GO-TRC105 and (66)Ga-NOTA-GO exhibited excellent stability in complete mouse serum. In 4T1 tumor-bearing mice, these GO conjugates were primarily cleared through the hepatobiliary pathway. (66)Ga-NOTA-GO-TRC105 accumulated quickly in the 4T1 tumors and tumor uptake remained stable over time (3.8 ± 0.4, 4.5 ± 0.4, 5.8 ± 0.3, and 4.5 ± 0.4 %ID/g at 0.5, 3, 7, and 24 h post-injection respectively; n = 4). Blocking studies with unconjugated TRC105 confirmed CD105 specificity of (66)Ga-NOTA-GO-TRC105, which was corroborated by biodistribution and histology studies. Furthermore, histological examination revealed that targeting of NOTA-GO-TRC105 is tumor vasculature CD105 specific with little extravasation. Successful demonstration of in vivo tumor targeting with GO, along with the versatile chemistry of graphene-based nanomaterials, makes them suitable nanoplatforms for future biomedical research such as cancer theranostics. PMID:22386918

  10. In Vivo Targeting and Positron Emission Tomography Imaging of Tumor Vasculature with 66Ga-Labeled Nano-Graphene

    Hong, Hao; Zhang, Yin; Engle, Jonathan W.; Nayak, Tapas R.; Theuer, Charles P.; Nickles, Robert J.; Barnhart, Todd E.; Cai, Weibo

    2012-01-01

    The goal of this study was to employ nano-graphene for tumor targeting in an animal tumor model, and quantitatively evaluate the pharmacokinetics and tumor targeting efficacy through positron emission tomography (PET) imaging using 66Ga as the radiolabel. Nano-graphene oxide (GO) sheets with covalently linked, amino group-terminated six-arm branched polyethylene glycol (PEG; 10 kDa) chains were conjugated to NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid, for 66Ga-labeling) and TRC105 (an antibody that binds to CD105). Flow cytometry analyses, size measurements, and serum stability studies were performed to characterize the GO conjugates before in vivo investigations in 4T1 murine breast tumor-bearing mice, which were further validated by histology. TRC105-conjugated GO was specific for CD105 in cell culture. 66Ga-NOTA-GO-TRC105 and 66Ga-NOTA-GO exhibited excellent stability in complete mouse serum. In 4T1 tumor-bearing mice, these GO conjugates were primarily cleared through the hepatobiliary pathway. 66Ga-NOTA-GO-TRC105 accumulated quickly in the 4T1 tumors and tumor uptake remained stable over time (3.8 ± 0.4, 4.5 ± 0.4, 5.8 ± 0.3, and 4.5 ± 0.4 %ID/g at 0.5, 3, 7, and 24 h post-injection respectively; n = 4). Blocking studies with unconjugated TRC105 confirmed CD105 specificity of 66Ga-NOTA-GO-TRC105, which was corroborated by biodistribution and histology studies. Furthermore, histological examination revealed that targeting of NOTA-GO-TRC105 is tumor vasculature CD105 specific with little extravasation. Successful demonstration of in vivo tumor targeting with GO, along with the versatile chemistry of graphene-based nanomaterials, makes them suitable nanoplatforms for future biomedical research such as cancer theranostics. PMID:22386918

  11. Multi-small molecule conjugations as new targeted delivery carriers for tumor therapy

    Shan L

    2015-09-01

    Full Text Available Lingling Shan,1 Ming Liu,2 Chao Wu,1 Liang Zhao,1 Siwen Li,3 Lisheng Xu,1 Wengen Cao,1 Guizhen Gao,1 Yueqing Gu3 1Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China; 2Department of Biology, University of South Dakota, Vermillion, SD, USA; 3Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Nanjing, People’s Republic of China Abstract: In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting ability, and harmful side effects, we developed a new tumor-targeted multi-small molecule drug delivery platform. Using paclitaxel (PTX as a model therapeutic, we prepared two prodrugs, ie, folic acid-fluorescein-5(6-isothiocyanate-arginine-paclitaxel (FA-FITC-Arg-PTX and folic acid-5-aminofluorescein-glutamic-paclitaxel (FA-5AF-Glu-PTX, composed of folic acid (FA, target, amino acids (Arg or Glu, linker, and fluorescent dye (fluorescein in vitro or near-infrared fluorescent dye in vivo in order to better understand the mechanism of PTX prodrug targeting. In vitro and acute toxicity studies demonstrated the low toxicity of the prodrug formulations compared with the free drug. In vitro and in vivo studies indicated that folate receptor-mediated uptake of PTX-conjugated multi-small molecule carriers induced high antitumor activity. Notably, compared with free PTX and with PTX-loaded macromolecular carriers from our previous study, this multi-small molecule-conjugated strategy improved the water solubility, loading rate, targeting ability, antitumor activity, and toxicity profile of PTX. These results support the use of multi-small molecules as tumor-targeting drug delivery systems. Keywords: multi-small molecules, paclitaxel, prodrugs, targeting, tumor therapy

  12. Metabolically active volumes automatic delineation methodologies in PET imaging: Review and perspectives

    PET imaging is now considered a gold standard tool in clinical oncology, especially for diagnosis purposes. More recent applications such as therapy follow-up or tumor targeting in radiotherapy require a fast, accurate and robust metabolically active tumor volumes delineation on emission images, which cannot be obtained through manual contouring. This clinical need has sprung a large number of methodological developments regarding automatic methods to define tumor volumes on PET images. This paper reviews most of the methodologies that have been recently proposed and discusses their framework and methodological and/or clinical validation. Perspectives regarding the future work to be done are also suggested. (authors)

  13. Bitargeted microemulsions based on coix seed ingredients for enhanced hepatic tumor delivery and synergistic therapy.

    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

  14. Experimental radiotherapy and clinical radiobiology. Vol. 22. Proceedings; Experimentelle Strahlentherapie und Klinische Strahlenbiologie. Bd. 22. Proceedings

    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.

  15. Low-Molecular Weight Polyethylenimine Modified with Pluronic 123 and RGD- or Chimeric RGD-NLS Peptide: Characteristics and Transfection Efficacy of Their Complexes with Plasmid DNA

    Jing Hu; Wenfang Zhao; Kehai Liu; Qian Yu; Yuan Mao; Zeyu Lu; Yaguang Zhang; Manman Zhu

    2016-01-01

    To solve the problem of transfection efficiency vs. cytotoxicity and tumor-targeting ability when polyethylenimine (PEI) was used as a nonviral gene delivery vector, new degradable PEI polymers were synthesized via cross-linking low-molecular-weight PEI with Pluronic P123 and then further coupled with a targeting peptide R4 (RGD) and a bifunctional R11 (RGD-NLS), which were termed as P123-PEI-R4 and P123-PEI-R11, respectively. Agarose gel electrophoresis showed that both P123-PEI-R4 and P123-...

  16. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors

    Zhang, Ting; Lee, Yuk Wai; Rui, Yun Feng; Cheng, Tin Yan; Jiang, Xiao Hua; Li, Gang

    2013-01-01

    Introduction Mesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors. Methods Bone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-cul...

  17. Oncolytic Adenoviruses in Cancer Treatment

    Ramon Alemany

    2014-02-01

    Full Text Available The therapeutic use of viruses against cancer has been revived during the last two decades. Oncolytic viruses replicate and spread inside tumors, amplifying their cytotoxicity and simultaneously reversing the tumor immune suppression. Among different viruses, recombinant adenoviruses designed to replicate selectively in tumor cells have been clinically tested by intratumoral or systemic administration. Limited efficacy has been associated to poor tumor targeting, intratumoral spread, and virocentric immune responses. A deeper understanding of these three barriers will be required to design more effective oncolytic adenoviruses that, alone or combined with chemotherapy or immunotherapy, may become tools for oncologists.

  18. A novel Indium-111-labeled gonadotropin-releasing hormone peptide for human prostate cancer imaging

    Guo, Haixun; Gallazzi, Fabio; Sklar, Larry A.; Miao, Yubin

    2011-01-01

    The purpose of this study was to evaluate the tumor targeting and imaging properties of a novel 111In-labeled gonadotropin-releasing hormone (GnRH) peptide {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-Ahx-(d-Lys6-GnRH1)} for human prostate cancer. The biodistribution and tumor imaging properties of 111In-DOTA-Ahx-(d-Lys6-GnRH1) were determined in DU145 human prostate cancer-xenografted nude mice. 111In-DOTA-Ahx-(d-Lys6-GnRH1) exhibited rapid tumor uptake (1.27 ± 0.40 %ID/g...

  19. Multiscale Modeling of Virus Structure, Assembly, and Dynamics

    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.

  20. Biodistribution and Dosimetry of 177Lu-tetulomab, a New Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma

    Repetto-Llamazares, Ada H. V.; Larsen, Roy H.; Mollatt, Camilla; Lassmann, Michael; Dahle, Jostein

    2013-01-01

    The biodistribution of the anti-CD37 radioimmunoconjugate 177Lu-tetraxetan-tetulomab (177Lu-DOTA-HH1) was evaluated. Biodistribution of 177Lu-tetraxetan-tetulomab was compared with 177Lu-tetraxetan-rituximab and free 177Lu in nude mice implanted with Daudi lymphoma xenografts. The data showed that 177Lu-tetulomab had a relevant stability and tumor targeting properties in the human lymphoma model. The half-life of 177Lu allowed significant tumor to normal tissue ratios to be obtained indicatin...

  1. Nano-oncologicals new targeting and delivery approaches

    Alonso, Maria Jose

    2014-01-01

    This authoritative volume focuses on emerging technologies in cancer nano medicine, characterized by their multi-functionality and potential to address simultaneously diverse issues of clinical relevance in the treatment of cancer. The book consists of sixteen chapters divided into six sections: 1) Biological Barriers in Cancer; 2) Tumor Targeting; 3) Targeting the Immune System; 4) Gene Therapy; 5) Nano theranostics and 6) Translational Aspects of Nano-Oncologicals. The volume starts with an introduction describing the biological barriers associated with cancer therapy and highlighting ways

  2. Near-Infrared Imaging of Adoptive Immune Cell Therapy in Breast Cancer Model Using Cell Membrane Labeling

    Youniss, Fatma M.; Gobalakrishnan Sundaresan; Graham, Laura J.; Li Wang; Berry, Collin R.; Dewkar, Gajanan K.; Purnima Jose; Bear, Harry D; Jamal Zweit

    2014-01-01

    The overall objective of this study is to non-invasively image and assess tumor targeting and retention of directly labeled T-lymphocytes following their adoptive transfer in mice. T-lymphocytes obtained from draining lymph nodes of 4T1 (murine breast cancer cell) sensitized BALB/C mice were activated in-vitro with Bryostatin/Ionomycin for 18 hours, and were grown in the presence of Interleukin-2 for 6 days. T-lymphocytes were then directly labeled with 1,1-dioctadecyltetramethyl indotricarbo...

  3. SURVIVIN AND TUMOR

    宋文哲; 宋燕; 叶剑桥; 邱东涛

    2003-01-01

    As a new member of IAP (inhibitors of apoptosis protein) family, survivin has potent anti-apoptotic activities, and involves in the mitosis and angiogenesis. Researches have demonstrated that surviving is a tumor-specific anti-apoptotic factor, expressed in fetal tissues, and common human cancers, while not in normal, terminally differentiated adult tissues. The overexpression of survivin in tumor tissues is correlated with poor prognosis of the patients. Survivin can be used as a prognostic factor and a new target in tumor targeting therapy.

  4. From Diagnosis to Treatment: Clinical Applications of Nanotechnology in Thoracic Surgery.

    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. PMID:27112260

  5. Immunotherapy with GD2 specific monoclonal antibodies

    Targeted immunotherapy focuses anti-tumor activity of antibodies and effector cells, which are actively developed by the host or adoptively transferred, onto tumor cells and into tumor sites. Such tumor selective therapy can be more specific and efficient. The value of such an approach is evident in the classical interaction of antibodies. This paper reports that the ganglioside GD2 is an ideal antigen for specific tumor targeting because of its relative lack of heterogeneity among human neuroblastoma, its high density on tumor cells, its lack of antigen modulation upon binding to antibody, and its restricted distribution in normal tissues

  6. Preclinical evaluation of (111)In-DTPA-INCA-X anti-Ku70/Ku80 monoclonal antibody in prostate cancer.

    Evans, Susan; Vilhelmsson Timmermand, Oskar; Welinder, Charlotte; Borrebaeck, Carl AK; Strand, Sven-Erik; Tran, Thuy; Jansson, Bo; Bjartell, Anders

    2014-01-01

    The aim of this investigation was to assess the Ku70/Ku80 complex as a potential target for antibody imaging of prostate cancer. We evaluated the in vivo and ex vivo tumor targeting and biodistribution of the (111)In-labeled human internalizing antibody, INCA-X ((111)In-DTPA-INCA-X antibody), in NMRI-nude mice bearing human PC-3, PC-3M-Lu2 or DU145 xenografts. DTPA-conjugated, non-labeled antibody was pre-administered at different time-points followed by a single intravenous injection of (111...

  7. Combination of Single-Photon Emission Computed Tomography and Magnetic Resonance Imaging to Track ¹¹¹In-Oxine-Labeled Human Mesenchymal Stem Cells in Neuroblastoma-Bearing Mice

    Cussó, Lorena; Mirones, Isabel; Peña-Zalbidea, Santiago; García-Vázquez, Verónica; García-Castro, Javier; Desco, Manuel

    2014-01-01

    Homing is an inherent, complex, multistep process performed by cells such as human bone marrow mesenchymal stem cells (hMSCs) to travel from a distant location to inflamed or damaged tissue and tumors. This ability of hMSCs has been exploited as a tumor-targeting strategy in cell-based cancer therapy. The purpose of this study was to investigate the applicability of ¹¹¹In-oxine for tracking hMSCs in vivo by combining single-photon emission computed tomography (SPECT) and magnetic resonance im...

  8. Development of chimeric gene promoters responsive to hypoxia and ionizing radiation

    The authors describe two systems that make use of gene-directed enzyme prodrug therapy, regulated by radiation or hypoxic-responsive promoters. The use of treatment-, condition- or tumor-specific promoters to control gene-directed enzyme prodrug therapy is one such method for targeting gene expression to the tumor. The development of such strategies that achieve tumor targeted expression of genes via selective promoters will enable improved specificity and targeting thereby addressing one of the major limitations of cancer gene therapy

  9. Aminopeptidase N/CD13 targeting fluorescent probes: synthesis and application to tumor cell imaging.

    Zhang, Zhouen; Harada, Hiroshi; Tanabe, Kazuhito; Hatta, Hiroshi; Hiraoka, Masahiro; Nishimoto, Sei-ichi

    2005-11-01

    A family of fluorescein-peptide conjugates (CNP1-3) for aminopeptidase N (APN/CD13) targeting fluorescent probes were designed and synthesized. Among the three conjugates, CNP1 bearing tumor-homing cyclic peptide CNGRC, could selectively label APN/CD13 over-expressing on the surface of tumor cells of HT-1080, as identified by means of fluorescent microscopic cell imaging. CNP1 was shown to be a promising fluorescent probe applicable to tumor-targeting molecular imaging. PMID:15885853

  10. Theranostics: Optical Imaging and Gene Therapy with Neuroblastoma-Targeting Polymeric Nanoparticles for Potential Theranostic Applications (Small 9/2016).

    Lee, Jangwook; Jeong, Eun Ju; Lee, Yeon Kyung; Kim, Kwangmeyung; Kwon, Ick Chan; Lee, Kuen Yong

    2016-03-01

    Ligand-modified, gene-loaded nanoparticles (NPs) are designed and prepared as a tumor-targeting theranostic agent by I. C. Kwon, K. Y. Lee, and co-workers. The nanoparticles offer neuroblastoma-specific in-vivo optical imaging, and adding a therapeutic gene cocktail into the NPs could play a critical role for gene-therapy-based on RNAi. On page 1201, dye-labeled NPs are modified with rabies virus glycoprotein peptide to enhance the receptor-mediated uptake by neuroblastoma, and an siRNA cocktail is loaded into the NPs, inducing RNA interference and significantly suppressing tumor growth in a mouse model. PMID:26928991

  11. Final Report: 8th International Symposium on Neutron Capture Therapy (NCT) for Cancer, May 15, 1998 - May 15, 1999

    The 8th International Symposium on Neutron Capture Therapy for Cancer (8th ISNCTC) was held in La Jolla, CA on Sept. 13-18, 1998. This biennial meeting of the International Society for Neutron Capture Therapy (ISNCT) was hosted by Society President M.F. Hawthorne (UCLA Dept. of Chemistry and Biochemistry). The Symposium brought together scientists (300 registrants from 21 countries) from diverse fields to report the latest developments in NCT. Topics of the 275 papers presented (30 plenary lectures, 81 oral presentations, and 164 posters) included the physics of neutron sources, chemistry of tumor-targeting agents, dosimetry, radiobiological studies, and clinical applications

  12. Preliminary study of the internal margin of the gross tumor volume in thoracic esophageal cancer

    Purpose. - 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). Methods. - 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. Results. - 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). Conclusions. - Because of respiratory and organ movements, the displacement of the tumor target volume was different in all directions. Therefore, we recommend that

  13. 111In-labeled KCCYSL peptide as an imaging probe for ErbB-2-expressing ovarian carcinomas

    Deutscher, Susan L.; Figueroa, Said D.; Kumar, Senthil R.

    2009-01-01

    Aberrant expression of ErbB-2, a member of the epidermal growth factor family of receptors, has been implicated in the formation of various malignancies including ovarian cancer. The objective of this study was to determine if the bacteriophage (phage) display-selected ErbB-2 targeting peptide, KCCYSL, once radiolabeled with 111In would serve as a tumor targeting and Single Photon Emission Computed Tomography (SPECT/CT) imaging agent in a mouse model of human ovarian carcinoma expressing ErbB...

  14. Layered Double Hydroxide Modified by PEGylated Hyaluronic Acid as a Hybrid Nanocarrier for Targeted Drug Delivery

    董岸杰; 李雪; 王伟伟; 韩尚聪; 刘鉴锋; 刘金剑; 赵军强; 许舒欣; 邓联东

    2016-01-01

    In recent years, organic-inorganic hybrid nanocarriers are explored for effective drug delivery and pref-erable disease treatments. In this study, using 5-fluorouracil(5-FU)as electronegative model drug, a new type of organic-inorganic hybrid drug delivery system(LDH/HA-PEG/5-FU)was conceived and manufactured by the ad-sorption of PEGylated hyaluronic acid(HA-PEG)on the surface of layered double hydroxide(LDH, prepared via hydrothermal method)and the intercalation of 5-FU in the interlamination of LDH via ion exchange strategy. The drug loading amount of LDH/HA-PEG/5-FU achieved as high as 34.2%. LDH, LDH/5-FU and LDH/HA-PEG/5-FU were characterized by FT-IR, XRD, TGA, laser particle size analyzer and SEM. With the benefit of pH-degradable feature of LDH and enzyme-degradable feature of HA, LDH/HA-PEG/5-FU showed pH-degradable and enzyme-degradable capacity inin vitro drug release. Moreover, the drug carrier LDH/HA-PEG contained biocom-patible PEG and tumor-targeted HA, resulting in lower cytotoxicity and better endocytosis compared with LDHin vitro. It was suggested that the organic-inorganic hybrid drug delivery system, which was endowed with the proper-ties of controlled release, low toxicity and tumor-targeting delivery for ameliorative cancer therapy, was advisable and might be applied further to fulfill other treatments.

  15. The application of hyaluronic acid-derivatized carbon nanotubes in hematoporphyrin monomethyl ether-based photodynamic therapy for in vivo and in vitro cancer treatment

    Shi J

    2013-07-01

    Full Text Available Jinjin Shi,* Rourou Ma,* Lei Wang, Jing Zhang, Ruiyuan Liu, Lulu Li, Yan Liu, Lin Hou, Xiaoyuan Yu, Jun Gao, Zhenzhong Zhang School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, People's Republic of China*These authors contributed equally to this workAbstract: Carbon nanotubes (CNTs have shown great potential in both photothermal therapy and drug delivery. In this study, a CNT derivative, hyaluronic acid-derivatized CNTs (HA-CNTs with high aqueous solubility, neutral pH, and tumor-targeting activity, were synthesized and characterized, and then a new photodynamic therapy agent, hematoporphyrin monomethyl ether (HMME, was adsorbed onto the functionalized CNTs to develop HMME-HA-CNTs. Tumor growth inhibition was investigated both in vivo and in vitro by a combination of photothermal therapy and photodynamic therapy using HMME-HA-CNTs. The ability of HMME-HA-CNT nanoparticles to combine local specific photodynamic therapy with external near-infrared photothermal therapy significantly improved the therapeutic efficacy of cancer treatment. Compared with photodynamic therapy or photothermal therapy alone, the combined treatment demonstrated a synergistic effect, resulting in higher therapeutic efficacy without obvious toxic effects to normal organs. Overall, it was demonstrated that HMME-HA-CNTs could be successfully applied to photodynamic therapy and photothermal therapy simultaneously in future tumor therapy.Keywords: photodynamic therapy, photothermal therapy, HA-derivatized carbon nanotubes, tumor targeting, synergistic effect, hematoporphyrin monomethyl ether

  16. Quantitative analysis of proton boron fusion therapy (PBFT) in various conditions

    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)

  17. Enhanced antitumor efficacy by d-glucosamine-functionalized and paclitaxel-loaded poly(ethylene glycol)-co-poly(trimethylene carbonate) polymer nanoparticles.

    Jiang, Xinyi; Xin, Hongliang; Gu, Jijin; Du, Fengyi; Feng, Chunlai; Xie, Yike; Fang, Xiaoling

    2014-05-01

    The poor selectivity of chemotherapeutics for cancer treatment may lead to dose-limiting side effects that compromise clinical outcomes. To solve the problem, surface-functionalized polymer nanoparticles are regarded as promising tumor-targeting delivery system. On the basis of glucose transporter (GLUT) overexpression on cancer cells, d-glucosamine-conjugated and paclitaxel-loaded poly(ethylene glycol)-co-poly(trimethylene carbonate) copolymer nanoparticles (DGlu-NP/PTX) were developed as potential tumor-targeting drug delivery system in this study. Because of the high affinity between d-glucosamine and GLUT, DGlu-NP/PTX could target to tumor tissue through GLUT-mediated endocytosis to improve the selectivity of PTX. DGlu-NP/PTX was prepared by emulsion/solvent evaporation technique and characterized in terms of morphology, size, and zeta potential. In vitro evaluation of two-dimensional cells and three-dimensional tumor spheroids revealed that DGlu-NP/PTX was more potent than those of plain nanoparticles (NP/PTX) and Taxol. In vivo multispectral fluorescent imaging indicated that DGlu-NP had higher specificity and efficiency on subcutaneous xenografts tumor of mouse. Furthermore, DGlu-NP/PTX showed the greatest tumor growth inhibitory effect on in vivo subcutaneous xenografts model with no evident toxicity. Therefore, these results demonstrated that DGlu-NP/PTX could be used as potential vehicle for cancer treatment. PMID:24619482

  18. Effect of introduction of chondroitin sulfate into polymer-peptide conjugate responding to intracellular signals

    Tomiyama, Tetsuro; Toita, Riki; Kang, Jeong-Hun; Koga, Haruka; Shiosaki, Shujiro; Mori, Takeshi; Niidome, Takuro; Katayama, Yoshiki

    2011-09-01

    We recently developed a novel tumor-targeted gene delivery system responding to hyperactivated intracellular signals. Polymeric carrier for gene delivery consists of hydrophilic neutral polymer as main chains and cationic peptide substrate for target enzyme as side chains, and was named polymer-peptide conjugate (PPC). Introduction of chondroitin sulfate (CS), which induces receptor-medicated endocytosis, into polymers mainly with a high cationic charge density such as polyethylenimine can increase tumor-targeted gene delivery. In the present study, we examined whether introduction of CS into PPC containing five cationic amino acids can increase gene expression in tumor cells. Size and zeta potential of plasmid DNA (pDNA)/PPC/CS complex were stability and gene regulation, compared with that of pDNA/PPC. Moreover, no difference in gene expression was identified between positive and negative polymer. These results were caused by fast disintegration of pDNA/PPC/CS complexes in the presence of serum. Thus, we suggest that introduction of negatively charged CS into polymers with a low charge density may lead to low stability and gene regulation of complexes.

  19. Gold Nanorods Conjugated with Doxorubicin and cRGD for Combined Anticancer Drug Delivery and PET Imaging

    Yuling Xiao, Hao Hong, Vyara Z. Matson, Alireza Javadi, Wenjin Xu, Yunan Yang, Yin Zhang, Jonathan W. Engle, Robert J. Nickles, Weibo Cai, Douglas A. Steeber, Shaoqin Gong

    2012-01-01

    Full Text Available A multifunctional gold nanorod (GNR-based nanoplatform for targeted anticancer drug delivery and positron emission tomography (PET imaging of tumors was developed and characterized. An anti-cancer drug (i.e., doxorubicin (DOX was covalently conjugated onto PEGylated (PEG: polyethylene glycol GNR nanocarriers via a hydrazone bond to achieve pH-sensitive controlled drug release. Tumor-targeting ligands (i.e., the cyclo(Arg-Gly-Asp-D-Phe-Cys peptides, cRGD and 64Cu-chelators (i.e., 1,4,7-triazacyclononane-N, N', N''-triacetic acid (NOTA were conjugated onto the distal ends of the PEG arms to achieve active tumor-targeting and PET imaging, respectively. Based on flow cytometry analysis, cRGD-conjugated nanocarriers (i.e., GNR-DOX-cRGD exhibited a higher cellular uptake and cytotoxicity than non-targeted ones (i.e., GNR-DOX in vitro. However, GNR-DOX-cRGD and GNR-DOX nanocarriers had similar in vivo biodistribution according to in vivo PET imaging and biodistribution studies. Due to the unique optical properties of GNRs, this multifunctional GNR-based nanoplatform can potentially be optimized for combined cancer therapies (chemotherapy and photothermal therapy and multimodality imaging (PET, optical, X-ray computed tomography (CT, etc..

  20. In Vivo Targeting and Imaging of Tumor Vasculature with Radiolabeled, Antibody-Conjugated Nano-Graphene

    Hong, Hao; Yang, Kai; Zhang, Yin; Engle, Jonathan W.; Feng, Liangzhu; Yang, Yunan; Nayak, Tapas R.; Goel, Shreya; Bean, Jero; Theuer, Charles P.; Barnhart, Todd E.; Liu, Zhuang; Cai, Weibo

    2012-01-01

    Herein we demonstrate that nano-graphene can be specifically directed to the tumor neovasculature in vivo through targeting of CD105 (i.e. endoglin), a vascular marker for tumor angiogenesis. The covalently functionalized nano-graphene oxide (GO) exhibited excellent stability and target specificity. Pharmacokinetics and tumor targeting efficacy of the GO conjugates were investigated with serial non-invasive positron emission tomography (PET) imaging and biodistribution studies, which were validated by in vitro, in vivo, and ex vivo experiments. The incorporation of an active targeting ligand (TRC105, a monoclonal antibody that binds to CD105) led to significantly improved tumor uptake of functionalized GO, which was specific for the neovasculature with little extravasation, warranting future investigation of these GO conjugates for cancer-targeted drug delivery and/or photothermal therapy to enhance therapeutic efficacy. Since poor extravasation is a major hurdle for nanomaterial-based tumor targeting in vivo, this study also establishes CD105 as a promising vascular target for future cancer nanomedicine. PMID:22339280

  1. In vivo targeting and imaging of tumor vasculature with radiolabeled, antibody-conjugated nanographene.

    Hong, Hao; Yang, Kai; Zhang, Yin; Engle, Jonathan W; Feng, Liangzhu; Yang, Yunan; Nayak, Tapas R; Goel, Shreya; Bean, Jero; Theuer, Charles P; Barnhart, Todd E; Liu, Zhuang; Cai, Weibo

    2012-03-27

    Herein we demonstrate that nanographene can be specifically directed to the tumor neovasculature in vivo through targeting of CD105 (i.e., endoglin), a vascular marker for tumor angiogenesis. The covalently functionalized nanographene oxide (GO) exhibited excellent stability and target specificity. Pharmacokinetics and tumor targeting efficacy of the GO conjugates were investigated with serial noninvasive positron emission tomography imaging and biodistribution studies, which were validated by in vitro, in vivo, and ex vivo experiments. The incorporation of an active targeting ligand (TRC105, a monoclonal antibody that binds to CD105) led to significantly improved tumor uptake of functionalized GO, which was specific for the neovasculature with little extravasation, warranting future investigation of these GO conjugates for cancer-targeted drug delivery and/or photothermal therapy to enhance therapeutic efficacy. Since poor extravasation is a major hurdle for nanomaterial-based tumor targeting in vivo, this study also establishes CD105 as a promising vascular target for future cancer nanomedicine. PMID:22339280

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

    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 < 0.05) inhibition of tumor growth and improved survival (p < 0.0001) in an orthotopic metastatic ovarian tumor model. These results provide evidence for the potential of MSC-based two-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. PMID:26946263

  3. Photo-acoustic imaging of blue nanoparticle targeted brain tumor for intra-operative glioma delineation

    Ray, Aniruddha; Wang, Xueding; Koo Lee, Yong-Eun; Hah, HoeJin; Kim, Gwangseong; Chen, Thomas; Orrienger, Daniel; Sagher, Oren; Kopelman, Raoul

    2011-07-01

    Distinguishing the tumor from the background neo-plastic tissue is challenging for cancer surgery such as surgical resection of glioma. Attempts have been made to use visible or fluorescent markers to delineate the tumors during surgery. However, the systemic injection of the dyes requires high dose, resulting in negative side effects. A novel method to delineate rat brain tumors intra-operatively, as well as post-operatively, using a highly sensitive photoacoustic imaging technique enhanced by tumor targeting blue nanoparticle as contrast agent is demonstrated. The nanoparticles are made of polyacrylamide (PAA) matrix with covalently linked Coomassie-Blue dye. They contain 7.0% dye and the average size is 80nm. Their surface was conjugated with F3 peptide for active tumor targeting. These nanoparticles are nontoxic, chemically inert and have long plasma circulation lifetime, making them suitable as nanodevices for imaging using photoacoustics. Experiments on phantoms and rat brains tumors ex-vivo demonstrate the high sensitivity of photoacoustic imaging in delineating the tumor, containing contrast agent at concentrations too low to be visualized by eye. The control tumors without nanoparticles did not show any enhanced signal. This study shows that photoacoustic imaging facilitated with the nanoparticle contrast agent could contribute to future surgical procedures for glioma.

  4. Hybrid-Actuating Macrophage-Based Microrobots for Active Cancer Therapy.

    Han, Jiwon; Zhen, Jin; Du Nguyen, Van; Go, Gwangjun; Choi, Youngjin; Ko, Seong Young; Park, Jong-Oh; Park, Sukho

    2016-01-01

    Using macrophage recruitment in tumors, we develop active, transportable, cancer theragnostic macrophage-based microrobots as vector to deliver therapeutic agents to tumor regions. The macrophage-based microrobots contain docetaxel (DTX)-loaded poly-lactic-co-glycolic-acid (PLGA) nanoparticles (NPs) for chemotherapy and Fe3O4 magnetic NPs (MNPs) for active targeting using an electromagnetic actuation (EMA) system. And, the macrophage-based microrobots are synthesized through the phagocytosis of the drug NPs and MNPs in the macrophages. The anticancer effects of the microrobots on tumor cell lines (CT-26 and 4T1) are evaluated in vitro by cytotoxic assay. In addition, the active tumor targeting by the EMA system and macrophage recruitment, and the chemotherapeutic effect of the microrobots are evaluated using three-dimensional (3D) tumor spheroids. The microrobots exhibited clear cytotoxicity toward tumor cells, with a low survivability rate (<50%). The 3D tumor spheroid assay showed that the microrobots demonstrated hybrid actuation through active tumor targeting by the EMA system and infiltration into the tumor spheroid by macrophage recruitment, resulting in tumor cell death caused by the delivered antitumor drug. Thus, the active, transportable, macrophage-based theragnostic microrobots can be considered to be biocompatible vectors for cancer therapy. PMID:27346486

  5. Nano/microparticles and ultrasound contrast agents

    Shu-Guang; Zheng; Hui-Xiong; Xu; Hang-Rong; Chen

    2013-01-01

    Microbubbles have been used for many years now in clinical practice as contrast agents in ultrasound imaging.Recently,their therapeutic applications have also attracted more attention.However,the short circulation time(minutes)and relatively large size(two to ten micrometers)of currently used commercial microbubbles do not allow effective extravasation into tumor tissue,preventing efficient tumor targeting.Fortunately,more multifunctional and theranostic nanoparticles with some special advantages over the traditional microbubbles have been widely investigated and explored for biomedical applications.The way to synthesize an ideal ultrasound contrast agent based on nanoparticles in order to achieve an expected effect on contrast imaging is a key technique.Currently a number of nanomaterials,including liposomes,polymers,micelles,dendrimers,emulsions,quantum dots,solid nanoparticles etc.,have already been applied to pre or clinical trials.Multifunctional and theranostic nanoparticles with some special advantages,such as the tumor-targeted(passive or active),multi-mode contrast agents(magnetic resonance imaging,ultrasonography or fluorescence),carrier or enhancer of drug delivery,and combined chemo or thermal therapy etc.,are rapidly gaining popularity and have shown a promising application in the field of cancer treatment.In this mini review,the trends and the advances of multifunctional and theranostic nanoparticles are briefly discussed.

  6. Core-shell nanocarriers with high paclitaxel loading for passive and active targeting

    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.

  7. Synthesis of dimeric cyclic RGD based near-infrared probe for in vivo tumor diagnosis

    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.

  8. A bispecific peptide based near-infrared probe for in vivo tumor diagnosis

    Ding, Li; Chen, Wei R.; Gu, Yueqing

    2013-02-01

    The epidermal growth factor receptor EGFR and HER2 are members of recepeter tyrosine kinase family. Overexpression of EGFR and HER2 has been observed in a variety of human tumors, making these receptors promising targets for tumor diagnosis. An affibody targeting HER2 and a nanobody targeting EGFR were reported before. In this Manuscript, we described an bispecific peptide combined with an affibody and a nanonbody through a linker―(G4S)3 . And the bispecific peptide was labeled with near-infrared (NIR) fluorochrome ICG-Der-02 for in vivo tumor EGFR and HER2 targeting. Afterwards, the EGFR and HER2 specificity of the fluorescent probe was tested in vitro for receptor binding assay and fluorescence microscopy and in vivo for subcutaneous MDA-MB-231 tumor targeting. The results indicated that the bispecific peptide had a high affinity to EGFR and HER2. Besides, in vitro and in vivo tumor targeting experiment indicated that the ICG-Der-02-( bispecific peptide) showed excellent tumor activity accumulation. Noninvasive NIR fluorescence imaging is able to detect tumor EGFR and HER2 expression based upon the highly potent bispecific peptide probe.

  9. Bovine milk-derived exosomes for drug delivery.

    Munagala, Radha; Aqil, Farrukh; Jeyabalan, Jeyaprakash; Gupta, Ramesh C

    2016-02-01

    Exosomes are biological nanovesicles that are involved in cell-cell communication via the functionally-active cargo (such as miRNA, mRNA, DNA and proteins). Because of their nanosize, exosomes are explored as nanodevices for the development of new therapeutic applications. However, bulk, safe and cost-effective production of exosomes is not available. Here, we show that bovine milk can serve as a scalable source of exosomes that can act as a carrier for chemotherapeutic/chemopreventive agents. Drug-loaded exosomes showed significantly higher efficacy compared to free drug in cell culture studies and against lung tumor xenografts in vivo. Moreover, tumor targeting ligands such as folate increased cancer-cell targeting of the exosomes resulting in enhanced tumor reduction. Milk exosomes exhibited cross-species tolerance with no adverse immune and inflammatory response. Thus, we show the versatility of milk exosomes with respect to the cargo it can carry and ability to achieve tumor targetability. This is the first report to identify a biocompatible and cost-effective means of exosomes to enhance oral bioavailability, improve efficacy and safety of drugs. PMID:26604130

  10. CT/FMT dual-model imaging of breast cancer based on peptide-lipid nanoparticles

    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.

  11. Photosensitizer-Conjugated Human Serum Albumin Nanoparticles for Effective Photodynamic Therapy

    Hayoung Jeong, MyungSook Huh, So Jin Lee, Heebeom Koo, Ick Chan Kwon, Seo Young Jeong, Kwangmeyung Kim

    2011-01-01

    Full Text Available Photodynamic therapy (PDT is an emerging theranostic modality for various cancers and diseases. The focus of this study was the development of tumor-targeting albumin nanoparticles containing photosensitizers for efficient PDT. To produce tumor-targeting albumin nanoparticles, the hydrophobic photosensitizer, chlorin e6 (Ce6, was chemically conjugated to human serum albumin (HSA. The conjugates formed self-assembled nanoparticle structures with an average diameter of 88 nm under aqueous conditions. As expected, the Ce6-conjugated HSA nanoparticles (Ce6-HSA-NPs were nontoxic in their native state, but upon illumination with the appropriate wavelength of light, they produced singlet oxygen and damaged target tumor cells in a cell culture system. Importantly, when the nanoparticles were injected through the tail vein into tumor-bearing HT-29 mice, Ce6-HSA-NPs compared with free Ce6 revealed enhanced tumor-specific biodistribution and successful therapeutic results following laser irradiation. These results suggest that highly tumor-specific albumin nanoparticles have the potential to serve not only as efficient therapeutic agents, but also as photodynamic imaging (PDI reagents in cancer treatment.

  12. Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution.

    Tzeng, Alice; Kwan, Byron H; Opel, Cary F; Navaratna, Tejas; Wittrup, K Dane

    2015-03-17

    Cytokine therapy can activate potent, sustained antitumor responses, but collateral toxicity often limits dosages. Although antibody-cytokine fusions (immunocytokines) have been designed with the intent to localize cytokine activity, systemic dose-limiting side effects are not fully ameliorated by attempted tumor targeting. Using the s.c. B16F10 melanoma model, we found that a nontoxic dose of IL-2 immunocytokine synergized with tumor-specific antibody to significantly enhance therapeutic outcomes compared with immunocytokine monotherapy, concomitant with increased tumor saturation and intratumoral cytokine responses. Examination of cell subset biodistribution showed that the immunocytokine associated mainly with IL-2R-expressing innate immune cells, with more bound immunocytokine present in systemic organs than the tumor microenvironment. More surprisingly, immunocytokine antigen specificity and Fcγ receptor interactions did not seem necessary for therapeutic efficacy or biodistribution patterns because immunocytokines with irrelevant specificity and/or inactive mutant Fc domains behaved similarly to tumor-specific immunocytokine. IL-2-IL-2R interactions, rather than antibody-antigen targeting, dictated immunocytokine localization; however, the lack of tumor targeting did not preclude successful antibody combination therapy. Mathematical modeling revealed immunocytokine size as another driver of antigen targeting efficiency. This work presents a safe, straightforward strategy for augmenting immunocytokine efficacy by supplementary antibody dosing and explores underappreciated factors that can subvert efforts to purposefully alter cytokine biodistribution. PMID:25733854

  13. Synthesis and characterization of near IR fluorescent albumin nanoparticles for optical detection of colon cancer

    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.

  14. Design criteria for a high energy Compton Camera and possible application to targeted cancer therapy

    The proposed research focuses on the design criteria for a Compton Camera with high spatial resolution and sensitivity, operating at high gamma energies and its possible application for molecular imaging. This application is mainly on the detection and visualization of the pharmacokinetics of tumor targeting substances specific for particular cancer sites. Expected high resolution (< 0.5 mm) permits monitoring the pharmacokinetics of labeled gene constructs in vivo in small animals with a human tumor xenograft which is one of the first steps in evaluating the potential utility of a candidate gene. The additional benefit of high sensitivity detection will be improved cancer treatment strategies in patients based on the use of specific molecules binding to cancer sites for early detection of tumors and identifying metastasis, monitoring drug delivery and radionuclide therapy for optimum cell killing at the tumor site. This new technology can provide high resolution, high sensitivity imaging of a wide range of gamma energies and will significantly extend the range of radiotracers that can be investigated and used clinically. The small and compact construction of the proposed camera system allows flexible application which will be particularly useful for monitoring residual tumor around the resection site during surgery. It is also envisaged as able to test the performance of new drug/gene-based therapies in vitro and in vivo for tumor targeting efficacy using automatic large scale screening methods

  15. Mitochondria and nuclei dual-targeted heterogeneous hydroxyapatite nanoparticles for enhancing therapeutic efficacy of doxorubicin.

    Xiong, Hui; Du, Shi; Ni, Jiang; Zhou, Jianping; Yao, Jing

    2016-07-01

    Dual-targeted nanoparticles have been increasingly used to realize greater anti-proliferation effect by attacking double key sites of tumor cells. In order to retain nuclei inhibition effect and enhance DOX-induced apoptosis by mitochondrial pathway simultaneously, hyaluronic acid (HA) modified hydroxyapatite (HAP) nanoparticles (HAP-HA), the functional calcium-based tumor targeting nanoparticles, have been developed. In this nanosystem, HA acts as an active tumor-targeting ligand to bind the CD44 receptors which are overexpressed on the surface of tumor cells while HAP can load and deliver DOX to both nuclei and mitochondria of tumor cells. In this study, DOX-loaded HAP-HA nanoparticles (DOX/HAP-HA) exhibited satisfactory drug loading efficiency which was up to 214.55 ± 51.05 μg mg(-1) and showed a uniform nano-scaled particle size. The mitochondrial and nuclei targetability of DOX/HAP-HA was confirmed by confocal laser scanning microscopy analyses. Besides, western blot assay demonstrated that DOX/HAP-HA could markedly enhance mitochondrial cytochrome C leakage and thereby activate apoptotic cascade associated with it. In addition, in vivo anti-tumor efficacy and toxicity evaluation of DOX/HAP-HA indicated that DOX/HAP-HA was more effective and less harmful compared to other groups. DOX/HAP-HA might be a new promising targeted delivery system for effective cancer therapy. PMID:27105438

  16. Design criteria for a high energy Compton Camera and possible application to targeted cancer therapy

    Conka Nurdan, T.; Nurdan, K.; Brill, A. B.; Walenta, A. H.

    2015-07-01

    The proposed research focuses on the design criteria for a Compton Camera with high spatial resolution and sensitivity, operating at high gamma energies and its possible application for molecular imaging. This application is mainly on the detection and visualization of the pharmacokinetics of tumor targeting substances specific for particular cancer sites. Expected high resolution (animals with a human tumor xenograft which is one of the first steps in evaluating the potential utility of a candidate gene. The additional benefit of high sensitivity detection will be improved cancer treatment strategies in patients based on the use of specific molecules binding to cancer sites for early detection of tumors and identifying metastasis, monitoring drug delivery and radionuclide therapy for optimum cell killing at the tumor site. This new technology can provide high resolution, high sensitivity imaging of a wide range of gamma energies and will significantly extend the range of radiotracers that can be investigated and used clinically. The small and compact construction of the proposed camera system allows flexible application which will be particularly useful for monitoring residual tumor around the resection site during surgery. It is also envisaged as able to test the performance of new drug/gene-based therapies in vitro and in vivo for tumor targeting efficacy using automatic large scale screening methods.

  17. Synthesis and characterization of near IR fluorescent albumin nanoparticles for optical detection of colon cancer

    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: ► Near IR human serum albumin nanoparticles were synthesized and characterized. ► Nanoparticles were shown to be physically and chemically stable and photostable. ► Tumor-targeting ligands were covalently conjugated to the nanoparticles. ► Specific colon cancer tumor detection was demonstrated in chicken-embryo and rat models.

  18. A kernel-based method for markerless tumor tracking in kV fluoroscopic images

    Markerless tracking of respiration-induced tumor motion in kilo-voltage (kV) fluoroscopic image sequence is still a challenging task in real time image-guided radiation therapy (IGRT). Most of existing markerless tracking methods are based on a template matching technique or its extensions that are frequently sensitive to non-rigid tumor deformation and involve expensive computation. This paper presents a kernel-based method that is capable of tracking tumor motion in kV fluoroscopic image sequence with robust performance and low computational cost. The proposed tracking system consists of the following three steps. To enhance the contrast of kV fluoroscopic image, we firstly utilize a histogram equalization to transform the intensities of original images to a wider dynamical intensity range. A tumor target in the first frame is then represented by using a histogram-based feature vector. Subsequently, the target tracking is then formulated by maximizing a Bhattacharyya coefficient that measures the similarity between the tumor target and its candidates in the subsequent frames. The numerical solution for maximizing the Bhattacharyya coefficient is performed by a mean-shift algorithm. The proposed method was evaluated by using four clinical kV fluoroscopic image sequences. For comparison, we also implement four conventional template matching-based methods and compare their performance with our proposed method in terms of the tracking accuracy and computational cost. Experimental results demonstrated that the proposed method is superior to conventional template matching-based methods. (paper)

  19. Quantitative analysis of proton boron fusion therapy (PBFT) in various conditions

    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)

  20. Influence of CT/MRI Fusion Image on Target Volume and 3-D Conformal Radiotherapy in Non-small Cell Lung Cancer with Brain Metastasis%CT/MRI诊断影像融合对非小细胞肺癌脑转移瘤靶区及三维适形治疗影响

    杨金山; 魏永兵; 侯超; 李静; 朱瑞霞

    2014-01-01

    目的:比较CT图像和CT/MRI融合图像来源的肺癌脑转移肿瘤靶区,评价CT/MRI融合靶区容积应用于三维适形放射治疗时,对治疗剂量的影响。方法:将20例非小细胞肺癌脑转移患者的增强CT和MRI扫描的图像传送至图像处理工作站,在CT和CT/MRI融合图像上分别勾画GTV和周围重要的器官。每个病例分别在CT图像和CT/MRI融合图像都做1个三维适形放射治疗计划。肿瘤的处方剂量为60 Gy,比较2个治疗计划中肿瘤靶区的95%容积(D95)受照平均剂量、周围正常组织的5%容积(D5)受照平均剂量。结果:CT/MRI融合图像上的肿瘤靶区平均比CT上的肿瘤靶区大21.32%。用CT上勾画的靶区有一部分肿瘤处于低剂量区,CT/MRI融合图像上的靶区D95剂量分布较好,但在周围重要器官的剂量分布较高。结论:CT/MRI融合图像有助于靶区的确定,在三维适形放射治疗计划上的肿瘤靶区剂量分布足够,能提高靶区勾画的准确性,更利于精确放疗的实施。%Objective:To compare the CT images and CT/MRI images fusion sources of lung cancer with brain metastasis tumor target,and to evaluae the effects of dose for treatment on target volume CT/MRI fusion for three-dimensional conformal radiotherapy. Method:The enhancement CT and MRI scan image of 20 patients with brain metastases from non-small cell lung cancer was transfer to image processing workstation,GTV and surrounding vital organs on CT and CT/MRI images fusion was delineated respectively. A three-dimensional conformal radiotherapy plan was done in CT images and CT/MRI fusion images of ach case. Tumor prescription dose was 60 Gy. Compared the average dose of the 95%volume(D95)tumor target,the average dose of the 5%of the normal tissue around of the two treatment plans. Result:The tumor targets of the CT/MRI images fusion was greater than those of the CT tumor targets on average 21.32%. A part of the tumor was

  1. Bufalin-loaded mPEG-PLGA-PLL-cRGD nanoparticles: preparation, cellular uptake, tissue distribution, and anticancer activity

    Duan YR

    2012-07-01

    Full Text Available Peihao Yin,1,* Yan Wang,1,* YanYan Qiu,1 LiLi Hou,1 Xuan Liu,1 Jianmin Qin,1 Yourong Duan,2 Peifeng Liu,2 Ming Qiu,3 Qi Li11Department of Clinical Oncology, Putuo Hospital and Interventional Cancer Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; 2Shanghai Cancer Institute, Jiaotong University, Shanghai, China; 3Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China *These authors contributed equally to this workBackground: Recent studies have shown that bufalin has a good antitumor effect but has high toxicity, poor water solubility, a short half-life, a narrow therapeutic window, and a toxic dose that is close to the therapeutic dose, which all limit its clinical application. This study aimed to determine the targeting efficacy of nanoparticles (NPs made of methoxy polyethylene glycol (mPEG, polylactic-co-glycolic acid (PLGA, poly-L-lysine (PLL, and cyclic arginine-glycine-aspartic acid (cRGD loaded with bufalin, ie, bufalin-loaded mPEG-PLGA-PLL-cRGD nanoparticles (BNPs, in SW620 colon cancer-bearing mice.Methods: BNPs showed uniform size. The size, shape, zeta potential, drug loading, encapsulation efficiency, and release of these nanoparticles were studied in vitro. The tumor targeting, cellular uptake, and growth-inhibitory effect of BNPs in vivo were tested.Results: BNPs were of uniform size with an average particle size of 164 ± 84 nm and zeta potential of 2.77 mV. The encapsulation efficiency was 81.7% ± 0.89%, and the drug load was 3.92% ± 0.16%. The results of in vitro cytotoxicity studies showed that although the blank NPs were nontoxic, they enhanced the cytotoxicity of bufalin in BNPs. Drug release experiments showed that the release of the drug was prolonged and sustained. The results of confocal laser scanning microscopy indicated that BNPs could effectively bind to human umbilical vein endothelial cells. In the SW620

  2. Future prospects for SPECT imaging using the radiolanthanide terbium-155 — production and preclinical evaluation in tumor-bearing mice

    Introduction: We assessed the suitability of the radiolanthanide 155Tb (t1/2 = 5.32 days, Eγ = 87 keV (32%), 105 keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging. Methods: 155Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (∼ 1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. 155Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules – a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) – were radiolabeled with 155Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner. Results: The total yield of the two-step separation process of 155Tb was 86%. 155Tb was obtained in a physiological L-lactate solution suitable for direct labeling processes. The 155Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (> 95%). 155Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of 155Tb-DOTATATE and 155Tb-MD, respectively. The relatively long physical half-life of 155Tb matched in particular the biological half-lives of 155Tb-cm09 and 155Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration. Conclusions: The radiolanthanide 155Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β--emitting radiolanthanides 177Lu, 161Tb, 166Ho, and the pseudo-radiolanthanide 90Y

  3. Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic anhydrase I, II and IX inhibitory activity and cytotoxic effects against breast cancer cell lines.

    Abdel Gawad, Nagwa M; Amin, Noha H; Elsaadi, Mohammed T; Mohamed, Fatma M M; Angeli, Andrea; De Luca, Viviana; Capasso, Clemente; Supuran, Claudiu T

    2016-07-01

    A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with KIs in the range of 0.84-702nM against hCA I, of 0.41-288nM against hCA II and of 5.6-29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibition of growth efficacy against breast cancer MCF-7 cell lines. PMID:27234893

  4. Application of hyaluronic acid in the novel drug delivery system for cancer therapy%透明质酸在肿瘤治疗药物新型给药系统中的应用

    邱丽筠; 黄丽丽; 俞淑文

    2014-01-01

    Due to the good physical and chemical properties and tumor targeting ability, hyaluronic acid (HA) has been used as drug carriers or targeting ligand in the novel drug delivery system for cancer therapy, and become the new hot point in the field of cancer therapy. This review mainly introduced the application of HA in the novel drug delivery system.%透明质酸(hyaluronic acid, HA)因其良好的理化性质和肿瘤靶向性,已作为药物载体或者靶向因子应用于肿瘤治疗的新型给药系统中,并成为肿瘤治疗研究的热点。本文主要对HA在新型给药系统的应用进行介绍。

  5. Chimeric antigen receptor engineering: a right step in the evolution of adoptive cellular immunotherapy.

    Figueroa, Jose A; Reidy, Adair; Mirandola, Leonardo; Trotter, Kayley; Suvorava, Natallia; Figueroa, Alejandro; Konala, Venu; Aulakh, Amardeep; Littlefield, Lauren; Grizzi, Fabio; Rahman, Rakhshanda Layeequr; Jenkins, Marjorie R; Musgrove, Breeanna; Radhi, Saba; D'Cunha, Nicholas; D'Cunha, Luke N; Hermonat, Paul L; Cobos, Everardo; Chiriva-Internati, Maurizio

    2015-03-01

    Cancer immunotherapy comprises different therapeutic strategies that exploit the use of distinct components of the immune system, with the common goal of specifically targeting and eradicating neoplastic cells. These varied approaches include the use of specific monoclonal antibodies, checkpoint inhibitors, cytokines, therapeutic cancer vaccines and cellular anticancer strategies such as activated dendritic cell (DC) vaccines, tumor-infiltrating lymphocytes (TILs) and, more recently, genetically engineered T cells. Each one of these approaches has demonstrated promise, but their generalized success has been hindered by the paucity of specific tumor targets resulting in suboptimal tumor responses and unpredictable toxicities. This review will concentrate on recent advances on the use of engineered T cells for adoptive cellular immunotherapy (ACI) in cancer. PMID:25901860

  6. Radioembolisation and portal vein embolization before resection of large hepatocellular carcinoma.

    Bouazza, Fikri; Poncelet, Arthur; Garcia, Camilo Alejandro; Delatte, Philippe; Engelhom, Jean Luc; Gomez Galdon, Maria; Deleporte, Amélie; Hendlisz, Alain; Vanderlinden, Bruno; Flamen, Patrick; Donckier, Vincent

    2015-08-28

    Resectability of hepatocellular carcinoma in patients with chronic liver disease is dramatically limited by the need to preserve sufficient remnant liver in order to avoid postoperative liver insufficiency. Preoperative treatments aimed at downsizing the tumor and promoting hypertrophy of the future remnant liver may improve resectability and reduce operative morbidity. Here we report the case of a patient with a large hepatocellular carcinoma arising from chronic liver disease. Preoperative treatment, including tumor downsizing with transarterial radioembolization and induction of future remnant liver hypertrophy with right portal vein embolization, resulted in a 53% reduction in tumor volume and compensatory hypertrophy in the contralateral liver. The patient subsequently underwent extended right hepatectomy with no postoperative signs of liver decompensation. Pathological examination demonstrated a margin-free resection and major tumor response. This new therapeutic sequence, combining efficient tumor targeting and subsequent portal vein embolization, could improve the feasibility and safety of major liver resection for hepatocellular carcinoma in patients with liver injury. PMID:26327775

  7. Enzymatically triggered multifunctional delivery system based on hyaluronic acid micelles

    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.

  8. Targeting of VX2 Rabbit Liver Tumor by Selective Delivery of 3-Bromopyruvate: A Biodistribution and Survival Study

    Vali, Mustafa; Vossen, Josephina A.; Buijs, Manon; Engles, James M; Liapi, Eleni; Ventura, Veronica Prieto; Khwaja, Afsheen; Acha-Ngwodo, Obele; Shanmugasundaram, Ganapathy; Syed, Labiq; Wahl, Richard L.; Geschwind, Jean-Francois H

    2008-01-01

    The aim of this study was to determine the biodistribution and tumor targeting ability of 14C-labeled 3-bromopyruvate ([14C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [14C]3-BrPA on tumor and healthy tissue glucose metabolism by determining 18F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM [14C]3-BrPA i.a., 1.75 mM [14...

  9. Liposomal cancer therapy: exploiting tumor characteristics

    Kaasgaard, Thomas; Andresen, Thomas Lars

    2010-01-01

    Importance of the field: More than 10 million people worldwide are diagnosed with cancer each year, and the development of effective cancer treatments is consequently of great significance. Cancer therapy is unfortunately hampered by severe dose-limiting side effects that reduce the efficacy of...... cancer treatments. In the search for more effective cancer treatments, nanoparticle- based drug delivery systems, such as liposomes, that are capable of delivering their drug payload selectively to cancer cells are among the most promising approaches. Areas covered in this review: This review provides an...... overview of current strategies for improving the different stages of liposomal cancer therapy, which involve transporting drug-loaded liposomes through the bloodstream, increasing tumor accumulation, and improving drug release and cancer cell uptake after accumulation at the tumor target site. What the...

  10. Dual Functional Peptide-Driven Nanoparticles for Highly Efficient Glioma-Targeting and Drug Codelivery.

    Kuang, Yuyang; Jiang, Xutao; Zhang, Yu; Lu, Yifei; Ma, Haojun; Guo, Yubo; Zhang, Yujie; An, Sai; Li, Jianfeng; Liu, Lisha; Wu, Yinhao; Liang, Jianying; Jiang, Chen

    2016-05-01

    Compared with peripheral tumors, glioma is very difficult to treat, not only because it has general features of tumor but also because the therapy has been restricted by the brain-blood barrier (BBB). The two main features of tumor growth are angiogenesis and proliferation of tumor cells. RNA interference (RNAi) can downregulate VEGF overexpression to inhibit tumor neovascularization. Meanwhile, doxorubicin (DOX) has been used for cytotoxic chemotherapy to kill tumor cells. Thus, combining RNAi and chemotherapy has been regarded as a potential strategy for cancer treatment. However, the BBB limits the shVEGF-DOX codelivery system to direct into glioma. Here, a smart drug delivery system modified with a dual functional peptide was established, which could target to transferrin receptor (TfR) overexpressing on both the BBB and glioma. It showed that the dual-targeting delivery system had high tumor targeting efficiency in vitro and in vivo. PMID:27058780

  11. High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody-Drug Conjugates

    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...... toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and...... cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF: FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable...

  12. Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors.

    Benešová, Martina; Bauder-Wüst, Ulrike; Schäfer, Martin; Klika, Karel D; Mier, Walter; Haberkorn, Uwe; Kopka, Klaus; Eder, Matthias

    2016-03-10

    Since prostate-specific membrane antigen (PSMA) is up-regulated in nearly all stages of prostate cancer (PCa), PSMA can be considered as a viable diagnostic biomarker and treatment target in PCa. This project is focused on the development and evaluation of a series of compounds directed against PSMA. The modifications to the linker are designed to improve the binding potential and pharmacokinetics for theranostic application. In addition, the results help to further elucidate the structure-activity relationships (SAR) of the resulting PSMA inhibitors. Both in vitro and in vivo experiments of 18 synthesized PSMA inhibitor variants showed that systematic chemical modification of the linker has a significant impact on the tumor-targeting and pharmacokinetic properties. This approach can lead to an improved management of patients suffering from recurrent prostate cancer by the use of one radiolabeling precursor, which can be radiolabeled either with (68)Ga for diagnosis or with (177)Lu or (225)Ac for therapy. PMID:26878194

  13. Engineering CAR-T Cells: Design Concepts

    Srivastava, Shivani; Riddell, Stanley R.

    2016-01-01

    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 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. PMID:26169254

  14. Metastatic Group 3 Medulloblastoma in a Patient With Tuberous Sclerosis Complex: Case Description and Molecular Characterization of the Tumor.

    Moavero, Romina; Folgiero, Valentina; Carai, Andrea; Miele, Evelina; Ferretti, Elisabetta; Po, Agnese; Diomedi Camassei, Francesca; Lepri, Francesca Romana; Vigevano, Federico; Curatolo, Paolo; Valeriani, Massimiliano; Colafati, Giovanna S; Locatelli, Franco; Tornesello, Assunta; Mastronuzzi, Angela

    2016-04-01

    Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment-induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; H&E, haematoxilin and eosin; Gd, gadolinium. PMID:26626406

  15. The impact of nuclear science on medicine

    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.

  16. Red fluorescent zinc oxide nanoparticle: a novel platform for cancer targeting.

    Hong, Hao; Wang, Fei; Zhang, Yin; Graves, Stephen A; Eddine, Savo Bou Zein; Yang, Yunan; Theuer, Charles P; Nickles, Robert J; Wang, Xudong; Cai, Weibo

    2015-02-11

    Multifunctional zinc oxide (ZnO) nanoparticles (NPs) with well-integrated multimodality imaging capacities have generated increasing research interest in the past decade. However, limited progress has been made in developing ZnO NP-based multimodality tumor-imaging agents. Here we developed novel red fluorescent ZnO NPs and described the successful conjugation of 64Cu (t1/2=12.7 h) and TRC105, a chimeric monoclonal antibody against CD105, to these ZnO NPs via well-developed surface engineering procedures. The produced dual-modality ZnO NPs were readily applicable for positron emission tomography (PET) imaging and fluorescence imaging of the tumor vasculature. Their pharmacokinetics and tumor-targeting efficacy/specificity in mice bearing murine breast 4T1 tumor were thoroughly investigated. ZnO NPs with dual-modality imaging properties can serve as an attractive candidate for future cancer theranostics. PMID:25607242

  17. In vivo tumor vasculature targeted PET/NIRF imaging with TRC105(Fab)-conjugated, dual-labeled mesoporous silica nanoparticles.

    Chen, Feng; Nayak, Tapas R; Goel, Shreya; Valdovinos, Hector F; Hong, Hao; Theuer, Charles P; Barnhart, Todd E; Cai, Weibo

    2014-11-01

    Multifunctional mesoporous silica nanoparticles (MSN) with well-integrated multimodality imaging properties have generated increasing research interest in the past decade. However, limited progress has been made in developing MSN-based multimodality imaging agents to image tumors. We describe the successful conjugation of, copper-64 ((64)Cu, t1/2 = 12.7 h), 800CW (a near-infrared fluorescence [NIRF] dye), and TRC105 (a human/murine chimeric IgG1 monoclonal antibody) to the surface of MSN via well-developed surface engineering procedures, resulting in a dual-labeled MSN for in vivo targeted positron emission tomography (PET) imaging/NIRF imaging of the tumor vasculature. Pharmacokinetics and tumor targeting efficacy/specificity in 4T1 murine breast tumor-bearing mice were thoroughly investigated through various in vitro, in vivo, and ex vivo experiments. Dual-labeled MSN is an attractive candidate for future cancer theranostics. PMID:24937108

  18. In Vivo Tumor Vasculature Targeting of CuS@MSN Based Theranostic Nanomedicine.

    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. PMID:25843647

  19. Efficient Rejoining of DNA Double-Strand Breaks despite Increased Cell-Killing Effectiveness following Spread-Out Bragg Peak Carbon-Ion Irradiation.

    Averbeck, Nicole B; Topsch, Jana; Scholz, Michael; Kraft-Weyrather, Wilma; Durante, Marco; Taucher-Scholz, Gisela

    2016-01-01

    Radiotherapy of solid tumors with charged particles holds several advantages in comparison to photon therapy; among them conformal dose distribution in the tumor, improved sparing of tumor-surrounding healthy tissue, and an increased relative biological effectiveness (RBE) in the tumor target volume in the case of ions heavier than protons. A crucial factor of the biological effects is DNA damage, of which DNA double-strand breaks (DSBs) are the most deleterious. The reparability of these lesions determines the cell survival after irradiation and thus the RBE. Interestingly, using phosphorylated H2AX as a DSB marker, our data in human fibroblasts revealed that after therapy-relevant spread-out Bragg peak irradiation with carbon ions DSBs are very efficiently rejoined, despite an increased RBE for cell survival. This suggests that misrepair plays an important role in the increased RBE of heavy-ion radiation. Possible sources of erroneous repair will be discussed. PMID:26904506

  20. Efficient rejoining of DNA double-strand breaks despite increased cell-killing effectiveness following spread-out Bragg peak carbon-ion irradiation

    Nicole Bernadette Averbeck

    2016-02-01

    Full Text Available Radiotherapy of solid tumors with charged particles holds several advantages in comparison to photon therapy; among them conformal dose distribution in the tumor, improved sparing of tumor-surrounding healthy tissue, and an increased relative biological effectiveness (RBE in the tumor target-volume in the case of ions heavier than protons. A crucial factor of the biological effects is DNA damage, of which DNA double strand breaks (DSBs are the most deleterious. The reparability of these lesions determines the cell survival after irradiation and thus the RBE. Interestingly, using phosphorylated H2AX as a DSB marker, our data in human fibroblasts revealed that after therapy-relevant spread-out Bragg Peak irradiation with carbon ions DSBs are very efficiently rejoined, despite an increased RBE for cell survival. This suggests that misrepair plays an important role in the increased RBE of heavy-ion radiation. Possible sources of erroneous repair will be discussed.

  1. Dosimetric commissioning of a CBCT system for IGRT purposes

    During the last few years the use of tomographic imaging systems based on kilo voltage, cone shaped photon beams (kV-CBCT) for ensuring an accurate positioning of patients in radiotherapy treatments has expanded to low income departments, such as those existing in public health systems of low and middle income countries (LMIC). Although several dosimetric studies have been published so far, showing results of collateral dose in patients exposed to kV-CBCT studies for image guidance radiotherapy purposes (IGRT), their main objective is to demonstrate that these doses are significantly lower than the prescribed dose to the target volume and even the dose to organs and healthy tissues. In the actual study a methodology is proposed to reduce the CBCT dose during IGRT procedures for tumor targets located in the thorax region, where motion management is crucial. Criteria for dose optimization, based on image quality indexes and automated positioning accuracy, were implemented. (Author)

  2. Bispecific antibodies.

    Kontermann, Roland E; Brinkmann, Ulrich

    2015-07-01

    Bispecific antibodies (bsAbs) combine specificities of two antibodies and simultaneously address different antigens or epitopes. BsAbs with 'two-target' functionality can interfere with multiple surface receptors or ligands associated, for example with cancer, proliferation or inflammatory processes. BsAbs can also place targets into close proximity, either to support protein complex formation on one cell, or to trigger contacts between cells. Examples of 'forced-connection' functionalities are bsAbs that support protein complexation in the clotting cascade, or tumor-targeted immune cell recruiters and/or activators. Following years of research and development (R&D), the first bsAb was approved in 2009. Another bsAb entered the market in December 2014 and several more are in clinical trials. Here, we describe the potentials of bsAbs to become the next wave of antibody-based therapies, focusing on molecules in clinical development. PMID:25728220

  3. Hyaluronic acid grafted PLGA copolymer nanoparticles enhance the targeted delivery of Bromelain in Ehrlich's Ascites Carcinoma.

    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. PMID:27287553

  4. Differentiating Between Cancer and Inflammation: A Metabolic-Based Method for Functional Computed Tomography Imaging.

    Motiei, Menachem; Dreifuss, Tamar; Betzer, Oshra; Panet, Hana; Popovtzer, Aron; Santana, Jordan; Abourbeh, Galith; Mishani, Eyal; Popovtzer, Rachela

    2016-03-22

    One of the main limitations of the highly used cancer imaging technique, PET-CT, is its inability to distinguish between cancerous lesions and post treatment inflammatory conditions. The reason for this lack of specificity is that [(18)F]FDG-PET is based on increased glucose metabolic activity, which characterizes both cancerous tissues and inflammatory cells. To overcome this limitation, we developed a nanoparticle-based approach, utilizing glucose-functionalized gold nanoparticles (GF-GNPs) as a metabolically targeted CT contrast agent. Our approach demonstrates specific tumor targeting and has successfully distinguished between cancer and inflammatory processes in a combined tumor-inflammation mouse model, due to dissimilarities in angiogenesis occurring under different pathologic conditions. This study provides a set of capabilities in cancer detection, staging and follow-up, and can be applicable to a wide range of cancers that exhibit high metabolic activity. PMID:26886076

  5. Ribosome-Inactivating Proteins: From Plant Defense to Tumor Attack

    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.

  6. The theoretical implications and experimental and clinical results of radiolabeled antiferritin

    Ferritin is produced in malignant and normal tissues. It acts both as an immunosuppressant and as an iron storage protein. As a tumor associated protein, it is related to virally induced tumors, and selective tumor targeting by radiolabeled antiferritin antibodies has led to its use in clinical trials. In patients with advanced Hodgkin's disease who have failed conventional therapy, 131I antiferritin produced partial remissions, while 90Y antiferritin led to complete remissions and a demonstrable dose-response relationship. Combining the variable low-dose radiation patterns produced by radiolabeled antibody therapy with chemotherapy in the treatment of hepatocellular cancer has led to enhanced tumor cytotoxicity and, in some cases, the conversion of non-resectable hepatoma to resectable. Further, the potential for clinical and laboratory investigation of radiolabeled antibody therapy is discussed in light of new findings. (orig.)

  7. Targeted Drug Delivery in Pancreatic Cancer

    Yu, Xianjun; Zhang, Yuqing; Chen, Changyi; Yao, Qizhi; Li, Min

    2009-01-01

    Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor and antibody has been a success in recent pre-clinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer, and provides important information on potential therapeutic targets for pancreatic cancer treatment. PMID:19853645

  8. Proton therapy for pancreatic cancer

    Romaine; C; Nichols; Soon; Huh; Zuofeng; Li; Michael; Rutenberg

    2015-01-01

    Radiotherapy is commonly offered to patients with pancreatic malignancies although its ultimate utility is compromised since the pancreas is surrounded by exquisitely radiosensitive normal tissues, such as the duodenum, stomach, jejunum, liver, and kidneys. Proton radiotherapy can be used to create dose distributions that conform to tumor targets with significant normal tissue sparing. Because of this, protons appear to represent a superior modality for radiotherapy delivery to patients with unresectable tumors and those receiving postoperative radiotherapy. A particularly exciting opportunity for protons also exists for patients with resectable and marginally resectable disease. In this paper, we review the current literature on proton therapy for pancreatic cancer and discuss scenarios wherein the improvement in the therapeutic index with protons may have the potential to change the management paradigm for this malignancy.

  9. Polyamine metabolism-based dual functional gene delivery system to synergistically inhibit the proliferation of cancer.

    Cui, Peng-Fei; Xing, Lei; Qiao, Jian-Bin; Zhang, Jia-Liang; He, Yu-Jing; Zhang, Mei; Lyu, Jin-Yuan; Luo, Cheng-Qiong; Jin, Liang; Jiang, Hu-Lin

    2016-06-15

    Polyamine content, which is associated with tumor growth, can be regulated by ornithine decarboxylase (ODC) and S-adenosyl methionine decarboxylase (SAMDC), two key enzymes in polyamine biosynthesis. Here we aim to develop a pH-responsive cationic poly(agmatine) based on a polyamine analogue-agmatine that can dually function as a gene delivery vector as well as an anticancer agent by inhibiting ODC after intracellular degradation. The core-shell nanoparticles, formed by poly(agmatine)/SAMDC siRNA complex as a core, were coated with bovine serum albumin for better in vivo circulation stability and tumor targeting. When the nanoparticles were taken up by tumor cells via endocytosis and degraded in endosome, the released agmatine and SAMDC siRNA can synergistically inhibit polyamines biosynthesis, inducing inhibition of tumor proliferation. Our study offered a potential way in tumor therapy based on polyamine metabolism. PMID:27102990

  10. Therapeutic Cancer Vaccines in Prostate Cancer: The Quest for Intermediate Markers of Response

    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

  11. PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status.

    Lütje, Susanne; Heskamp, Sandra; Cornelissen, Alexander S; Poeppel, Thorsten D; van den Broek, Sebastiaan A M W; Rosenbaum-Krumme, Sandra; Bockisch, Andreas; Gotthardt, Martin; Rijpkema, Mark; Boerman, Otto C

    2015-01-01

    Prostate cancer (PCa) is the most common malignancy in men worldwide, leading to substantial morbidity and mortality. At present, imaging of PCa has become increasingly important for staging, restaging, and treatment selection. Until recently, choline-based positron emission tomography/computed tomography (PET/CT) represented the state-of-the-art radionuclide imaging technique for these purposes. However, its application is limited to patients with high PSA levels and Gleason scores. Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of PCa, because it is upregulated in the majority of PCa. Moreover, PSMA can serve as a target for therapeutic applications. Currently, several small-molecule PSMA ligands with excellent in vivo tumor targeting characteristics are being investigated for their potential in theranostic applications in PCa. Here, a review of the recent developments in PSMA-based diagnostic imaging and therapy in patients with PCa with radiolabeled PSMA ligands is provided. PMID:26681984

  12. GTV and CTV in radiation therapy of tumours of the oral cavity; Volume tumoral macroscopique et volume-cible anatomoclinique en radiotherapie. Tumeur de la cavite buccale

    Bardet, E. [Centre Regional de Lutte Contre le Cancer Rene-Gauducheau, Service de Radiotherapie, 44 - Nantes (France); Piot, B.; Savary, V. [Centre Hospitalier Universitaire de Nantes, Service de Stomatologie, 44 - Nantes (France); Gayet, M. [Centre Hospitalier Universitaire de Nantes, Service de Radiologie, 44 - Nantes (France)

    2001-10-01

    Radiation therapy, either alone or combined with surgery is a cornerstone in the treatment of oral cavity tumors. Target volumes to be treated with external beam radiation must take under consideration the initial tumor location, providing information on satellites lymph nodes to be irradiated as well. Modern imaging, with emphasis on CT scan with injection, is now mandatory for a better analysis of initial lesions including both tumor location and invaded lymph nodes. Tumor volumes based on clinical examination and CT scan analysis might be divided in two groups. First, volumes susceptible to receive a prophylactic irradiation for an hypothetical microscopic spread (CTV) to be treated with a prophylactic dose; second, volumes including lesions visible clinically or on CT scan that should receive a higher radiation dose (GTV). Clinical tolerance will largely be depending upon radiation-induced mucositis, impairing food intake. Radiation techniques aiming at normal tissues preservation should be used, including devices allowing keeping an open mouth during radiation delivery. (authors)

  13. Mycoplasma pneumoniae induces cytotoxic activity in guinea pig bronchoalveolar cells

    Precultured guinea pig alveolar macrophages (AM) and freshly harvested alveolar cells (FHAC) activated by interaction with Mycoplasma pneumoniae were cytotoxic for xenogeneic 75selenomethionine-labeled tumor target cells. Phagocytosis of whole opsonized or nonopsonized M. pneumoniae cells was more effective in eliciting cytotoxicity than uptake of sonicated microorganisms. The addition of living mycoplasma cells to the assay system enhanced the cytotoxic effect considerably. Target cells were significantly more susceptible to the cytotoxic action of phagocytes if they were coated with mycoplasma antigen or cocultured together with M. pneumoniae. The activation of the phagocytes could be inhibited by 2-deoxy-D-glucose but not by antimicrobial substances suppressing mycoplasma protein synthesis. It was accompanied by 51Cr release without detectable signs of cell damage. The supernatants of activated cells were cytotoxic for approximately 24 h. Inhibition, release, and cytotoxic activity indicate the necessity of an intact metabolism of the effector cells and suggest a secretion of cytotoxic substances

  14. Clinical guidance on the perioperative use of targeted agents in solid tumor oncology.

    Mellor, James D; Cassumbhoy, Michelle; Jefford, Michael

    2011-06-01

    The use of targeted anti-cancer agents is increasing. It is common to utilize a multi-modal treatment approach towards solid tumors, often including surgical resection, and it has become apparent that some targeted agents can impair wound healing or cause an increased risk of perioperative complications. This article reviews targeted agents used in solid tumor oncology with an emphasis on clinically relevant details. Overall, the evidence of targeted agents causing surgical complications is limited. The greatest amount of evidence exists for bevacizumab causing perioperative complications, possibly due to its extended half-life. There are limited data for cetuximab, sorafenib and sunitinib and very little for other solid tumor targeted agents. Our findings suggest that there should be heightened pharmacovigilence around targeted agents with respect to perioperative complications and increased post-surgical support for patients to aid early detection of postoperative complications until definitive data become available. PMID:21585689

  15. Preparation of Polyion Complex Micelles Using Block Copolymers for SiRNA Delivery.

    Kim, Hyun Jin; Zheng, Meng; Miyata, Kanjiro; Kataoka, Kazunori

    2016-01-01

    Polyion complex (PIC) micelles can be prepared through the spontaneous assembly of cationic block copolymers with oppositely charged short interfering RNAs (SiRNAs). Their core-shell architectures offer a delivery platform for vulnerable SiRNA, improving their biological activities for medicinal applications such as tumor-targeted therapy. Here, we report a protocol for the preparation of SiRNA-loaded PIC micelles using a poly(ethylene glycol)-block-poly(aspartamide) derivative, providing the physicochemical criteria for well-defined micellar formulation. In addition, we describe protocols for a stability assay for SiRNA-loaded PIC micelles in the presence of serum using fluorescence correlation spectroscopy and a luciferase assay for cultured cancer cells stably expressing luciferase, thus providing the biological criteria for further medicinal applications. PMID:26472445

  16. 99mTc direct labeling of anti-CEA monoclonal antibodies: Quality control and preclinical studies

    The anti-carcinoembryonic B2C114 monoclonal antibody was radiolabeled with 99mTc by a direct method and quality control tested in vitro by instant thin layer chromatography, gel column scanning and cellulose acetate electrophoresis and assessed in vivo for radioimmunodetection on a murine spontaneous mammary carcinoma. The optimal results of percent 99mTc bound to protein were obtained at a dithiothreitol: antibody molar ratio ranging from 800:1 to 1000:1 and at a methylene diphosphonate: stannous fluoride weight ratio of 4.3:1. Although cysteine removed up to 18% of the label during the first 4 h, the stability of the tracer appeared to be excellent in human serum at 37 deg. C and when challenged with DTPA. 99mTc-labeled B2C114 demonstrated good and specific in vivo tumor targeting

  17. Design, Synthesis and Evaluation of Dual-Modality Glyco-Nanoparticles for Tumor Imaging

    Zhi Yang

    2013-05-01

    Full Text Available d-Glucosamine (DG was conjugated to a core-cross linked polymeric micelle (CCPM system equipped with both a near-infrared fluorophore (NIRF and a gamma emitter (111In. The resultant nano-scale tumor-targeting imaging tracer, 111In-DG-NIRF-CCPM, selectively accumulated in a human epithelial carcinoma A-431 xenograft model in mice. At 24 hrs post injection, the tumor uptake was 2.62 ± 0.80 % of the injected dose per gram of tissue (%ID/g. Tumors were clearly delineated in both single-photon emission computed tomography (SPECT and optical imaging. The results suggest that the prepared imaging tracer is a promising agent for tumor diagnosis.

  18. Co-delivery of doxorubicin and siRNA using octreotide-conjugated gold nanorods for targeted neuroendocrine cancer therapy

    Xiao, Yuling; Jaskula-Sztul, Renata; Javadi, Alireza; Xu, Wenjin; Eide, Jacob; Dammalapati, Ajitha; Kunnimalaiyaan, Muthusamy; Chen, Herbert; Gong, Shaoqin

    2012-10-01

    A multifunctional gold (Au) nanorod (NR)-based nanocarrier capable of co-delivering small interfering RNA (siRNA) against achaete-scute complex-like 1 (ASCL1) and an anticancer drug (doxorubicin (DOX)) specifically to neuroendocrine (NE) cancer cells was developed and characterized for combined chemotherapy and siRNA-mediated gene silencing. The Au NR was conjugated with (1) DOX, an anticancer drug, via a pH-labile hydrazone linkage to enable pH-controlled drug release, (2) polyarginine, a cationic polymer for complexing siRNA, and (3) octreotide (OCT), a tumor-targeting ligand, to specifically target NE cancer cells with overexpressed somatostatin receptors. The Au NR-based nanocarriers exhibited a uniform size distribution as well as pH-sensitive drug release. The OCT-conjugated Au NR-based nanocarriers (Au-DOX-OCT, targeted) exhibited a much higher cellular uptake in a human carcinoid cell line (BON cells) than non-targeted Au NR-based nanocarriers (Au-DOX) as measured by both flow cytometry and confocal laser scanning microscopy (CLSM). Moreover, Au-DOX-OCT-ASCL1 siRNA (Au-DOX-OCT complexed with ASCL1 siRNA) resulted in significantly higher gene silencing in NE cancer cells than Au-DOX-ASCL1 siRNA (non-targeted Au-DOX complexed with ASCL1 siRNA) as measured by an immunoblot analysis. Additionally, Au-DOX-OCT-ASCL1 siRNA was the most efficient nanocarrier at altering the NE phenotype of NE cancer cells and showed the strongest anti-proliferative effect. Thus, combined chemotherapy and RNA silencing using NE tumor-targeting Au NR-based nanocarriers could potentially enhance the therapeutic outcomes in treating NE cancers.A multifunctional gold (Au) nanorod (NR)-based nanocarrier capable of co-delivering small interfering RNA (siRNA) against achaete-scute complex-like 1 (ASCL1) and an anticancer drug (doxorubicin (DOX)) specifically to neuroendocrine (NE) cancer cells was developed and characterized for combined chemotherapy and siRNA-mediated gene silencing. The

  19. NK cell imaging by in vitro and in vivo labelling approaches.

    Galli, F; Histed, S; Aras, O

    2014-09-01

    Natural killer (NK) cells are a particular lymphocyte subset with a documented cytotoxic activity against cancer cells. Evidence of NK antitumoral effect led researchers to focus on the development of immunotherapies aimed at augmenting NK recruitment and infiltration into tumor and their anti-cancer functions. Studies in animal models proved that the right combination of drugs, cytokines, chemokines and other factors might be used to enhance or suppress tumor targeting by NK cells. Therefore, it would be necessary to have a tool to non-invasively monitor the efficacy of such novel therapies. Available imaging techniques comprise magnetic resonance, optical and nuclear medicine imaging with a pool of compounds that ranges from radiolabelled nanoparticles and radiopharmaceuticals to fluorescent probes. Each tracer and technique has its own pros and cons, but till now, no one emerged as superior among the others. PMID:25265248

  20. NK cell imaging by in vitro and in vivo labelling approaches

    Natural killer (NK) cells are a particular lymphocyte subset with a documented cytotoxic activity against cancer cells. Evidence of NK antitumoral effect led researchers to focus on the development of immunotherapies aimed at augmenting NK recruitment and infiltration into tumor and their anti-cancer functions. Studies in animal models proved that the right combination of drugs, cytokines, chemokines and other factors might be used to enhance or suppress tumor targeting by NK cells. Therefore, it would be necessary to have a tool to non-invasively monitor the efficacy of such novel therapies. Available imaging techniques comprise magnetic resonance, optical and nuclear medicine imaging with a pool of compounds that ranges from radiolabelled nanoparticles and radiopharmaceuticals to fluorescent probes. Each tracer and technique has its own pros and cons, but till now, no one emerged as superior among the others.

  1. Development of picture and voice gated intermittent irradiation system connected without linear accelerator for voluntary breath-hold synchronized with respiration

    In patients with lung cancer of the lower lobes and liver cancer, treatment volume including respiratory motion is an important therapeutic problem. We developed a voluntary breath-hold system using pictures and voice messages so as to reduce the excessive safety margin that covers respiratory motion. The system consists of two sets of monitor and speaker, and a computer and software for control without direct connection to a linear accelerator. When the patient repeatedly holds his or her breath in response to a picture and voice message, irradiation is manually performed and then proceeds intermittently. Although safety problems remain to be solved because of off-line, synchronized irradiation with our system is simple, inexpensive, and could be widely used. It also would be expected to reduce the tumor target volume around the diaphragm. (author)

  2. Preparation of 90Y-labeled different cyclic RGD peptides and evaluation in nude mice bearing human glioma xenografts

    90Y-DTPA-Bz-NH-SA-c(KRGDf) and 90Y-DTPA-Bz-NH-c(ERGDf) were prepared, and their in vitro and in vivo properties were compared. ITLC and HPLC show that the labeling yields of both compounds are more than 99% under the optimal conditions(pH=5.5, reac- ting at 80 degree C for 20 min), and they are stable in vitro. The biodistribution in nude mice bearing human glioma xenografts reveals no significant difference between these two radiolabeled com- pounds on uptake for all of tissues at the experimental time points; and pretty good tumor targeting and in vivo stability; and two radiolabeled compounds are mainly excreted through kid- neys, partly excreted through hepatobiliary system. The experimental data demonstrate that both of cyclic KRGDf and cyclic ERGDf are suitable for the further development of polymerconjugated RGD peptide drugs. (authors)

  3. mRNA Transfection to Improve NK Cell Homing to Tumors.

    Levy, Emily R; Carlsten, Mattias; Childs, Richard W

    2016-01-01

    The ability of natural killer (NK) cells to mediate antitumor effects following adoptive transfer is dependent on their capacity to traffic to the microenvironment where tumors reside. Recent studies have shown that cytokine-activated and ex vivo-expanded NK cells lack or express at low levels homing receptors required to achieve tissue-specific tumor targeting by cells administered intravenously. In this chapter, we describe a method to enhance NK cell homing toward specific chemoattractants expressed in secondary lymphoid tissues through genetic modification of NK cells using mRNA electroporation. The method described here is scalable, cGMP-compliant, and offers a strategy to bolster the efficacy of adoptive NK cell immunotherapy for the treatment of hematological malignancies in the clinic. PMID:27177670

  4. Boron Drug Delivery via Encapsulated Magnetic Nanocomposites: A New Approach for BNCT in Cancer Treatment

    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.

  5. Radioimmunodetection of cancer

    Intravenous administration of 150-300 μg of a radiolabelled, affinity-purified, goat IgG having 70% immunoreactivity against carcinoembryonic antigen to over 90 patients with a history of confirmed malignancy resulted in successful tumor imaging by external scintigraphy (radioimmunodetection) in about 90% of the primary and secondary tumor sites. In order to enhance tumor target radioactivity, computer-assisted scanning subtraction of non-target background radioactivity was accomplished. The immune scintigrams were negative in patients without demonstrable tumors, with tumors apparently devoid of carcinoembryonic antigen, or in cancer patients who received a radioactive normal goat IgG preparation. Circulating antigen levels up to 5,600 ng/ml did not hinder successful tumor imaging after injection of the [131 I]-labeled antibody. (Auth.)

  6. Expression and purification of recombinant ATF-mellitin, a new type fusion protein targeting ovarian cancer cells, in P. pastoris.

    Su, Manman; Chang, Weiqin; Zhang, Kun; Cui, Manhua; Wu, Shuying; Xu, Tianmin

    2016-02-01

    Melittin is well known to possess cytolytic activity with wide-spectrum lytic properties and its potential use as an agent to treat several types of cancer has been tested. Due to the non-specific toxicity, melittin can impair not only cancer cells but also normal tissue. Thus, tumor-targeted toxins may be helpful for developing novel anticancer therapeutics. The urokinase-type plasminogen activator (uPA) plays a central role in tissue remodelling events occurring in normal physiology and in pathophysiology, including cancer invasion and metastasis. Heartening findings showed that uPA receptor is predominantly expressed on many types of cancer. Therefore, the amino-terminal fragment (ATF) of uPA which was able to identify and bond with cancer cells was used as the cell-targeting domain to make up tumor-targeted toxin in this study. In the present study, pPICZαC-ATF-melittin eukaryotic expression vector was successfully constructed. After transformed into P. pastoris and induced by methanol, rATF-mellitin was detected by SDS-PAGE and western blot analysis. After induction with methanol, the expression level of rATF-mellitin was 312 mg/l in 80-l fermentor. rATF‑mellitin was purified to >95% purity using SP Sepharose ion exchange chromatography and source™ 30 RPC with 67.2% recovery. Cell proliferation assay showed that rATF-melittin inhibited growth of SKOV3 cells and had no cytotoxicity effect on normal cells. For the first time, we established a stable and effective rATF-mellitin P. pastoris expression system to obtain a high level of expression of secreted rATF-mellitin which was purified by a highly efficient purification procedure. PMID:26718643

  7. Brain tumor magnetic targeting and biodistribution of superparamagnetic iron oxide nanoparticles linked with 70-kDa heat shock protein study by nonlinear longitudinal response

    Shevtsov, Maxim A.; Nikolaev, Boris P.; Ryzhov, Vyacheslav A.; Yakovleva, Ludmila Y.; Dobrodumov, Anatolii V.; Marchenko, Yaroslav Y.; Margulis, Boris A.; Pitkin, Emil; Guzhova, Irina V.

    2015-08-01

    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-M2). 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 T2-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-M2 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.

  8. Generation and antitumor effects of an engineered and energized fusion protein VL-LDP-AE composed of single-domain antibody and lidamycin.

    Miao, QingFang; Shang, BoYang; Ouyang, ZhiGang; Liu, XiaoYun; Zhen, YongSu

    2007-08-01

    Type IV collagenase plays a pivotal role in invasion, metastasis and angiogenesis of tumor. Single domain antibodies are attractive as tumor-targeting vehicle because of their much smaller size compared with antibody molecules produced by conventional methods. Lidamycin (LDM) is a potent enediyne-containing antitumor antibiotic. In this study an engineered and energized fusion protein VL-LDP-AE composed of lidamycin and VL domain of mAb 3G11 directed against type IV collagenase was prepared using a novel two-step method. First a VL-LDP fusion protein was constructed by DNA recombination. Secondly VL-LDP-AE was obtained by molecular reconstitution. In MTT assay, VL-LDP-AE showed potent cytotoxicity to HT-1080 cells and KB cells with IC(50) values of 8.55 x 10(-12) and 1.70 x 10(-11) mol/L, respectively. VL-LDP-AE showed antiangiogenic activity in chick chrorioallantoic membrane (CAM) assay and tube formation assay. In in vivo experiments, VL-LDP-AE was proved to be more effective than free LDM against the growth of subcutaneously transplanted hepatoma 22 in mice. Drugs were given intravenously on day 3 and 10 after tumor transplantation. Compared in terms of maximal tolerated doses, VL-LDP-AE at 0.25 mg/kg suppressed the tumor growth by 89.5%, LDM at 0.05 mg/kg by 69.9%, and mitomycin at 1 mg/kg by 35%. Having a molecular weight of 25.2 kDa, VL-LDP-AE was much smaller than other reported antibody-based drugs. The results suggested that VL-LDP-AE would be a promising candidate for tumor targeting therapy. And the 2-step approach could serve as a new technology platform for making a series of highly potent engineered antibody-based drugs for a variety of cancers. PMID:17653664

  9. Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease

    Ray, Geoffrey L.; Baidoo, Kwamena E.; Keller, Lanea M. M.; Albert, Paul S.; Brechbiel, Martin W.; Milenic, Diane E.

    2011-01-01

    Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of 177Lu was investigated. The combination of a 6.7 d half-life, lower energy β−-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make 177Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-particle radiation. Radiolabeling trastuzumab-CHX-A″-DTPA with 177Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administeringescalating doses of 177Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered 177Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with 177Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease. PMID:22229017

  10. Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease

    Diane E. Milenic

    2011-12-01

    Full Text Available Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC vector, use of 177Lu was investigated. The combination of a 6.7 d half-life, lower energy β−-emissions (500 keV max; 130 keV ave, and an imagable γ-emission make 177Lu an attractive candidate for radioimmunotherapy (RIT regimens for treatment of larger tumor burdens not possible with α-particle radiation. Radiolabeling trastuzumab-CHX-A″-DTPA with 177Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h and 31.70 ± 16.20 (72 h, respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of 177Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered 177Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated group. In conclusion, trastuzumab radiolabeled with 177Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease.

  11. Advantage of highly immunoreactive monoclonal antibodies in radioimmunoscintigraphy for tumor detection, (2)

    There is theoretically a potential benefit in using a highly immunoreactive monoclonal antibody. The effect of immunoreactivity (IR) on the antibody biodistribution, however, has not yet been described in detail. Thus, this study was designed to investigate the effect of IR on the biodistribution in an animal model. The hydroxylapatite high performance liquid chromatography (HA-HPLC) system has been tested and confirmed to separate the F ab 96.5, an anti melanoma p97 antigen, into high and low IR fractions. 125I-F ab 96.5 preparations with a different IR were administered to groups of nude mice bearing FEM-XII human skin melanoma xenografts for biodistribution and imaging studies. The biodistribution data showed that the high IR antibody improved tumor targeting by increasing activity ratios of tumor to non tumor tissue; the mechanism for the increased tumor to non tumor ratios was increased tumor activity uptake and prolonged tumor activity retention with associated rapid clearance from the blood and non tumor sites. The imaging study visually supported the results obtained in the biodistribution study; the high IR antibody demonstrated better and earlier tumor delineation and the tumor to non tumor contrast continued to improve with time. In this model system, where the whole body clearance rate was the same for the high IR and low IR preparations, the overall antibody metabolism and excretion were not significantly dependent on IR. Therefore, the effect of IR is to alter the distribution of antibody between tumor and blood, with high IR having increased tumor activity and reduced blood activity (consequently reduced non tumor organ activity). This would also be beneficial for therapeutic use of radiolabeled antibodies, since high IR antibodies can minimize undesirable radiation exposure to normal organs. In conclusion, high IR antibodies are essential for optimal tumor targeting. (author)

  12. Optimizing the Delivery of Short-Lived Alpha Particle-Emitting Isotopes to Solid Tumors

    The underlying hypothesis of this project was that optimal alpha emitter-based radioimmunotherapy (RAIT) could be achieved by pairing the physical half-life of the radioisotope to the biological half-life of the targeting vehicle. The project had two specific aims. The first aim was to create and optimize the therapeutic efficacy of 211At-SAPS-C6.5 diabody conjugates. The second aim was to develop bispecific-targeting strategies that increase the specificity and efficacy of alpha-emitter-based RAIT. In the performance of the first aim, we created 211At-SAPS-C6.5 diabody conjugates that specifically targeted the HER2 tumor associated antigen. In evaluating these immunoconjugates we determined that they were capable of efficient tumor targeting and therapeutic efficacy of established human tumor xenografts growing in immunodeficient mice. We also determined that therapeutic doses were associated with late renal toxicity, likely due to the role of the kidneys in the systemic elimination o f these agents. We are currently performing more studies focused on better understanding the observed toxicity. In the second aim, we successfully generated bispecific single-chain Fv (bs-scFv) molecules that co-targeted HER2 and HER3 or HER2 and HER4. The in vitro kinetics and in vivo tumor-targeting properties of these molecules were evaluated. These studies revealed that the bs-scFv molecules selectively localized in vitro on tumor cells that expressed both antigens and were capable of effective tumor localization in in vivo studies

  13. Preparation and In Vitro Evaluation of Antitumor Activity of TGFαL3-SEB as a Ligand-Targeted Superantigen.

    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. PMID:25759426

  14. [131I]FIAU labeling of genetically transduced, tumor-reactive lymphocytes: cell-level dosimetry and dose-dependent toxicity

    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 [131I]-2'-fluoro-2'-deoxy-1-β-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 131I (even at tracer levels), the nucleus absorbed dose (Dn) and dose-dependent immune functionality were evaluated for NIT + T cells labeled ex vivo in [131I ]FIAU-containing medium. Based on in vitro kinetic studies of [131I ]FIAU uptake by NIT + T cells, Dn was calculated using an adaptation of the MIRD formalism and the recently published MIRD cellular S factors. Immune cytotoxicity of [131I ]FIAU-labeled cells was assayed against 51Cr-labeled target cells [B-lymphoblastoid cells (BLCLs) ] in a standard 4-h release assay. At median nuclear absorbed doses up to 830 cGy, a 51Cr-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.)

  15. Brain tumor magnetic targeting and biodistribution of superparamagnetic iron oxide nanoparticles linked with 70-kDa heat shock protein study by nonlinear longitudinal response

    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-M2). 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 T2-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-M2 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-M2 ensures high sensibility in detection of SPIONs in tissue. • SPION–Hsp70 conjugates effectively target the glioma

  16. Enhanced effect of photodynamic therapy in ovarian cancer using a nanoparticle drug delivery system.

    Li, Zhao; Sun, Liping; Lu, Zaijun; Su, Xuantao; Yang, Qifeng; Qu, Xun; Li, Li; Song, Kun; Kong, Beihua

    2015-09-01

    Nanoparticles are promising novel drug delivery carriers that allow tumor targeting and controlled drug release. In the present study, we prepared poly butyl-cyanoacrylate nanoparticles (PBCA-NP) entrapped with hypocrellin B (HB) to improve the effect of photodynamic therapy (PDT) in ovarian cancer. An ovarian cancer ascites model using Fischer 344 rats and PBCA-NP entrapped with HB (HB-PBCA-NP) were formed successfully. The pharmacodynamic characteristics and biodistribution of the HB-PBCA-NP system were evaluated by comparison with HB dimethyl sulfoxide (HB-DMSO) and testing at various time-points following intraperitoneal drug administration. HB-PBCA-NP-based PDT combined with cytoreductive surgery was then administrated to the tumor-bearing animals. Kaplan-Meier survival analysis was performed to assess the therapeutic effect of the nanoparticle system. The serum HB concentration peaked 4 h after drug administration in the nanoparticle system, and 1 h with HB-DMSO. The peak exposure time of tumor tissues was also extended (4 vs. 2 h), and PBCA-NP remained present for much longer than HB-DMSO. Although PDT combined with surgery prolonged the survival time significantly compared with surgery alone (84 days, Panimals that received either HB-PBCA-NP- or HB-DMSO-based PDT after cytoreductive surgery (99 vs. 95 days, P=0.293). PBCA-NP exhibited potential advantages in controlled drug release and tumor targeting, which was beneficial for HB-based PDT. PDT combined with surgery prolonged the survival time, suggesting that this might be an alternative treatment option for ovarian cancer. PMID:26165140

  17. The effect of internalizing human single chain antibody fragment on liposome targeting to epithelioid and sarcomatoid mesothelioma

    Iyer, Arun K.; Su, Yang; Feng, Jinjin; Lan, Xiaoli; Zhu, Xiaodong; Liu, Yue; Gao, Dongwei; Seo, Youngho; VanBrocklin, Henry F.; Broaddus, V. Courtney; Liu, Bin; He, Jiang

    2011-01-01

    Immunoliposomes (ILs) anchored with internalizing human antibodies capable of targeting all subtypes of mesothelioma can be useful for targeted imaging and therapy of this malignant disease. The objectives of this study were to evaluate both the in vitro and in vivo tumor targeted internalization of novel internalizing human single chain antibody (scFv) anchored ILs on both epithelioid (M28) and sarcomatoid (VAMT-1) subtypes of human mesothelioma. ILs were prepared by post-insertion of mesothelioma-targeting human scFv (M1) onto preformed liposomes and radiolabeled with 111In (111In-IL-M1), along with control non-targeted liposomes (111In-CL). Incubation of 111In-IL-M1 with M28, VAMT-1, and a control non-tumorigenic cell-line (BPH-1) at 37°C for 24 h revealed efficient binding and rapid internalization of ILs into both subtypes of tumor cells but not into the BPH-1 cells; internalization accounted for approximately 81-94% of total cell accumulation in mesothelioma cells compared to 37-55% in control cells. In tumor bearing mice intravenous (i.v.) injection of 111In-IL-M1 led to remarkable tumor accumulation: 4 % and 4.7% injected dose per gram (% ID/g) for M28 and VAMT-1 tumors, respectively, 48 h after injection. Furthermore, tumor uptake of 111In-IL-M1 in live xenograft animal models was verified by single photon emission computed tomography (SPECT/CT). In contrast, i.v. injection of 111In-CL in tumor-bearing mice revealed very low uptake in both subtypes of mesothelioma, 48 h after injection. In conclusion, M1 scFv-anchored ILs showed selective tumor targeting and rapid internalization into both epithelioid and sarcomatoid subtypes of human mesothelioma, demonstrating its potential as a promising vector for enhanced tumor drug targeting. PMID:21255833

  18. Folic acid-targeted disulfide-based cross-linking micelle for enhanced drug encapsulation stability and site-specific drug delivery against tumors.

    Zhang, Yumin; Zhou, Junhui; Yang, Cuihong; Wang, Weiwei; Chu, Liping; Huang, Fan; Liu, Qiang; Deng, Liandong; Kong, Deling; Liu, Jianfeng; Liu, Jinjian

    2016-01-01

    Although the shortcomings of small molecular antitumor drugs were efficiently improved by being entrapped into nanosized vehicles, premature drug release and insufficient tumor targeting demand innovative approaches that boost the stability and tumor responsiveness of drug-loaded nanocarriers. Here, we show the use of the core cross-linking method to generate a micelle with enhanced drug encapsulation ability and sensitivity of drug release in tumor. This kind of micelle could increase curcumin (Cur) delivery to HeLa cells in vitro and improve tumor accumulation in vivo. We designed and synthesized the core cross-linked micelle (CCM) with polyethylene glycol and folic acid-polyethylene glycol as the hydrophilic units, pyridyldisulfide as the cross-linkable and hydrophobic unit, and disulfide bond as the cross-linker. CCM showed spherical shape with a diameter of 91.2 nm by the characterization of dynamic light scattering and transmission electron microscope. Attributed to the core cross-linking, drug-loaded CCM displayed higher Nile Red or Cur-encapsulated stability and better sensitivity to glutathione than noncross-linked micelle (NCM). Cellular uptake and in vitro antitumor studies proved the enhanced endocytosis and better cytotoxicity of CCM-Cur against HeLa cells, which had a high level of glutathione. Meanwhile, the folate receptor-mediated drug delivery (FA-CCM-Cur) further enhanced the endocytosis and cytotoxicity. Ex vivo imaging studies showed that CCM-Cur and FA-CCM-Cur possessed higher tumor accumulation until 24 hours after injection. Concretely, FA-CCM-Cur exhibited the highest tumor accumulation with 1.7-fold of noncross-linked micelle Cur and 2.8-fold of free Cur. By combining cross-linking of the core with active tumor targeting of FA, we demonstrated a new and effective way to design nanocarriers for enhanced drug encapsulation, smart tumor responsiveness, and elevated tumor accumulation. PMID:27051287

  19. Inhibition of Histone Deacetylation and DNA Methylation Improves Gene Expression Mediated by the Adeno-Associated Virus/Phage in Cancer Cells

    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.

  20. Synthesis and properties of a new micellar polyphosphazene-platinum(II) conjugate drug.

    Avaji, Prakash G; Joo, Hye In; Park, Jung Hyun; Park, Kyung Su; Jun, Yong Joo; Lee, Hwa Jeong; Sohn, Youn Soo

    2014-11-01

    Aiming at tumor targeting delivery of oxaliplatin using polymer therapy, a new monomeric platinum(II) complex (dach)Pt[HEDM] (dach: trans-(±)-1,2-diaminocyclohexane; HEDM: 2-hydroxyethoxydiethylmalate) was designed to include the antitumor moiety (dach)Pt and HEDM as a linker to the polyphosphazene backbone. This monomeric Pt-complex could easily be grafted to the PEGylated polyphosphazene backbone to prepare a novel polyphosphazene-Pt conjugate, [NP(MPEG550)(dach)Pt(EM)]n [MPEG550: methoxy poly(ethylene glycol) with an average molecular weight of 550; EM: ethoxymalate]. This amphiphilic polyphosphazene-Pt conjugate was found to self-assemble into stable polymeric micelles of a mean diameter of 130nm, which is suitable for passive tumor targeting by enhanced permeability and retention (EPR) effect. Pharmacokinetic study of this polymer conjugate exhibited long blood circulation as expected and longer half-life (t1/2β=9.52h) compared with oxaliplatin (3.47h), and much larger AUC (area under the curve) value (25,831ng·h/mL) compared with oxaliplatin (1194ng·h/mL). Biodistribution study of the polymer conjugate has shown excellent tumor selectivity with the tumor to tissue ratio of 3.84 at 2h post injection and 11.7 at 24h post injection probably due to the EPR effect of the polymer conjugate while no tumor selectivity was observed for monomeric oxaliplatin. Furthermore, accumulation of this polymer conjugate in kidney was much lower compared with oxaliplatin. Also the nude mouse xenograft trial of the polymer conjugate has shown higher antitumor efficacy compared with oxaliplatin. PMID:25061690

  1. A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine

    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. 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. 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. Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate

    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.

  3. Dual targeting luminescent gold nanoclusters for tumor imaging and deep tissue therapy.

    Chen, Dan; Li, Bowen; Cai, Songhua; Wang, Peng; Peng, Shuwen; Sheng, Yuanzhi; He, Yuanyuan; Gu, Yueqing; Chen, Haiyan

    2016-09-01

    Dual targeting towards both extracellular and intracellular receptors specific to tumor is a significant approach for cancer diagnosis and therapy. In the present study, a novel nano-platform (AuNC-cRGD-Apt) with dual targeting function was initially established by conjugating gold nanocluster (AuNC) with cyclic RGD (cRGD) that is specific to αvβ3integrins over-expressed on the surface of tumor tissues and aptamer AS1411 (Apt) that is of high affinity to nucleolin over-expressed in the cytoplasm and nucleus of tumor cells. Then, AuNC-cRGD-Apt was further functionalized with near infrared (NIR) fluorescence dye (MPA), giving a NIR fluorescent dual-targeting probe AuNC-MPA-cRGD-Apt. AuNC-MPA-cRGD-Apt displays low cytotoxicity and favorable tumor-targeting capability at both in vitro and in vivo level, suggesting its clinical potential for tumor imaging. Additionally, Doxorubicin (DOX), a widely used clinical chemotherapeutic drug that kill cancer cells by intercalating DNA in cellular nucleus, was immobilized onto AuNC-cRGD-Apt forming a pro-drug, AuNC-DOX-cRGD-Apt. The enhanced tumor affinity, deep tumor penetration and improved anti-tumor activity of this pro-drug were demonstrated in different tumor cell lines, tumor spheroid and tumor-bearing mouse models. Results in this study suggest not only the prospect of non-toxic AuNC modified with two targeting ligands for tumor targeted imaging, but also confirm the promising future of dual targeting AuNC as a core for the design of prodrug in the field of cancer therapy. PMID:27236844

  4. Thiol antioxidant-functionalized CdSe/ZnS quantum dots: synthesis, characterization, cytotoxicity.

    Zheng, Hong; Mortensen, Luke J; DeLouise, Lisa A

    2013-03-01

    Nanotechnology is a growing industry with wide ranging applications in consumer product and technology development. In the biomedical field, nanoparticles are finding increasing use as imaging agents for biomolecular labeling and tumor targeting. The nanoparticle physiochemical properties must be tailored for the specific application. For example, nanoparticle chemical and physical stability in the biological milieu (no oxidation, aggregation, agglomeration or toxicity) are often required. Nanoparticles used for biomolecular fluorescent imaging should also have high quantum yield (QY). The aim of this paper is to examine the QY, stability, and cell toxicity of a series of positive, negative and neutral surface charge quantum dot (QD) nanoparticles. Simple protocols are described to prepare water soluble QDs by modifying the surface with thiol containing antioxidant ligands and polymers keeping the QD core/shell composition constant. The ligands used to produce negatively charged QDs include glutathione (GSH), N-acetyl-L-cysteine (NAC), dihydrolipoic acid (DHLA), tiopronin (TP), bucilliamine (BUC), and mercaptosuccinic acid (MSA). Ligands used to produce positively charged QDs include cysteamine (CYS) and polyethylenimine (PEI). Dithiothreitol (DTT) was used to produce neutral charged QDs. Commercially available nonaqueous octadecylamine (ODA) capped QDs served as the starting material. Our results suggest that QD uptake and cytotoxicity are both dependent on surface ligand coating composition. The negative charged GSH coated QDs show superior performance exhibiting low cytotoxicity, high stability, high QY and therefore are best suited for bioimaging applications. PEI coated QD also show superior performance exhibiting high QY and stability. However, they are considerably more cytotoxic due to their high positive charge which is an advantageous property that can be exploited for gene transfection and/or tumor targeting applications. The synthetic procedures

  5. Development of multifunctional nanoparticles for brain tumor diagnosis and therapy

    Veiseh, Omid

    Magnetic nanoparticles (MNPs) represent a class of non-invasive imaging agents developed for magnetic resonance (MR) imaging and drug delivery. MNPs have traditionally been developed for disease imaging via passive targeting, but recent advances in nanotechnology have enabled cellular-specific targeting, drug delivery and multi-modal imaging using these nanoparticles. Opportunities now exist to engineer MNP with designated features (e.g., size, coatings, and molecular functionalizations) for specific biomedical applications. The goal of this interdisciplinary research project is to develop targeting multifunctional nanoparticles, serving as both contrast agents and drug carriers that can effectively pass biological barriers, for diagnosis, staging and treatment of brain tumors. The developed nanoparticle system consists of a superparamagnetic iron oxide nanoparticle core (NP) and a shell comprised of biodegradable polymers such as polyethylene glycol (PEG) and chitosan. Additionally, near-infrared fluorescing (NIRF) molecules were integrated onto the NP shell to enable optical detection. Tumor targeting was achieved by the addition of chlorotoxin, a peptide with that has high affinity to 74 out of the 79 classifications of primary brain tumors and ability to illicit a therapeutic effect. This novel NP system was tested both in vitro and in vivo and was shown to specifically target gliomas in tissue culture and medulloblastomas in transgenic mice with an intact blood brain barriers (BBB), and delineate tumor boundaries in both MR and optical imaging. Additionally, the therapeutic potential of this NP system was explored in vitro, which revealed a unique nanoparticle-enabled pathway that enhances the therapeutic potential of bound peptides by promoting the internalization of membrane bound cell surface receptors. This NP system was further modified with siRNA and evaluated as a carrier for brain tumor targeted gene therapy. Most significantly, the evaluation of

  6. Drug-targeting methodologies with applications: A review.

    Kleinstreuer, Clement; Feng, Yu; Childress, Emily

    2014-12-16

    Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung-airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system. PMID:25516850

  7. Evaluation of 188Re-MAG2-RGD-bombesin for potential prostate cancer therapy

    Glu-RGD-bombesin (RGD-BBN) is a heterodimeric peptide that contains motifs recognizing both integrin αvβ3 and gastrin releasing peptide receptor (GRPR). We evaluated here 188Re (t1/2 = 16.9 h) labeled RGD-BBN as a potential agent for radionuclide therapy of prostate cancer. RGD-BBN was conjugated with S-benzoylmercaptoacetylglycylglycyl (MAG2), and then labeled with 99mTc or 188Re, respectively. The dual-receptor binding affinity of MAG2-RGD-BBN was investigated by a radioligand competition binding assay. Biodistribution study of 188Re-MAG2-RGD-BBN was carried out in normal BALB/c mice and PC-3 human prostate tumor-bearing nude mice. Gamma imaging studies were performed in PC-3 tumor-bearing nude mice. Biodistribution in normal mice showed that both 99mTc and 188Re-labeled MAG2-RGD-BBN possessed high pancreas uptake due to the high GRPR expression of this organ. Gamma imaging with both 99mTc and 188Re-labeled RGD-BBN in PC-3 tumor-bearing nude mice demonstrated high tumor uptake. The PC-3 tumors were clearly visible at 1 postinjection, with high contrast to the contralateral background. The use of chelator MAG2 enables successful and high-yield 99mTc and 188Re radiolabeling of RGD-BBN with favorable tumor targeting specificity. Further optimization may allow potential clinical application of 188Re-MAG2-RGD-BBN for tumor-targeted radionuclide therapy

  8. A new PET tracer specific for vascular endothelial growth factor receptor

    Noninvasive positron emission tomography (PET) imaging of vascular endothelial growth factor receptor 2 (VEGFR-2) expression could be a valuable tool for evaluation of patients with a variety of malignancies, and particularly for monitoring those undergoing antiangiogenic therapies that block VEGF/VEGFR-2 function. The aim of this study was to develop a VEGFR-2-specific PET tracer. The D63AE64AE67A mutant of VEGF121 (VEGFDEE) was generated by recombinant DNA technology. VEGF121 and VEGFDEE were purified and conjugated with DOTA for 64Cu labeling. The DOTA conjugates were tested in vitro for VEGFR-2 specificity and functional activity. In vivo tumor targeting efficacy and pharmacokinetics of 64Cu-labeled VEGF121 and VEGFDEE were compared using an orthotopic 4T1 murine breast tumor model. Blocking experiments, biodistribution studies, and immunofluorescence staining were carried out to confirm the noninvasive imaging results. Cell binding assay demonstrated that VEGFDEE had about 20-fold lower VEGFR-1 binding affinity and only slightly lower VEGFR-2 binding affinity as compared with VEGF121. MicroPET imaging studies revealed that both 64Cu-DOTA-VEGF121 and 64Cu-DOTA-VEGFDEE had rapid and prominent activity accumulation in VEGFR-2-expressing 4T1 tumors. The renal uptake of 64Cu-DOTA-VEGFDEE was significantly lower than that of 64Cu-DOTA-VEGF121 as rodent kidneys expressed high levels of VEGFR-1 based on immunofluorescence staining. Blocking experiments and biodistribution studies confirmed the VEGFR specificity of 64Cu-DOTA-VEGFDEE. We have developed a VEGFR-2-specific PET tracer, 64Cu-DOTA-VEGFDEE. It has comparable tumor targeting efficacy to 64Cu-DOTA-VEGF121 but much reduced renal toxicity. This tracer may be translated into the clinic for imaging tumor angiogenesis and monitoring antiangiogenic treatment efficacy. (orig.)

  9. Optimizing the Delivery of Short-Lived Alpha Particle-Emitting Isotopes to Solid Tumors

    Adams, Gregory P.

    2004-11-24

    The underlying hypothesis of this project was that optimal alpha emitter-based radioimmunotherapy (RAIT) could be achieved by pairing the physical half-life of the radioisotope to the biological half-life of the targeting vehicle. The project had two specific aims. The first aim was to create and optimize the therapeutic efficacy of 211At-SAPS-C6.5 diabody conjugates. The second aim was to develop bispecific-targeting strategies that increase the specificity and efficacy of alpha-emitter-based RAIT. In the performance of the first aim, we created 211At-SAPS-C6.5 diabody conjugates that specifically targeted the HER2 tumor associated antigen. In evaluating these immunoconjugates we determined that they were capable of efficient tumor targeting and therapeutic efficacy of established human tumor xenografts growing in immunodeficient mice. We also determined that therapeutic doses were associated with late renal toxicity, likely due to the role of the kidneys in the systemic elimination o f these agents. We are currently performing more studies focused on better understanding the observed toxicity. In the second aim, we successfully generated bispecific single-chain Fv (bs-scFv) molecules that co-targeted HER2 and HER3 or HER2 and HER4. The in vitro kinetics and in vivo tumor-targeting properties of these molecules were evaluated. These studies revealed that the bs-scFv molecules selectively localized in vitro on tumor cells that expressed both antigens and were capable of effective tumor localization in in vivo studies.

  10. 局部晚期肺癌三维适型放射治疗和调强放射治疗的剂量学比较研究%COMPARATIVE DOSIMETRY STUDY OF 3DCRT AND IMRT FOR TREATMENT OF LOCAL ADVANCED LUNG CANCER

    张慕娟; 周素珠; 汤亚莉; 丁春江; 陈沃培; 梁兵

    2015-01-01

    Objective To observe and analyze the tumor target sections and dose distribution of 3DCRT and IMRT in the treatment of local advanced non -small cell lung cancer (LANSCLC) and compare the advantages of the 2 treatment methods on dosimetry .Methods 52 patients with IIIa and IIIb stage non -small cell lung cancer were given both 3DCRT and IMRT.GTV, CTV, PTV and harmed trachea were sketched by CT .Dose of both treatment methods was 66Gy, and the criterion was that prescribed dose at least covered 95%PTV.Organ harmful doses were all within tolerable doses .Differences of tumor target section doses were compared according to dose distribution , conformity index and mean index of target section .Results Both groups got dose distributions satisfying criteria . PTV dose comparison of the 2 treatment methods showed that differences of mean dose and max dose group were sig -nificant (p0.05).Differences of CI and HI values were significant (p<0.05).Conclusion IMRT and 3DCRT can improve tumor target formability , but reduce uniformity .%目的:观察和分析局部晚期非小细胞肺癌三维适型放射治疗和动态多叶准直器调强放射治疗在肿瘤靶区和剂量分布,比较两种治疗方法在剂量学上的优势性。方法入选2012年7月~2013年7月就诊于我院的未手术的IIIa期和IIIb期非小细胞肺癌患者52例,按随机抽样法分为两组各26例,分别给予三维适型放射治疗(Three Dimensional Conformal Radiation Therapy ,3DCRT)和动态多叶准直器调强放射治疗(Intensity-modulated radiation therapy,IMRT),根据CT分别勾画大体肿瘤体积(Gross Tumor Volume,GTV)、临床靶体积( Clinical Target Volume ,CTV)、计划靶体积( Planning Target Volume ,PTV)和危害气管,两种治疗方法剂量均为66Gy,标准为处方剂量至少覆盖95%的PTV,危害器官剂量均在耐受剂量范围内,通过靶区等剂量分布、适型指数和均数指数等对比

  11. Radiolabeled antibodies in prostate cancer: A case study showing the effect of host immunity on antibody bio-distribution

    Objectives: Human tumors xenografted in immunodeficient mice are crucial models in nuclear medicine to evaluate the effectiveness of candidate diagnostic and therapeutic compounds. However, little attention has been focused on the biological profile of the host model and its potential effects on the bio-distribution and tumor targeting of the tracer compound under study. We specifically investigated the dissimilarity in bio-distribution of 111In-DTPA-5A10, which targets free prostate specific antigen (fPSA), in two animal models. Methods: In vivo bio-distribution studies of 111In-DTPA-5A10 were performed in immunodeficient BALB/c-nu or NMRI-nu mice with subcutaneous (s.c.) LNCaP tumors. Targeting-specificity of the tracer was assessed by quantifying the uptake in (a) mice with s.c. xenografts of PSA-negative DU145 cells as well as (b) BALB/c-nu or NMRI-nu mice co-injected with an excess of non-labeled 5A10. Finally, the effect of neonatal Fc-receptor (FcRn) inhibition on the bio-distribution of the conjugate was studied by saturating FcRn-binding capacity with nonspecific IgG1. Results: The inherent biological attributes of the mouse model substantially influenced the bio-distribution and pharmacokinetics of 111In-DTPA-5A10. With LNCaP xenografts in BALB/c-nu mice (with intact B and NK cells but with deficient T cells) versus NMRI-nu mice (with intact B cells, increased NK cells and absent T cells), we observed a significantly higher hepatic accumulation (26 ± 3.9 versus 3.5 ± 0.4%IA/g respectively), and concomitantly lower tumor uptake (25 ± 11 versus 52 ± 10%IA/g respectively) in BALB/c-nu mice. Inhibiting FcRn by administration of nonspecific IgG1 just prior to 111In-DTPA-5A10 did not change tumor accumulation significantly. Conclusions: We demonstrated that the choice of immunodeficient mouse model importantly influence the bio-distribution of 111In-DTPA-5A10. This study further highlighted important considerations in the evaluation of preclinical tracers

  12. Imaging cancer using PET - the effect of the bifunctional chelator on the biodistribution of a {sup 64}Cu-labeled antibody

    Dearling, Jason L.J., E-mail: jason.dearling@childrens.harvard.ed [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Harvard Medical School, Boston, MA 02115 (United States); Voss, Stephan D. [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Harvard Medical School, Boston, MA 02115 (United States); Dunning, Patricia; Snay, Erin [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Fahey, Frederic [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Harvard Medical School, Boston, MA 02115 (United States); Smith, Suzanne V. [Australian National Science and Technology Organisation (ANSTO), New Illawarra Road, PMB1, Menai, New South Wales 2234 (Australia); Huston, James S. [EMD Serono Research Center, 45A Middlesex Turnpike, Billerica, MA 01821-3936 (United States); Boston Biomedical Research Institute, Watertown, MA 02472-2899 (United States); Meares, Claude F. [Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616-5295 (United States); Treves, S. Ted; Packard, Alan B. [Division of Nuclear Medicine and Department of Radiology, Children' s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (United States); Harvard Medical School, Boston, MA 02115 (United States)

    2011-01-15

    Introduction: 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 {sup 64}Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with {sup 64}Cu using these chelators in tumor-bearing mice. Methods: The chelators [S-2-(aminobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH{sub 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{sub 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 {sup 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. Results: 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 [{sup 64}Cu]ch14.18-p-NH{sub 2}-Bn-NOTA was 4.74 {+-} 0.77 per cent of the injected dose per gram of tissue (%ID/g), and for [{sup 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. Conclusions: The results of this

  13. Self-assembled nanoparticles based on the c(RGDfk peptide for the delivery of siRNA targeting the VEGFR2 gene for tumor therapy

    Liu L

    2014-07-01

    Full Text Available Li Liu,1 Xiaoxia Liu,1 Qian Xu,1 Ping Wu,2 Xialin Zuo,3 Jingjing Zhang,1 Houliang Deng,1 Zhuomin Wu,1 Aimin Ji1 1Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Pharmacy, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu, People’s Republic of China; 3Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, People’s Republic of China Abstract: The clinical application of small interfering RNA (siRNA has been restricted by their poor intracellular uptake, low serum stability, and inability to target specific cells. During the last several decades, a great deal of effort has been devoted to exploring materials for siRNA delivery. In this study, biodegradable, tumor-targeted, self-assembled peptide nanoparticles consisting of cyclo(Arg–Gly–Asp–d–Phe–Lys-8–amino–3,6–dioxaoctanoic acid–β–maleimidopropionic acid (hereafter referred to as RPM were found to be an effective siRNA carrier both in vitro and in vivo. The nanoparticles were characterized based on transmission electron microscopy, circular dichroism spectra, and dynamic light scattering. In vitro analyses showed that the RPM/VEGFR2-siRNA exhibited negligible cytotoxicity and induced effective gene silencing. Delivery of the RPM/VEGFR2 (zebrafish-siRNA into zebrafish embryos resulted in inhibition of neovascularization. Administration of RPM/VEGFR2 (mouse-siRNA to tumor-bearing nude mice led to a significant inhibition of tumor growth, a marked reduction of vessels, and a downregulation of VEGFR2 (messenger RNA and protein in tumor tissue. Furthermore, the levels of IFN-α, IFN-γ, IL-12, and IL-6 in mouse serum, assayed via enzyme-linked immunosorbent assay, did not indicate any immunogenicity of the RPM/VEGFR2

  14. Radiopaque tantalum oxide coated persistent luminescent nanoparticles as multimodal probes for in vivo near-infrared luminescence and computed tomography bioimaging

    Lu, Yu-Chen; Yang, Cheng-Xiong; Yan, Xiu-Ping

    2015-10-01

    The design and fabrication of multimodal imaging nanoparticles is of great importance in medical diagnosis. Here we report the fabrication of core-shell structured Zn2.94Ga1.96Ge2O10:Cr3+,Pr3+@TaOx@SiO2 nanoparticles for persistent luminescence and X-ray computed tomography (CT) imaging. Persistent luminescent nanoparticles Zn2.94Ga1.96Ge2O10:Cr3+,Pr3+ were used as the core to provide near-infrared luminescence, and a TaOx layer was grown on the core to serve as the contrast agent for CT. The tenuous outermost SiO2 shell was fabricated on the TaOx layer to gain high biocompatibility and to facilitate post-modification with tumor-targeting peptides. The fabricated core-shell structured nanoparticle shows intense near-infrared luminescence and the CT contrast effect. No obvious mutual interference was found in these two modalities, which ensures that each imaging modality merits could be brought in a full play. Furthermore, covalent bonding of cyclic-Asn-Gly-Arg peptides makes the core-shell structured nanoparticles promising for in vivo targeted imaging of tumor-bearing mice.The design and fabrication of multimodal imaging nanoparticles is of great importance in medical diagnosis. Here we report the fabrication of core-shell structured Zn2.94Ga1.96Ge2O10:Cr3+,Pr3+@TaOx@SiO2 nanoparticles for persistent luminescence and X-ray computed tomography (CT) imaging. Persistent luminescent nanoparticles Zn2.94Ga1.96Ge2O10:Cr3+,Pr3+ were used as the core to provide near-infrared luminescence, and a TaOx layer was grown on the core to serve as the contrast agent for CT. The tenuous outermost SiO2 shell was fabricated on the TaOx layer to gain high biocompatibility and to facilitate post-modification with tumor-targeting peptides. The fabricated core-shell structured nanoparticle shows intense near-infrared luminescence and the CT contrast effect. No obvious mutual interference was found in these two modalities, which ensures that each imaging modality merits could be brought

  15. Imaging cancer using PET - the effect of the bifunctional chelator on the biodistribution of a 64Cu-labeled antibody

    Introduction: 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 64Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with 64Cu using these chelators in tumor-bearing mice. Methods: The chelators [S-2-(aminobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH2-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-NH2-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 64Cu 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. Results: 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 64Cu]ch14.18-p-NH2-Bn-NOTA was 4.74 ± 0.77 per cent of the injected dose per gram of tissue (%ID/g), and for [64Cu]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. Conclusions: The results of this study indicate that differences in the thermodynamic stability of these chelator-Cu(II) complexes were not associated with significant differences in uptake of the tracer by the tumor

  16. The correlation between DVH at CT-image based 192Ir intracavitary brachytherapy and effects or complications for patients with locally advanced cervical cancer

    Objective: To investigate the correlation between dose volume histogram (DVH) of tumor targets and organs at risk (OAR) at CT-image based 192Ir brachytherapy and effects and complications for patients with locally advanced cervical cancer. Methods: Ten patients with FIGO stage IIIB cervical cancer received CT image-based 192Ir intracavitary brachytherapy after 54 Gy of three-dimensional four-field pelvic external beam radiotherapy and concurrent weekly cisplatin chemotherapy. Before each brachytherapy, CT images were acquired with applicators in place. Gross tumor volume (GTV), clinical target volume (CTV) and OAR were contoured and inverse treatment planning was designed and optimized by using PLATO treatment planning system. Conventional two-dimensional plans were also designed for comparison.The total intracavitary brachytherapy dose was 30-42 Gy in 5-7 fractions. The patients were followed, and the local control and complications were analyzed. The biologically equivalent dose (BED) and biologically equivalent dose in 2 Gy fractions (BED2) for GTV, CTV and OAR were calculated. The minimum dose in the most irradiated tissue volume 2 cm3 (D2cm3)adjacent to the applicator of the sigmoid colon, rectum,bladder and small bowel was determined from the DVH. Results: The 1-year local pelvic control rate was 90% and grade 1-2 late complication of sigmoid colon and rectum was 50%. No grade 3 or more complications developed. On CT-image based planning, the BED and BED2 to 90% of the CTV (D90) were 95.50 Gy ± 7. 81 Gy and 79. 73 Gy ± 6. 57 Gy. The BED and BED2 to 90% of the GTV (D90) were 101.86 Gy ± 7.27 Gy and 84. 95 Gy ± 6. 1 Gy. The volume enclosed by 90% of prescribed dose (V90) for GTV and CTV were 92% ±4% and 87% ±7% respectively. The D2cm3 for rectum and sigmoid colon were 74. 97 Gy ±1.64 Gy and 67. 93 Gy ± 4. 30 Gy(EQD2, α/β = 3). Comparing with 2D brachytherapy plans , CT - image based planning has improved D90 and V90 for GTV and CTV with similar dose

  17. Monitoring bacteriolytic therapy of salmonella typhimurium with optical imaging system

    Systemically administrated Salmonella has been studied for targeting tumor and developed as an anticancer agent. In Salmonella, because msbB gene plays role in the terminal myristoylation of lipid A and induces tumor necrosis factor a (TNF-a) -mediated septic shock, Salmonella msbB mutant strain is safe and useful for tumor-targeting therapy. Here we report that Salmonella msbB mutant strain induce onco lysis after intravenous injection in tumor bearing mice. The CT26 mouse colon cancer cells were stably transfected with firefly luciferase gene and subcutaneously implantated in Balb/C mice. After establishing subcutaneous tumor mass, we intravenously injected 1x108 cfu Salmonella msbB mutant strain or MG1655 E coli strain. Not only tumor size but also total photon flux from the tumor mass were monitored. everyday and compared among experimental groups (No treatment, Salmonella treatment, E. coli MG1655 treatment group). After intraperitoneal injection of D-Iuciferin (3 mg/animal), in vivo optical imaging for firefly luciferase was performed using cooled CCD camera. Imaging signal from Salmonella injected group were significantly lower than that of no treatment or E. coli treatment group on day 2 after injection. On day 4 after injection, imaging signal of salmonella-injected group was 43.8 or 20.7 times lower than that of no treatment or E. coli treatment group, respectively (no treatment: 2.78E+07 p/s/cm2/sr, Salmonella treatment: 6.35E+05 p/s/cm2/sr, E. coli treatment: 1.29E+07 p/s/cm2/sr, P<0.05). However. when we injected E. coli MG1655 into tumor bearing mice, the intensity of imaging signal was not different from no treatment group. These findings suggest that Salmonella msbB mutant strain retains its tumor-targeting properties and have therapeutical effect. Bioluminescent tumor bearing animal model was useful for assessing tumor viability after bacteriolytic therapy using Salmonella

  18. Folate receptor-targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for H22 hepatocellular carcinoma both in vitro and in vivo

    Liu MC

    2016-04-01

    Full Text Available Min-Chen Liu,1 Lin Liu,1 Xia-Rong Wang,1 Wu-Ping Shuai,2 Ying Hu,3 Min Han,1 Jian-Qing Gao1 1Institute of Pharmaceutics, College of Pharmaceutical Sciences, 2First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 3Zhejiang Pharmaceutical College, Ningbo, People’s Republic of China Abstract: The diacid metabolite of norcantharidin (DM-NCTD is clinically effective against hepatocellular carcinoma (HCC, but is limited by its short half-life and high incidence of adverse effects at high doses. We developed a DM-NCTD-loaded, folic acid (FA-modified, polyethylene glycolated (DM-NCTD/FA-PEG liposome system to enhance the targeting effect and antitumor potency for HCC at a moderate dose based on our previous study. The DM-NCTD/FA-PEG liposome system produced liposomes with regular spherical morphology, with mean particle size approximately 200 nm, and an encapsulation efficiency >80%. MTT cytotoxicity assays demonstrated that the DM-NCTD/FA-PEG liposomes showed significantly stronger cytotoxicity effects on the H22 hepatoma cell line than did PEG liposomes without the FA modification (P<0.01. We used liquid chromatography–mass spectrometry for determination of DM-NCTD in tissues and tumors, and found it to be sensitive, rapid, and reliable. In addition, the biodistribution study showed that DM-NCTD liposomes improved tumor-targeting efficiency, and DM-NCTD/FA-PEG liposomes exhibited the highest efficiency of the treatments (P<0.01. Meanwhile, the results indicated that although the active liposome group had an apparently increased tumor-targeting efficiency of DM-NCTD, the risk to the kidney was higher than in the normal liposome group. With regard to in vivo antitumor activity, DM-NCTD/FA-PEG liposomes inhibited tumors in H22 tumor-bearing mice better than either free DM-NCTD or DM-NCTD/PEG liposomes (P<0.01, and induced considerably more significant cellular apoptosis in the tumors, with no obvious toxicity to the tissues

  19. Targeting Prostate Cancer Cells In Vivo Using a Rapidly Internalizing Novel Human Single-Chain Antibody Fragment

    He, Jiang; Wang, Yong; Feng, Jinjin; Zhu, Xiaodong; Lan, Xiaoli; Iyer, Arun K.; Zhang, Niu; Seo, Youngho; VanBrocklin, Henry F.; Liu, Bin

    2010-01-01

    Human antibodies targeting prostate cancer cell surface epitopes may be useful for imaging and therapy. The objective of this study was to evaluate the tumor targeting of an internalizing human antibody fragment, a small-size platform, to provide high contrast in a mouse model of human prostate carcinoma. Methods A prostate tumor-targeting single-chain antibody fragment (scFv), UA20, along with a nonbinding control scFv, N3M2, were labeled with 99mTc and evaluated for binding and rapid internalization into human prostate tumor cells in vitro and tumor homing in vivo using xenograft models. For the in vitro studies, the labeled UA20 scFv was incubated at 37°C for 1 h with metastatic prostate cancer cells (DU145) to assess the total cellular uptake versus intracellular uptake. For the animal studies, labeled UA20 and N3M2 scFvs were administered to athymic mice implanted subcutaneously with DU145 cells. Mice were imaged with small-animal SPECT/CT with concomitant biodistribution at 1 and 3 h after injection. Results The UA20 scFv was labeled in 55%–65% yield and remained stable in phosphate buffer within 24 h. The labeled UA20 scFv was taken up specifically by prostate tumor cells. Internalization was rapid, because incubation at 37°C for less than 1 h resulted in 93% internalization of total cell-associated scFvs. In animal studies, SPECT/CT showed significant tumor uptake as early as 1 h after injection. At 3 h after injection, tumor uptake was 4.4 percentage injected dose per gram (%ID/g), significantly greater than all organs or tissues studied (liver, 2.7 %ID/g; other organs or tissues, <1 %ID/g), except the kidneys (81.4 %ID/g), giving tumor-to-blood and tumor-to-muscle ratios of 12:1 and 70:1, respectively. In contrast, the control antibody exhibited a tumor uptake of only 0.26 %ID/g, similar to that of muscle and fat. Tumor-specific targeting was evidenced by reduced tumor uptake of nearly 70% on administration of a 10-fold excess of unlabeled UA20 sc

  20. Folic acid-targeted disulfide-based cross-linking micelle for enhanced drug encapsulation stability and site-specific drug delivery against tumors

    Zhang Y

    2016-03-01

    Full Text Available Yumin Zhang,1,* Junhui Zhou,2,* Cuihong Yang,1 Weiwei Wang,3 Liping Chu,1 Fan Huang,1 Qiang Liu,1 Liandong Deng,2 Deling Kong,3 Jianfeng Liu,1 Jinjian Liu1 1Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, 2Department of Polymer Science and Technology, School of Chemical Engineering and Technology, Tianjin University, 3Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, People’s Republic of China *These authors contributed equally in this work Abstract: Although the shortcomings of small molecular antitumor drugs were efficiently improved by being entrapped into nanosized vehicles, premature drug release and insufficient tumor targeting demand innovative approaches that boost the stability and tumor responsiveness of drug-loaded nanocarriers. Here, we show the use of the core cross-linking method to generate a micelle with enhanced drug encapsulation ability and sensitivity of drug release in tumor. This kind of micelle could increase curcumin (Cur delivery to HeLa cells in vitro and improve tumor accumulation in vivo. We designed and synthesized the core cross-linked micelle (CCM with polyethylene glycol and folic acid-polyethylene glycol as the hydrophilic units, pyridyldisulfide as the cross-linkable and hydrophobic unit, and disulfide bond as the cross-linker. CCM showed spherical shape with a diameter of 91.2 nm by the characterization of dynamic light scattering and transmission electron microscope. Attributed to the core cross-linking, drug-loaded CCM displayed higher Nile Red or Cur-encapsulated stability and better sensitivity to glutathione than noncross-linked micelle (NCM. Cellular uptake and in vitro antitumor studies proved the enhanced endocytosis and better cytotoxicity of CCM-Cur against

  1. Dendritic cells fused with different pancreatic carcinoma cells induce different T-cell responses

    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

  2. Near infrared light-actuated gold nanorods with cisplatin-polypeptide wrapping for targeted therapy of triple negative breast cancer

    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

  3. A new PET tracer specific for vascular endothelial growth factor receptor 2

    Wang, Hui; Cai, Weibo; Chen, Kai; Li, Zi-Bo; Kashefi, Amir; He, Lina; Chen, Xiaoyuan [Stanford University School of Medicine, The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford, CA (United States)

    2007-12-15

    Noninvasive positron emission tomography (PET) imaging of vascular endothelial growth factor receptor 2 (VEGFR-2) expression could be a valuable tool for evaluation of patients with a variety of malignancies, and particularly for monitoring those undergoing antiangiogenic therapies that block VEGF/VEGFR-2 function. The aim of this study was to develop a VEGFR-2-specific PET tracer. The D63AE64AE67A mutant of VEGF{sub 121} (VEGF{sub DEE}) was generated by recombinant DNA technology. VEGF{sub 121} and VEGF{sub DEE} were purified and conjugated with DOTA for {sup 64}Cu labeling. The DOTA conjugates were tested in vitro for VEGFR-2 specificity and functional activity. In vivo tumor targeting efficacy and pharmacokinetics of {sup 64}Cu-labeled VEGF{sub 121} and VEGF{sub DEE} were compared using an orthotopic 4T1 murine breast tumor model. Blocking experiments, biodistribution studies, and immunofluorescence staining were carried out to confirm the noninvasive imaging results. Cell binding assay demonstrated that VEGF{sub DEE} had about 20-fold lower VEGFR-1 binding affinity and only slightly lower VEGFR-2 binding affinity as compared with VEGF{sub 121}. MicroPET imaging studies revealed that both {sup 64}Cu-DOTA-VEGF{sub 121} and {sup 64}Cu-DOTA-VEGF{sub DEE} had rapid and prominent activity accumulation in VEGFR-2-expressing 4T1 tumors. The renal uptake of {sup 64}Cu-DOTA-VEGF{sub DEE} was significantly lower than that of {sup 64}Cu-DOTA-VEGF{sub 121} as rodent kidneys expressed high levels of VEGFR-1 based on immunofluorescence staining. Blocking experiments and biodistribution studies confirmed the VEGFR specificity of {sup 64}Cu-DOTA-VEGF{sub DEE}. We have developed a VEGFR-2-specific PET tracer, {sup 64}Cu-DOTA-VEGF{sub DEE}. It has comparable tumor targeting efficacy to {sup 64}Cu-DOTA-VEGF{sub 121} but much reduced renal toxicity. This tracer may be translated into the clinic for imaging tumor angiogenesis and monitoring antiangiogenic treatment efficacy. (orig.)

  4. Labelling of anti-human bladder tumor chimeric antibody with 99Tcm and radioimmunoimaging of bladder carcinoma xenograft in nude mice

    Objective: To study the in vitro immunoreactivity and in vivo tissue distribution, tumor targeting property of anti-human bladder tumor human-murine chimeric antibody (ch-BDI) labeled with 99Tcm and to investigate its possibility for being used in guiding diagnosis and guiding therapy of bladder cancer. Methods: The ch-BDI was labeled with 99Tcm by improved Schwarz method and the labeled antibody was purified by Sephadex G-50. Labeling yield and radiochemical purity were measured by paper chromatography. The immunoreactive fraction and association constant (Ka) were measured by Lindmo method and Scatchard analysis, respectively. 11.1 MBq (30 μg) 99Tcm-ch-BDI was intravenously injected into nude mice bearing human bladder cancer xenografts in the right thigh and radioimmunoimaging (RII) was performed 2, 6, 20 and 24 h postinjection. The images were processed by region of interest (ROI) method to acquire the counts of whole body and the tumor and the counts ratios of tumor to contralateral normal tissue or to tissues of other non-tumor bearing organs. The mice were killed after 24 h postinjection imaging and tissue distribution was measured. %ID/g and target to nontarget (T/NT) ratios were calculated. Results: The labeling yield and radiochemical purity of 99Tcm-ch-BDI were (66.5±7.3)% and >90%, respectively. The immunoreactive fraction was 76% and Ka was 3.56 x 109 L/mol. RII showed that the tumor was clearly visualized 6 h postinjection and becoming clearer along with time prolonging. The radioactivity of whole body decreased rapidly with time, whereas the radioactivity of the tumor decreased slowly. The T/NT ratios was increased with time. Biodistribution results showed that tumor uptake was 17.4%ID/g 24 h postinjection. T/NT ratios were very high except for the kidney. T/NT ratios for brain, muscle, intestinal wall, bone and heart wall were 136.0, 55.1, 39.3, 29.7 and 27.9, respectively. Conclusion: 99Tcm-ch-BDI exhibits excellent immunoreactivity and tumor

  5. Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using90Y or177Lu

    Introduction: Therapeutic potential of β-emitting cytotoxic radionuclides 90Y and 177Lu has been demonstrated in numerous preclinical and clinical trials. A bifunctional chelate that can effectively complex with the radioisotopes is a critical component for molecular targeted radiotherapy 90Y and 177Lu. A new bifunctional chelate 5p-C-NETA with a relatively long alkyl spacer between the chelating backbone and the functional unit for conjugation to a tumor targeting moiety was synthesized. 5p-C-NETA was conjugated to a model targeting moiety, a cyclic Arg-Gly-Asp-D-Tyr-Lys (RGDyK) peptide binding integrin αvβ3 protein overexpressed on various cancers. 5p-C-NETA was conjugated to c(RGDyK) peptide and evaluated for potential use in molecular targeted radiotherapy of 90Y and 177Lu. Methods: 5p-C-NETA conjugated with c(RGDyK) was evaluated in vitro for radiolabeling, serum stability, binding affinity, and the result of the in vitro studies of 5p-C-NETA-c(RGDyK) was compared to that of 3p-C-NETA-c(RGDyK). 177Lu-5p-C-NETA-c(RGDyK) was further evaluated for in vivo biodistribution using gliobastoma bearing mice. Result: The new chelate rapidly and tightly bound to a cytotoxic radioisotope for cancer therapy, 90Y or 177Lu with excellent radiolabeling efficiency and maximum specific activity under mild condition (> 99%, RT, < 1 min). 90Y- and 177Lu-radiolabeled complexes of the new chelator remained stable in human serum without any loss of the radiolanthanide for 14 days. Introduction of the tumor targeting RGD moiety to the new chelator made little impact on complexation kinetics and stability with 90Y or 177Lu. 177Lu-radiolabeled 5p-C-NETA-c(RGDyK) conjugate was shown to target tumors in mice and produced a favorable in vivo stability profile. Conclusion: The results of in vitro and in vivo evaluation suggest that 5p-C-NETA is an effective bifunctional chelate of 90Y and 177Lu that can be applied for generation of versatile molecular targeted radiopharmaceuticals

  6. Brain tumor magnetic targeting and biodistribution of superparamagnetic iron oxide nanoparticles linked with 70-kDa heat shock protein study by nonlinear longitudinal response

    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

  7. Reconstituted high density lipoprotein mediated targeted co-delivery of HZ08 and paclitaxel enhances the efficacy of paclitaxel in multidrug-resistant MCF-7 breast cancer cells.

    Zhang, Fangrong; Wang, Xiaoyi; Xu, Xiangting; Li, Min; Zhou, Jianping; Wang, Wei

    2016-09-20

    In the past decades, reconstituted high density lipoprotein (rHDL) has been successfully developed as a drug carrier since the enhanced HDL-lipids uptake is demonstrated in several human cancers. In this paper, rHDL, for the first time, was utilized to co-encapsulate two hydrophobic drugs: an anticancer drug, paclitaxel (PTX), and a new reversal agent for P-gp (P-glycoprotein)-mediated multidrug resistance (MDR) of cancer, N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide (HZ08). We proposed this drug co-delivery strategy to reverse PTX resistance. The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted PTX-HZ08 delivery for cancer therapy. Using sodium cholate dialysis method, we successfully formulated dual-agent co-delivering rHDL nanoparticles (PTX-HZ08-rHDL NPs) with a typical spherical morphology, well-distributed size (~100nm), high drug encapsulation efficiency (approximately 90%), sustained drug release properties and exceptional stability even after storage for 1month or incubation in 10% fetal bovine serum (FBS) DMEM for up to 2days. Results demonstrated that PTX-HZ08-rHDL NPs significantly enhanced anticancer efficacy in vitro, including higher cytotoxicity and better ability to induce cell apoptosis against both PTX-sensitive and -resistant MCF-7 human breast cancer cell lines (MCF-7 and MCF-7/PTX cells). Mechanism studies demonstrated that these improvements could be correlated with increased cellular uptake of PTX mediated by scavenger receptor class B type I (SR-BI) as well as prolonged intracellular retention of PTX due to the HZ08 mediated drug-efflux inhibition. In addition, in vivo investigation showed that the PTX-HZ08-rHDL NPs were substantially safer, have higher tumor-targeted capacity and have stronger antitumor activity than the corresponding dosage of paclitaxel injection. These findings suggested that rHDL NPs could

  8. Cytolysin a expressing E. coli a promising candidate for imageable therapeutic probe

    Using bacteria for cancer treatment has a long history. Discovery of optical reporter genes consisting of fluorescent and luminescent protein facilitates the monitor of bacteria in vivo, non-invasively and repeatedly. E. coli, the natural enteric bacteria possessing capacity of tumor-targeting ability, seems to be suitable candidate for cancer treatment. In this study, we established the strain light-emitting E. coli for diagnostic purpose and Cytolysin A (Cly A) expressing E. coli for therapeutic purpose. E. coli (MG1655, wild type strain) was transformed plasmid pUC19 carrying lux gene to create the light expressing bacteria and test the tumor targeting-capacity by injecting the bacteria into CT26-tumor bearing mice via tail vein. On the other hand, for therapeutic purpose, plasmid containing Cly A gene, which is encoded for a pore-forming protein toxin, was introduced into E. coli. The toxicity of Cly A was evaluated in vitro by inoculating the bacteria with various cultured cancer cell lines. On the other hand, to test the therapeutic effect, the bacteria were injected intratumorally and intravenously into s.c.CT26-bearing as well as CT26-lung metastasized Balb/c mice. In vivo imaging data showed that the E. coli strains selectively located in the tumor. The in vitro result showed that the number of death cells were significantly higher in the samples containing E. coli expressing Cly A (E. coli Cly A) compared with the samples containing wild type strain. The growth of tumors was repressed in mice injected with either E. coli Cly A (significantly) or wild type E. coli (mildly), while tumors in no treatment group still grew fast. Furthermore, the tumors inoculated with E. coli cly A were necrotized but not with wild type E. coli. In the CT26-lung metastasized mouse model, the life span of mice was elongated when inject E. coli and longer in the group injected with E. coli cly A. Cly A expressing E. coli can become an effective candidate for imageable

  9. MR-Guided High-Intensity Focused Ultrasound Ablation of Breast Cancer with a Dedicated Breast Platform

    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.

  10. Oncolytic immunotherapy through tumor-specific translation and cytotoxicity of poliovirus.

    Brown, Michael C; Gromeier, Matthias

    2015-05-01

    Achieving tumor-specific, robust, and durable effector cytotoxic immune responses is key to successful immunotherapy. This has been accomplished with adoptive cell transfer of ex vivo-expanded autologous tumor-infiltrating or engineered T cells, or with immune checkpoint inhibitors, enhancing inherent T cell reactivity. A natural ability to recruit effector responses makes tumor-targeting ('oncolytic') viruses attractive as immunotherapy vehicles. However, most viruses actively block inflammatory and immunogenic events; or, host innate immune responses may prevent immune initiating events in the first place. Moreover, the mechanisms of how virus infection can produce effector responses against host (tumor) neo-antigens are unclear. We are pioneering oncolytic immunotherapy based on poliovirus, which has no specific mechanism to interfere with host immune activation, exhibits lytic cytotoxicity in the presence of an antiviral interferon response and pre-existing immunity, and engages a powerful innate immune sensor implicated in recruiting cytotoxic T cell responses. Central to this approach is a unique confluence of factors that drive tumor-specific viral translation and cytotoxicity. PMID:26105699

  11. Studies related to antibody-mediated boron delivery for BNCT

    Of the many methods of selective boron delivery to tumor presently under consideration the use of boron-labeled tumor-targeted monoclonal antibodies (Mabs) and their immunoreactive fragments appears to offer the most general, but complex, approach. Assuming that tumor cells generally carry 106 characteristic antigenic sites of any one type and that there are approximately 109 cells per gram of tumor, one calculates that about 600 10B atoms must be attached to each individual Mab molecule (if all antigenic sites are complexed) for each 10 ppm of 10B supplied to tumor. Rather than randomly attack IgG Mab molecules with a large number of relatively small boron-containing conjugation reagent molecules the authors have chosen to assemble a series of discrete, precisely synthesized oligomeric reagents ('trailers') each of which contains a fixed number of B-atoms up to approximately 200. These oligomeric reagents would carry a radioactive or fluorescent group for analytical purposes attached to a terminal-NH2 group of their chain and the remaining -COOH terminus would be free for conjugation with the lysine var-epsilon-NH2 groups of Mab protein. Two types of oligomeric trailer reagents are envisioned; hydrophilic peptides and polyamides

  12. Investigating the photosensitizer-potential of targeted gallium corrole using multimode optical imaging

    Hwang, Jae Youn; Lubow, Jay; Chu, David; Gross, Zeev; Gray, Harry B.; Farkas, Daniel L.; Medina-Kauwe, Lali K.

    2011-02-01

    We recently developed a novel therapeutic particle, HerGa, for breast cancer treatment and detection. HerGa consists of a tumor-targeted cell penetration protein noncovalently assembled with a gallium-metallated corrole. The corrole is structurally similar to porphyrin, emits intense fluorescence, and has proven highly effective for breast tumor treatment preclinically, without light exposure. Here, we tested HerGa as a photosensitizer for photodynamic therapy and investigated its mechanism of action using multimode optical imaging. Using confocal fluorescence imaging, we observed that HerGa disrupts the mitochondrial membrane potential in situ, and this disruption is substantially augmented by light exposure. In addition, spectral and fluorescence lifetime imaging were utilized to both validate the mitochondrial membrane potential disruption and investigate HerGa internalization, allowing us to optimize the timing for light dosimetry. We observed, using advanced multimode optical imaging, that light at a specific wavelength promotes HerGa cytotoxicity, which is likely to cause disruption of mitochondrial function. Thus, we can identify for the first time the capacity of HerGa as a photosensitizer for photodynamic therapy and reveal its mechanism of action, opening possibilities for therapeutic intervention in human breast cancer management.

  13. Escherichia coli Nissle 1917 targets and restrains mouse B16 melanoma and 4T1 breast tumors through expression of azurin protein.

    Zhang, Yunlei; Zhang, Youming; Xia, Liqiu; Zhang, Xiangli; Ding, Xuezhi; Yan, Fu; Wu, Feng

    2012-11-01

    Many studies have demonstrated that intravenously administered bacteria can target and proliferate in solid tumors and then quickly be released from other organs. Here, we employed the tumor-targeting property of Escherichia coli Nissle 1917 to inhibit mouse B16 melanoma and 4T1 breast tumors through the expression of azurin protein. For this purpose, recombinant azurin-expressing E. coli Nissle 1917 was developed. The levels of in vitro and in vivo azurin secretion in the engineered bacterium were determined by immunochemistry. Our results demonstrated that B16 melanoma and orthotopic 4T1 breast tumor growth were remarkably restrained and pulmonary metastasis was prevented in immunocompetent mice. It is worth noting that this therapeutic effect partially resulted from the antitumor activity of neutrophils and lymphocytes due to inflammatory responses caused by bacterial infections. No toxicity was observed in the animal during the experiments. This study indicates that E. coli Nissle 1917 could be a potential carrier to deliver antitumor drugs effectively for cancer therapy. PMID:22923405

  14. [Escherichia coli Nissle 1917 as safe vehicles for intestinal immune targeted therapy--a review].

    Xia, Pengpeng; Zhu, Jun; Zhu, Guoqiang

    2013-06-01

    It is difficult to stimulate efficient gut mucosal immune response to intestinal infection. This article critically reviews the research progressin Escherichia coli strain Nisslel917 ( EcN) actingas a safe vehicle for the intestinal mucosal immunity, to restore gastrointestinal disorder and relieve ulcerative colitis. EcN is an orally administered probiotics, combining the excellent colonization and non-immunogenic character, and can be an ideal live vector candidate. This strain could be a tumor-targeted delivery of TAT-Apoptin fusion gene to colorectal cancer. In the treatment of ulcerative colitis and Crohn's disease, the recombinant strain of EcN can be used as a target therapeutics for defensins presenting. Genetically modified EcN could be an ideal carrier organism for gut-focused in situ synthesis and expression of specific localized antigen delivery into the intestine, and stimulate specific mucosal immune response. In vitro trial demonstrated that intestinal recombinant E. coli Nissle-HA110-120 has the potential to stimulate antigen specific response, but EcN itself does not induce mucosal immune response and influence peripheral tolerance to self-antigen. At the same time, there are evidences that EcN is safe. Recombinant E. coli Nissle-HA110-120 does not migrate, clonally expand and activate specific CD4+ T cells, neither in healthy mice nor in other animals with acute colitis, even when the intestinal epithelium suffer from inflammation and the barrier function of the epithelial layer being destroyed. PMID:24028055

  15. pH-Responsive Hyaluronic Acid-Based Mixed Micelles for the Hepatoma-Targeting Delivery of Doxorubicin

    Jing-Liang Wu

    2016-03-01

    Full Text Available The tumor targetability and stimulus responsivity of drug delivery systems are crucial in cancer diagnosis and treatment. In this study, hepatoma-targeting mixed micelles composed of a hyaluronic acid–glycyrrhetinic acid conjugate and a hyaluronic acid-l-histidine conjugate (HA–GA/HA–His were prepared through ultrasonic dispersion. The formation and characterization of the mixed micelles were confirmed via 1H-NMR, particle size, and ζ potential measurements. The in vitro cellular uptake of the micelles was evaluated using human liver carcinoma (HepG2 cells. The antitumor effect of doxorubicin (DOX-loaded micelles was investigated in vitro and in vivo. Results indicated that the DOX-loaded HA–GA/HA–His micelles showed a pH-dependent controlled release and were remarkably absorbed by HepG2 cells. Compared with free DOX, the DOX-loaded HA–GA/HA–His micelles showed a higher cytotoxicity to HepG2 cells. Moreover, the micelles effectively inhibited tumor growth in H22 cell-bearing mice. These results suggest that the HA–GA/HA–His mixed micelles are a good candidate for drug delivery in the prevention and treatment of hepatocarcinoma.

  16. An image guided small animal stereotactic radiotherapy system

    Sha, Hao; Udayakumar, Thirupandiyur S.; Johnson, Perry B.; Dogan, Nesrin; Pollack, Alan; Yang, Yidong

    2016-01-01

    Small animal radiotherapy studies should be performed preferably on irradiators capable of focal tumor irradiation and healthy tissue sparing. In this study, an image guided small animal arc radiation treatment system (iSMAART) was developed which can achieve highly precise radiation targeting through the utilization of onboard cone beam computed tomography (CBCT) guidance. The iSMAART employs a unique imaging and radiation geometry where animals are positioned upright. It consists of a stationary x-ray tube, a stationary flat panel detector, and a rotatable and translational animal stage. System performance was evaluated in regards to imaging, image guidance, animal positioning, and radiation targeting using phantoms and tumor bearing animals. The onboard CBCT achieved good signal, contrast, and sub-millimeter spatial resolution. The iodine contrast CBCT accurately delineated orthotopic prostate tumors. Animal positioning was evaluated with ∼0.3 mm vertical displacement along superior-inferior direction. The overall targeting precision was within 0.4 mm. Stereotactic radiation beams conformal to tumor targets can be precisely delivered from multiple angles surrounding the animal. The iSMAART allows radiobiology labs to utilize an image guided precision radiation technique that can focally irradiate tumors while sparing healthy tissues at an affordable cost. PMID:26958942

  17. Development of pH sensitive 2-(diisopropylamino)ethyl methacrylate based nanoparticles for photodynamic therapy

    Photodynamic therapy is an effective treatment for tumors that involves the administration of light-activated photosensitizers. However, most photosensitizers are insoluble and non-specific. To target the acid environment of tumor sites, we synthesized three poly(ethylene glycol) methacrylate-co-2-(diisopropylamino)ethyl methacrylate (PEGMA-co-DPA) copolymers capable of self-assembly to form pH sensitive nanoparticles in an aqueous environment, as a means of encapsulating the water-insoluble photosensitizer, meso-tetra(hydroxyphenyl)chlorin (m-THPC). The critical aggregation pH of the PEGMA-co-DPA polymers was 5.8-6.6 and the critical aggregation concentration was 0.0045-0.0089 wt% at pH 7.4. Using solvent evaporation, m-THPC loaded nanoparticles were prepared with a high drug encapsulation efficiency (approximately 89%). Dynamic light scattering and transmission electron microscopy revealed the spherical shape and 132 nm diameter of the nanoparticles. The in vitro release rate of m-THPC at pH 5.0 was faster than at pH 7.0 (58% versus 10% m-THPC released within 48 h, respectively). The in vitro photodynamic therapy efficiency was tested with the HT-29 cell line. m-THPC loaded PEGMA-co-DPA nanoparticles exhibited obvious phototoxicity in HT-29 colon cancer cells after light irradiation. The results indicate that these pH sensitive nanoparticles are potential carriers for tumor targeting and photodynamic therapy.

  18. Polymer Nanoparticles Modified with Photo- and pH-Dual-Responsive Polypeptides for Enhanced and Targeted Cancer Therapy.

    Yang, Yang; Xie, Xiangyang; Yang, Yanfang; Li, Zhiping; Yu, Fanglin; Gong, Wei; Li, Ying; Zhang, Hui; Wang, Zhiyuan; Mei, Xingguo

    2016-05-01

    The cationic nature of cell penetrating peptides (CPPs) and their absence of cell selectivity restrains their applications in vivo. In this work, polymer nanoparticles (NPs) modified with photo- and pH-responsive polypeptides (PPPs) were successfully developed and respond to near-infrared (NIR) light illumination at the tumor site and a lowered tumor extracellular pH (pHe). In PPPs, the internalization function of CPPs (positively charged) is quenched by a pH-sensitive inhibitory peptide (negatively charged), which is linked via a photocleavable group. Small interfering RNA (siRNA) was loaded into NPs by a double-emulsion technique. In vivo experiments included siRNA loading, cellular uptake, cell apoptosis, siRNA transfection, tumor targeting delivery, and the in vivo antitumor efficacy. Results showed that the prepared PPP-NPs could selectively accumulate at the tumor sites and internalized into the tumor cells by the NIR light illumination and the lowered pHe at the tumor site. These studies demonstrated that PPP-NPs are a promising carrier for future tumor gene delivery. PMID:27043442

  19. Induction of antigen-specific TH 9 immunity accompanied by mast cell activation blocks tumor cell engraftment.

    Abdul-Wahid, Aws; Cydzik, Marzena; Prodeus, Aaron; Alwash, Mays; Stanojcic, Mile; Thompson, Megan; Huang, Eric H-B; Shively, John E; Gray-Owen, Scott D; Gariépy, Jean

    2016-08-15

    The engraftment of circulating cancer cells at distal sites represents a key step in the metastatic cascade, yet remains an unexplored target for therapeutic intervention. In this study, we establish that a vaccination strategy yielding an antigen-specific TH 9 response induces long term host surveillance and prevents the engraftment of circulating cancer cells. Specifically, we show that vaccination with a recombinant CEA IgV-like N domain, formulated with the TLR3 ligand poly I:C, elicits a CEA-specific TH 9 response, wherein IL-9 secreting TH cells act in concert with CEA N domain-specific antibodies as well as activated mast cells in preventing tumor cell engraftment. The development of this immune response was dependent on TLR3, since interference with the TLR3-dsRNA complex formation led to a reduction in vaccine-imparted protection and a shift in the resulting immune response toward a TH 2 response. These findings point to the existence of an alternate tumor targeting immune mechanism that can be exploited for the purpose of developing vaccine therapies targeting tumor dissemination and engraftment. PMID:27037842

  20. Magnetic hyperthermia in phosphate coated iron oxide nanofluids

    Lahiri, B. B.; Muthukumaran, T.; Philip, John

    2016-06-01

    We study the magnetic field induced hyperthermia in water based phosphate coated Fe3O4 nanofluids, synthesized by a co-precipitation method using ferrous and ferric salt solutions, ammonia and orthophosphoric acid. The specific absorption rate (SAR) values were measured at a fixed frequency of 126 kHz and at extremely low field amplitudes. The SAR values were determined from the initial rate of temperature rise curves under non-adiabatic conditions. It was observed that the SAR initially increases with sample concentration, attains a maximum at an optimum concentration and beyond which SAR decreases. The decrease in SAR values beyond the optimum concentration was attributed to the enhancement of dipolar interaction and agglomeration of the particles. The system independent intrinsic loss power (ILP) values, obtained by normalizing the SAR values with respect to field amplitude and frequency, were found to vary between 158-125 nHm2 kg-1, which were the highest benchmark values reported in the biologically safe experimental limit of 1.03-0.92×108 Am-1 s-1. The very high value of ILP observed in the bio-compatible phosphate coated iron oxide nanofluids may find practical applications for these nanoparticles in tumor targeted hyperthermia treatment.

  1. Prognostic and predictive value of DAMPs and DAMP-associated processes in cancer

    Jitka eFucikova

    2015-08-01

    Full Text Available It is now clear that human neoplasms form, progress and respond to therapy in the context of an intimate crosstalk with the host immune system. In particular, accumulating evidence demonstrates that the efficacy of most, if not all, chemo- and radiotherapeutic agents commonly employed in the clinic critically depends on the (reactivation of tumor-targeting immune response. One of the mechanisms whereby conventional chemotherapeutics, targeted anticancer agents and radiotherapy can provoke a therapeutically relevant, adaptive immune response against malignant cells is commonly known as „immunogenic cell death (ICD. Importantly, dying cancer cells are perceived as immunogenic only when they emit a set of immunostimulatory signals upon the activation of intracellular stress response pathways. The emission of these signals, which are generally referred to as „damage-associated molecular patterns (DAMPs, may therefore predict whether patients will respond to chemotherapy or not, at least in some settings. Here, we review clinical data indicating that DAMPs and DAMP-associated stress responses might have prognostic or predictive value for cancer patients.

  2. pH-Responsive Hyaluronic Acid-Based Mixed Micelles for the Hepatoma-Targeting Delivery of Doxorubicin

    Wu, Jing-Liang; Tian, Gui-Xiang; Yu, Wen-Jing; Jia, Guang-Tao; Sun, Tong-Yi; Gao, Zhi-Qin

    2016-01-01

    The tumor targetability and stimulus responsivity of drug delivery systems are crucial in cancer diagnosis and treatment. In this study, hepatoma-targeting mixed micelles composed of a hyaluronic acid–glycyrrhetinic acid conjugate and a hyaluronic acid-l-histidine conjugate (HA–GA/HA–His) were prepared through ultrasonic dispersion. The formation and characterization of the mixed micelles were confirmed via 1H-NMR, particle size, and ζ potential measurements. The in vitro cellular uptake of the micelles was evaluated using human liver carcinoma (HepG2) cells. The antitumor effect of doxorubicin (DOX)-loaded micelles was investigated in vitro and in vivo. Results indicated that the DOX-loaded HA–GA/HA–His micelles showed a pH-dependent controlled release and were remarkably absorbed by HepG2 cells. Compared with free DOX, the DOX-loaded HA–GA/HA–His micelles showed a higher cytotoxicity to HepG2 cells. Moreover, the micelles effectively inhibited tumor growth in H22 cell-bearing mice. These results suggest that the HA–GA/HA–His mixed micelles are a good candidate for drug delivery in the prevention and treatment of hepatocarcinoma. PMID:27043540

  3. Hyaluronic Acid Modified Hollow Prussian Blue Nanoparticles Loading 10-hydroxycamptothecin for Targeting Thermochemotherapy of Cancer

    Jing, Lijia; shao, shangmin; Wang, Yang; Yang, Yongbo; Yue, Xiuli; Dai, Zhifei

    2016-01-01

    This paper reported the fabrication of a multifunctional nanoplatform by modifying hollow Prussian blue nanoparticles with hyaluronic acid grafting polyethylene glycol, followed by loading 10-hydroxycamptothecin for tumor-targeted thermochemotherapy. It was found that the surface modification of hollow Prussian blue nanoparticles with hyaluronic acid grafting polyethylene endowed a great colloidal stability, long blood circulation time and the capability for targeting Hela cells over-expressing the CD44 receptor. The obtained nanoagent exhibited efficient photothermal effect and a light triggered and stepwise release behavior of 10-hydroxycamptothecin due to the strong optical absorption in the near-infrared region. The investigations on the body weight change, histological injury and blood biochemical indexes showed that such nanoagent had excellent biocompatibility for medical application. Both in vitro and in vivo experiments proved that the combination of chemotherapy and photothermal therapy through the agent of hyaluronic acid modified Prussian blue nanoparticles loading 10-hydroxycamptothecin could significantly improve the therapeutic efficacy compared with either therapy alone because of a good synergetic effect. PMID:26722372

  4. Computer simulation dose studies in heterogeneous media for electron and proton beam radiotherapy of static and moving targets

    Lee, Tae Kyu

    The energy-dependent electron loss model (ELM) and proton loss model (PLM) have been developed to predict dose deposition in heterogeneous slab media. Predictions of dose deposition in heterogeneous slab media are compared to the Monte Carlo calculations and experimental measurements. Slab media studied comprised water/bone/water and water/lung/water and incident beam energies between 10MeV and 18MeV for electron beams and 100MeV and 160MeV for proton beams. Dose discrepancies at large depths beyond the interface were within 5% of maximum dose. This error may be attributed to the assumption of a Gaussian energy distribution for the charge particles at depth. The computational cost is low compared to Monte Carlo simulations making the ELM and PLM attractive as a fast dose engine for dose optimization algorithms. To simulate a more realistic and challenging clinical treatment, a mathematical 3-D phantom was defined to simulate inferior-superior motion of a lung tumor target. Lung size and density change during the breathing cycle was modeled from full inspiration to full expiration. Sensitivity to dose error due to the respiratory motion of the target and the right lung, defined as the organ at risk (OAR), was studied for intensity modulated proton therapy (IMPT) and intensity modulated x-ray therapy (IMXT). Effects of rotational or lateral setup error on the dose distribution were studied independently and simultaneously with breathing.

  5. Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials

    To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs.

  6. 间质干细胞与肿瘤的关系研究进展%Mesenchymal stem cells and tumor

    田超; 江国荣; 周梁; 刘兆国; 朱智杰; 郑仕中; 王爱云; 陆茵

    2013-01-01

    Mesenchymal stem cells ( MSCs ),with a high degree of self-renewal and differentiation potential and well organized migration and tumor targeting, are from the mesoderm and are a class of non-hematopoietic stem cells. Extensive research has been carried out in the anti-tumor therapy of MSCs. MSCs can be used as a cell vehicle to resist tumots, meanwhile MSCs can promote malignant behavior of tumor by promoting tumor angio-genesis, immunesuppression and differentiating to tumor-associated fibroblasts. This article is a brief overview of the research progress in recent years in the field.%间质干细胞(mesenchymal stem cells,MSCs)是来源于中胚层的一类具有高度自我更新能力和多向分化潜能的非造血干细胞,具有很好的组织迁移能力和肿瘤靶向性.MSCs用于抗肿瘤治疗已经开展了广泛的研究,MSCs可以作为细胞载体发挥抗肿瘤作用,同时通过促肿瘤血管生成、免疫抑制、分化为肿瘤相关成纤维细胞等方式促进肿瘤的恶性行为.该文对近年来该领域的研究进展进行简要综述.

  7. A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer

    Kandalaft Lana E

    2012-08-01

    Full Text Available Abstract Purpose In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Rationale Genetically reprogrammed, patient-derived chimeric antigen receptor (CAR-T lymphocytes with the ability to recognize predefined surface antigens with high specificity in a non-MHC restricted manner have shown increasing anti-tumor efficacy in preclinical and clinical studies. Folate receptor-α (FRα is an ovarian cancer-specific tumor target; however, it is expressed at low levels in certain organs with risk for toxicity. Design Here we propose a phase I study testing the feasibility, safety and preliminary activity of FRα-redirected CAR-T cells bearing the CD137 (4-1BB costimulatory domain, administered after lymphodepletion for the treatment of recurrent ovarian cancer. A novel trial design is proposed that maximizes safety features. Innovation This design involves an initial accelerated dose escalation phase of FR-α CAR-T cells followed by a standard 3 + 3 escalation phase. A split-dose approach is proposed to mitigate acute adverse events. Furthermore, infusion of bulk untransduced autologous peripheral blood lymphocytes (PBL is proposed two days after CAR-T cell infusion at the lower dose levels of CAR-T cells, to suppress excessive expansion of CAR-T cells in vivo and mitigate toxicity.

  8. Characterization of human γδ T lymphocytes infiltrating primary malignant melanomas.

    Adriana Cordova

    Full Text Available T lymphocytes are often induced naturally in melanoma patients and infiltrate tumors. Given that γδ T cells mediate antigen-specific killing of tumor cells, we studied the representation and the in vitro cytokine production and cytotoxic activity of tumor infiltrating γδ T cells from 74 patients with primary melanoma. We found that γδ T cells represent the major lymphocyte population infiltrating melanoma, and both Vδ1(+ and Vδ2(+ cells are involved. The majority of melanoma-infiltrating γδ cells showed effector memory and terminally-differentiated phenotypes and, accordingly, polyclonal γδ T cell lines obtained from tumor-infiltrating immune cells produced IFN-γ and TNF-α and were capable of killing melanoma cell lines in vitro. The cytotoxic capability of Vδ2 cell lines was further improved by pre-treatment of tumor target cells with zoledronate. Moreover, higher rate of γδ T cells isolation and percentages of Vδ2 cells correlate with early stage of development of melanoma and absence of metastasis. Altogether, our results suggest that a natural immune response mediated by γδ T lymphocytes may contribute to the immunosurveillance of melanoma.

  9. A new approach to cancer therapy due to appropriate uptake and retention kinetics of meta-tetrahydroxy-phenylchlorin in a human fibroblast cell line.

    Wierrani, F; Fiedler, D; Schnitzhofer, G; Stewart, J C; Gharehbaghi, K; Henry, M; Grin, W; Grünberger, W; Krammer, B

    1996-04-01

    Studies have shown that meta-tetrahydroxy-phenylchlorin is an efficient tumor targeting agent for laser photodynamic therapy. The effectiveness of this approach for cancer treatment depends on drug concentration, incubation time and extracellular protein. We studied uptake and retention kinetics of mTHPC in a human fibroblast cell line. Our results clearly demonstrate a difference in the amount of extracellular mTHPC at an incubation temperature of 37 degrees C compared to 20 degrees C and 4 degrees C. pH-values were always constant and not responsible for the increase. Furthermore, both absorption and fluorescence of mTHPC increase when incubated at normal human body temperature. Incubation of human fibroblast cells with mTHPC (10 micg/mL) showed that intracellular mTHPC increases in a linear manner reaching saturation after 24 hours and declining until 48 hours with concommitant increase of supernatant mTHPC. Therefore, we believe that tumor cells can be treated optimally with PDT following a delay > 24 hours after drug administration with a minimum of damage to surrounding normal tissues. PMID:8937740

  10. Studies of the antitumor and immunomodulatory characteristics of an extract of Momordica charantia

    Cunnick, J.E.

    1987-01-01

    An extract from the fruit of the bitter melon (BME), Momordica charantia is able to act as a biological response modifier in the murine system. Injection of 8 ..mu..g of BME protein, intraperitoneally induces an infiltration of lymphocytes into the peritoneal cavity. These peritoneal exudate cells (PEC) are cytotoxic to a wide range of tumor targets, including the NK sensitive tumor cell line, YAC-1. Injections of BME given twice a week augments tumor cytotoxic PEC, for 4 weeks. Fractionation of BME induced PEC revealed that the non-specific, tumor cytotoxic population of PEC were non-adherent mononuclear cells. Fractionation of PEC using unit gravity sedimentation revealed that the cytotoxic population is either a neutrophil or a large granular lymphocyte (LGL) as observed in the /sup 51/Cr-release assay. The antitumor activity of the BME which confers a tumor-dormant state on L1210 tumor-bearing mice was found to correlate with an increase in tumor cytotoxic cells in the PEC of BME injected mice. Tumor-bearing mice which received treatment with saline did not exhibit any tumor cytotoxic activity. Oral administration of the BME augmented splenic NK cytotoxicity. BME is highly antigenic. The formation of antibodies against the BME is detectable by a solid-phase radioimmunoassay after three weeks of ip injections (two/week). The mechanism of NK activation is still unknown. Results indicated that a BME does not induce the production of interleukin-2 or interferon.

  11. Determining iron oxide nanoparticle heating efficiency and elucidating local nanoparticle temperature for application in agarose gel-based tumor model.

    Shah, Rhythm R; Dombrowsky, Alexander R; Paulson, Abigail L; Johnson, Margaret P; Nikles, David E; Brazel, Christopher S

    2016-11-01

    Magnetic iron oxide nanoparticles (MNPs) have been developed for magnetic fluid hyperthermia (MFH) cancer therapy, where cancer cells are treated through the heat generated by application of a high frequency magnetic field. This heat has also been proposed as a mechanism to trigger release of chemotherapy agents. In each of these cases, MNPs with optimal heating performance can be used to maximize therapeutic effect while minimizing the required dosage of MNPs. In this study, the heating efficiencies (or specific absorption rate, SAR) of two types of MNPs were evaluated experimentally and then predicted from their magnetic properties. MNPs were also incorporated in the core of poly(ethylene glycol-b-caprolactone) micelles, co-localized with rhodamine B fluorescent dye attached to polycaprolactone to monitor local, nanoscale temperatures during magnetic heating. Despite a relatively high SAR produced by these MNPs, no significant temperature rise beyond that observed in the bulk solution was measured by fluorescence in the core of the magnetic micelles. MNPs were also incorporated into a macro-scale agarose gel system that mimicked a tumor targeted by MNPs and surrounded by healthy tissues. The agarose-based tumor models showed that targeted MNPs can reach hyperthermia temperatures inside a tumor with a sufficient MNP concentration, while causing minimal temperature rise in the healthy tissue surrounding the tumor. PMID:27523991

  12. Folate-conjugated beta-cyclodextrin-based polymeric micelles with enhanced doxorubicin antitumor efficacy.

    Zhang, Lu; Lu, Jiafei; Jin, Yangmin; Qiu, Liyan

    2014-10-01

    In order to enhance the antitumor effects of doxorubicin (DOX), a novel micellar vector with high DOX loading and tumor targeting function based on folate-conjugated amphiphilic copolymer folate-poly(ethylene glycol)-poly(d,l-lactide)-β-cyclodextrin (FA-PEL-CD) was constructed. Cytotoxicity and cellular uptake experiments were performed in HeLa, KB, and A549 cell lines expressing different amounts of folate receptors in order to evaluate the targeting effect of the folate modification. The antitumor experiments performed in a KB cell-xenografted nude mouse model showed that the treatment with 10mg/kg DOX loaded FA-PEL-CD micelles achieved approximately 86% of tumor growth inhibition compared to the control. Ex vivo fluorescence imaging experiments and histological examination confirmed that folate modification can enhance the antitumorigenesis efficacy and reduce the cardiotoxicity of DOX. These results suggest that FA-PEL-CD copolymer-based micelles are promising nanocarriers for targeted doxorubicin delivery, with improved antitumor efficacy and reduced toxicity in normal tissues. PMID:25058857

  13. Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity

    Ulrich Wuellner

    2015-12-01

    Full Text Available CD3 bispecific therapies retargeting T cells to tumors have recently demonstrated striking activity in patients. Several CD3 bispecific antibodies directed against various tumor targets are currently being investigated in the clinic across different tumors. One limitation of these therapies is the risk of target-related toxicity due to low-level expression of tumor antigen in normal tissue. In this study we have engineered a bispecific CD3/HER2 FynomAb, COVA420, which redirects T cells with high potency and selectivity to tumor cells with high HER2 expression in vitro and in vivo. COVA420 activity depends on high HER2 density as no activity was observed on cells with lower HER2 levels as found in human normal tissue. These results suggest that COVA420 may spare normal tissue expressing low levels of HER2 while still having uncompromised efficacy on tumor cells with high HER2 expression. This concept may be applied to other cancer antigens that otherwise cannot be targeted by T cell redirecting approaches, and may therefore expand the applicability of CD3 bispecific FynomAbs to a larger number of solid tumors.

  14. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy

    Xiang-Hong Peng

    2008-10-01

    Full Text Available Xiang-Hong Peng1,4, Ximei Qian2,4, Hui Mao3,4, Andrew Y Wang5, Zhuo (Georgia Chen1,4, Shuming Nie2,4, Dong M Shin1,4*1Department of Medical Oncology/Hematology; 2Department of Biomedical Engineering; 3Department of Radiology; 4Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 5Ocean Nanotech, LLC, Fayetteville, AR, USAAbstract: Magnetic iron oxide (IO nanoparticles with a long blood retention time, biodegradability and low toxicity have emerged as one of the primary nanomaterials for biomedical applications in vitro and in vivo. IO nanoparticles have a large surface area and can be engineered to provide a large number of functional groups for cross-linking to tumor-targeting ligands such as monoclonal antibodies, peptides, or small molecules for diagnostic imaging or delivery of therapeutic agents. IO nanoparticles possess unique paramagnetic properties, which generate significant susceptibility effects resulting in strong T2 and T*2 contrast, as well as T1 effects at very low concentrations for magnetic resonance imaging (MRI, which is widely used for clinical oncology imaging. We review recent advances in the development of targeted IO nanoparticles for tumor imaging and therapy.Keywords: iron oxide nanoparticles, tumor imaging, MRI, therapy

  15. Radio-immunotherapy

    Radioimmunotherapy (R.I.T.) is a new modality of targeted therapy in which irradiation from radionuclides is delivered to tumor targets using monoclonal antibodies (MAb) directed to tumor-associated antigen. R.I.T. has been developed for more than 20 years. Today, R.I.T. can be used in clinical practice using non-ablative activity of murine anti-CD20 90Y-ibritumomab tiuxetan (Zevalin) for treatment of patients with relapsed or refractory follicular lymphomas (F.L.), with overall response rate of 70 to 80% and 20 to 30% of complete response. Different approaches are explored to improve efficacy of R.I.T. in N.H.L.: myelo-ablative R.I.T. or HD treatment, R.I.T. as consolidation after chemotherapy to target M.R.D., R.I.T. in first-line treatment, fractionated R.I.T., R.I.T. using other Ag targets. For solid tumors, interesting results have been obtained using anti-CEA R.I.T. delivered as consolidation treatment or using pre-targeting system. (authors)

  16. The performance of PEGylated nanocapsules of perfluorooctyl bromide as an ultrasound contrast agent.

    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. PMID:19948357

  17. Multimodal Imaging of Nanocomposite Microspheres for Transcatheter Intra-Arterial Drug Delivery to Liver Tumors

    Kim, Dong-Hyun; Li, Weiguo; Chen, Jeane; Zhang, Zhuoli; Green, Richard M.; Huang, Sui; Larson, Andrew C.

    2016-07-01

    A modern multi-functional drug carrier is critically needed to improve the efficacy of image-guided catheter-directed approaches for the treatment of hepatic malignancies. For this purpose, a nanocomposite microsphere platform was developed for selective intra-arterial transcatheter drug delivery to liver tumors. In our study, continuous microfluidic methods were used to fabricate drug-loaded multimodal MRI/CT visible microspheres that included both gold nanorods and magnetic clusters. The resulting hydrophilic, deformable, and non-aggregated microspheres were mono-disperse and roughly 25 um in size. Sustained drug release and strong MRI T2 and CT contrast effects were achieved with the embedded magnetic nano-clusters and radiopaque gold nanorods. The microspheres were successfully infused through catheters selectively placed within the hepatic artery in rodent models and subsequent distribution in the targeted liver tissues and hepatic tumors confirmed with MRI and CT imaging. These multimodal nanocomposite drug carriers should be ideal for selective intra-arterial catheter-directed administration to liver tumors while permitting MRI/CT visualization for patient-specific confirmation of tumor-targeted delivery.

  18. Biocompatible Hollow Polydopamine Nanoparticles Loaded Ionic Liquid Enhanced Tumor Microwave Thermal Ablation in Vivo.

    Tan, Longfei; Tang, Wenting; Liu, Tianlong; Ren, Xiangling; Fu, Changhui; Liu, Bo; Ren, Jun; Meng, Xianwei

    2016-05-11

    Tumor microwave thermal therapy (MWTT) has attracted more attention because of the minimal damage to body function, convenient manipulation and low complications. Herein, a novel polydopamine (PDA) nanoparticle loading ionic liquids (ILs/PDA) as microwave susceptible agent is introduced for enhancing the selectivity and targeting of MWTT. ILs/PDA nanocomposites have an excellent microwave heating efficiency under an ultralow microwave power irradiation. Encouraging antitumor effect was observed when tumor bearing mice received ILs/PDA nanoparticles by intravenous injection and only single microwave irradiation. PDA nanoparticles with gold nanoparticles in core were constructed for tumor targeting study by ICP-MS and about 15% PDA nanoparticles were founded in tumor. Furthermore, the cytotoxicity and acute toxicity study in vivo of PDA showed the excellent biocompatibility of ILs/PDA nanocomposites. In addition, the degradation of ILs/PDA nanocomposites in simulated body fluid illustrated the low potential hazard when they entered the blood. The emergence of PDA as a novel and feasible platform for cancer thermal therapy will promote the rapid development of microwave therapy in clinics. PMID:27089478

  19. Highly Stable PEGylated Poly(lactic-co-glycolic acid) (PLGA) Nanoparticles for the Effective Delivery of Docetaxel in Prostate Cancers

    Cao, Long-Bin; Zeng, Sha; Zhao, Wei

    2016-06-01

    In the present study, a highly stable luteinizing-hormone-releasing hormone (LHRH)-conjugated PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles were developed for the successful treatment of prostate cancers. We have demonstrated that a unique combination of targeted drug delivery and controlled drug release is effective against prostate cancer therapy. The docetaxel (DTX)/PLGA-LHRH micelles possessed a uniform spherical shape with an average diameter of ~170 nm. The micelles exhibited a controlled drug release for up to 96 h which can minimize the non-specific systemic spread of toxic drugs during circulation while maximizing the efficiency of tumor-targeted drug delivery. The LHRH-conjugated micelles showed enhanced cellular uptake and exhibited significantly higher cytotoxicity against LNCaP cancer cells. We have showed that PLGA-LHRH induced greater caspase-3 activity indicating its superior apoptosis potential. Consistently, LHRH-conjugated micelles induced threefold and twofold higher G2/M phase arrest than compared to free DTX or PLGA NP-treated groups. Overall, results indicate that use of LHRH-conjugated nanocarriers may potentially be an effective nanocarrier to effectively treat prostate cancer.

  20. Molecular Pathways: Breaking the Epithelial Cancer Barrier for Chimeric Antigen Receptor and T-cell Receptor Gene Therapy.

    Hinrichs, Christian S

    2016-04-01

    Adoptive transfer of T cells genetically engineered to express a tumor-targeting chimeric antigen receptor (CAR) or T-cell receptor (TCR) can mediate cancer regression in some patients. CARs are synthetic single-chain proteins that use antibody domains to target cell surface antigens. TCRs are natural heterodimeric proteins that can target intracellular antigens through recognition of peptides bound to human leukocyte antigens. CARs have shown promise in B-cell malignancies and TCRs in melanoma, but neither approach has achieved clear success in an epithelial cancer. Treatment of epithelial cancers may be particularly challenging because of a paucity of target antigens expressed by carcinomas and not by important healthy tissues. In addition, epithelial cancers may be protected by inhibitory ligands and soluble factors in the tumor microenvironment. One strategy to overcome these negative regulators is to modulate expression of T-cell genes to enhance intrinsic T-cell function. Programmable nucleases, which can suppress inhibitory genes, and inducible gene expression systems, which can enhance stimulatory genes, are entering clinical testing. Other work is delineating whether control of genes for immune checkpoint receptors (e.g.,PDCD1, CTLA4) and cytokine and TCR signaling regulators (e.g.,CBLB, CISH, IL12, IL15) can increase the antitumor activity of therapeutic T cells.Clin Cancer Res; 22(7); 1559-64. ©2016 AACR. PMID:27037253

  1. CRISPR-Cas9 as a Powerful Tool for Efficient Creation of Oncolytic Viruses.

    Yuan, Ming; Webb, Eika; Lemoine, Nicholas Robert; Wang, Yaohe

    2016-03-01

    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. PMID:26959050

  2. Three-dimensional velocity mapping of lung motion using vessel bifurcation pattern matching

    We present a new quantification technique for three-dimensional (3D) lung motion by means of tracking the anatomical features inside the lung using a set of sequential 3D-CT images (a 4D-CT image). The method is based on the conservation of topology, such as connections and junctions of vessels, during the motion. Lung CT images are used to do lung volume modeling, lung vessel extracting and thinning, and coordinates of vessel bifurcations are derived as feature points. Such feature points are tracked in a series of 3D-CT images, i.e., the points are individually tracked between two successive 3D-CT images, in which the lung is deformed. Consequently, 3D displacement vectors are obtained. The feature point tracking is carried out using point pattern matching with a probabilistic relaxation method. We examined this technique using a lung 3D-CT image and artificially deformed one, and separately scanned CT images for a rigid bifurcation phantom. The studies estimated that the error of the vectors is within ∼1 voxel, i.e., 1 mm or less. Therefore, the accuracy is expected to be high enough for radiation therapy. This technique enables us to quantify realistic 3D organ motion without any fiducial markers. It can be applied to the quantification of tumor (target volume) deformation by gridding interpolation into all voxels. We expect it to be useful for dose estimation in mobile organs and for 4D treatment planning in radiation therapy

  3. A curcumin-based TPA four-branched copper(II) complex probe for in vivo early tumor detection

    Pi, Zongxin [Department of Chemical and Chemical Engineering, Hefei Normal University, Hefei 230001 (China); Wang, Jiafeng; Jiang, Bo [Department of Pharmacy, Anhui University of Chinese Medicine, Hefei 230038 (China); Cheng, Gang [Department of Chemical and Chemical Engineering, Hefei Normal University, Hefei 230001 (China); Zhou, Shuangsheng, E-mail: zshuangsheng@126.com [Department of Pharmacy, Anhui University of Chinese Medicine, Hefei 230038 (China); Center of Modern Experimental Technology, Anhui University, Hefei 230038 (China)

    2015-01-01

    A multibranched Cu(II) complex CuL{sub 2} curcumin-based was synthesized and characterized by single-crystal X-ray diffraction analysis. The photophysical properties of the complex have been investigated both experimentally and theoretically. The results show that the target complex exhibits higher quantum yield and larger two-photon absorption (TPA) cross-section in the near infrared (NIR) region compared with its free ligand. The cell imaging studies in vitro and in vivo reveal that the complex shows good photostability and excellent tumor targeting capability to tested cancerous cells, which can be potentially used for early tumor detection. - Graphical abstract: A multibranched Cu(II) complex was prepared from curcumin. The photophysical properties of the obtained complex have been investigated. The results exhibit that the complex has high capability to test cancerous cells and can distinguish between the cancerous and noncancerous cells, which should be potentially used for early tumor detection. - Highlights: • A novel multi-branched copper complex was synthesized. • The obtained compounds exhibited obvious TPA in high polar solvents. • The complex is a low toxicity at low-micromolar concentrations. • The complex exhibits larger TPA cross-section and brighter TPF imaging. • The complex has excellent targeting capability to tested cancerous cells.

  4. A preclinical study of boron neutron capture therapy (BNCT) of spontaneous tumors in cats at RA-6 in Argentina

    BNCT is a binary treatment modality that combines irradiation with a thermal or epithermal neutron beam with tumor-seeking, boron containing drugs to produce selective irradiation of tumor tissue. Having demonstrated that BNCT mediated by boronophenylalanine (BPA) induced control of experimental squamous cell carcinomas (SCC) of the hamster cheek pouch mucosa with no damage to normal tissue we explored the feasibility and safety of treating spontaneous head and neck tumors, with particular focus on SCC, of terminal feline patients with low dose BPA-BNCT employing the thermal beam of RA-1. Having demonstrated partial tumor control with no radio toxic effects, the aim of the present study was to evaluate the effect of BPA-BNCT on tumor and normal tissue in 3 cases of spontaneous SCC in feline patients employing a higher neutron fluence than in the previous study. The present study was performed at RA-6 with the thermalized epithermal neutron beam. All three irradiations were successful. Except for an initial, moderate and reversible mucositis, no significant radio toxic effects were observed in terms of clinical follow-up, histological examination, biochemical analysis and assessment of autopsy material. Partial tumor control was evidenced in terms of growth inhibition and partial necrosis and improvement in the quality of life during the survival period. Optimization of the therapeutic efficacy of BNCT would require improvement in boron tumor targeting and strategies to increase in-depth dose in large tumors. (author)

  5. Pegylated polyelectrolyte nanoparticles containing paclitaxel as a promising candidate for drug carriers for passive targeting.

    Szczepanowicz, Krzysztof; Bzowska, Monika; Kruk, Tomasz; Karabasz, Alicja; Bereta, Joanna; Warszynski, Piotr

    2016-07-01

    Targeted drug delivery systems are of special importance in cancer therapies, since serious side effects resulting from unspecific accumulation of highly toxic chemotherapeutics in healthy tissues can restrict effectiveness of the therapy. In this work we present the method of preparing biocompatible, polyelectrolyte nanoparticles containing the anticancer drug that may serve as a vehicle for passive tumor targeting. The nanoparticles were prepared via direct encapsulation of emulsion droplets in a polyelectrolyte multilayer shell. The oil cores that contained paclitaxel were stabilized by docusate sodium salt/poly-l-lysine surface complex (AOT/PLL) and were encapsulated in shells formed by the LbL adsorption of biocompatible polyelectrolytes, poly-L-glutamic acid (PGA) and PLL up to 5 or 6 layers. The surface of the nanoparticles was pegylated through the adsorption of the pegylated polyelectrolyte (PGA-g-PEG) as the outer layer to prolong the persistence of the nanocarriers in the circulation. The synthesized nanoparticles were stable in cell culture medium containing serum and their average size was 100nm, which makes them promising candidates for passive targeted drug delivery. This notion was further confirmed by the results of studying the biological effects of nanoformulations on two tumor cell lines: mouse colon carcinoma cell line CT26-CEA and the mouse mammary carcinoma cell line 4T1. The empty polyelectrolyte nanoparticles did not affect the viability of the tested cells, whereas encapsulated paclitaxel retained its strong cytotoxic/cytostatic activity. PMID:27037784

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

    Hou Dong Zuo

    2014-01-01

    Full Text Available 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 transfected into cells using iRGD. Despite the many kinds of cell labeling studies that have been performed with SPIO nanoparticles and RGD peptide or its analogues, only a few have applied SPIO nanoparticles with iRGD peptide in pancreatic cancer cells. This paper reports our preliminary findings regarding the effect of iRGD peptide (CRGDK/RGPD/EC combined with SPIO on the labeling of pancreatic cancer cells. The results suggest that SPIO with iRGD peptide can enhance the positive labeling rate of cells and the uptake of SPIO. Optimal functionalization was achieved with the appropriate concentration or concentration range of SPIO and iRGD peptide. This study describes a simple and economical protocol to label panc-1 cells using SPIO in combination with iRGD peptide and may provide a useful method to improve the sensitivity of pancreatic cancer imaging.

  7. Indocyanine Green Loaded Reduced Graphene Oxide for In Vivo Photoacoustic/Fluorescence Dual-Modality Tumor Imaging

    Chen, Jingqin; Liu, Chengbo; Zeng, Guang; You, Yujia; Wang, Huina; Gong, Xiaojing; Zheng, Rongqin; Kim, Jeesu; Kim, Chulhong; Song, Liang

    2016-02-01

    Multimodality imaging based on multifunctional nanocomposites holds great promise to fundamentally augment the capability of biomedical imaging. Specifically, photoacoustic and fluorescence dual-modality imaging is gaining much interest because of their non-invasiveness and the complementary nature of the two modalities in terms of imaging resolution, depth, sensitivity, and speed. Herein, using a green and facile method, we synthesize indocyanine green (ICG) loaded, polyethylene glycol (PEG)ylated, reduced nano-graphene oxide nanocomposite (rNGO-PEG/ICG) as a new type of fluorescence and photoacoustic dual-modality imaging contrast. The nanocomposite is shown to have minimal toxicity and excellent photoacoustic/fluorescence signals both in vitro and in vivo. Compared with free ICG, the nanocomposite is demonstrated to possess greater stability, longer blood circulation time, and superior passive tumor targeting capability. In vivo study shows that the circulation time of rNGO-PEG/ICG in the mouse body can sustain up to 6 h upon intravenous injection; while after 1 day, no obvious accumulation of rNGO-PEG/ICG is found in any major organs except the tumor regions. The demonstrated high fluorescence/photoacoustic dual contrasts, together with its low toxicity and excellent circulation life time, suggest that the synthesized rNGO-PEG/ICG can be a promising candidate for further translational studies on both the early diagnosis and image-guided therapy/surgery of cancer.

  8. A Biomimic Reconstituted High-Density-Lipoprotein-Based Drug and p53 Gene Co-delivery System for Effective Antiangiogenesis Therapy of Bladder Cancer

    Ouyang, Qiaohong; Duan, Zhongxiang; Jiao, Guangli; Lei, Jixiao

    2015-07-01

    A biomimic reconstituted high-density-lipoprotein-based drug and p53 gene co-delivery system (rHDL/CD-PEI/p53 complexes) was fabricated as a targeted co-delivery nanovector of drug and gene for potential bladder cancer therapy. Here, CD-PEI was utilized to effectively condense the p53 plasmid, to incorporate the plasmid into rHDL, and to act as an antitumor drug to suppress tumor angiogenesis. The rHDL/CD-PEI/p53 complexes exhibited desirable and homogenous particle size, neutral surface charge, and low cytotoxicity in vitro. The results of confocal laser scanning microscopy and flow cytometry confirmed that SR-BI-targeted function induced specific cytoplasmic delivery and high gene transfection efficiency in MBT-2 murine bladder cells. In addition, rHDL/CD-PEI/p53 complexes co-delivering CD and p53 gene achieved synergistic angiogenesis suppression by more effectively downregulating the expression of vascular endothelial growth factor (VEGF) messenger RNA (mRNA) and protein via different pathways in vitro. In vivo investigation on C3H/He mice bearing MBT-2 tumor xenografts revealed that rHDL/CD-PEI/p53 complexes possessed strong antitumor activity. These findings suggested that rHDL/CD-PEI/p53 complexes could be an ideal tumor-targeting system for simultaneous transfer of drug and gene, which might be a new promising strategy for effective bladder cancer therapy.

  9. Liposome-based co-delivery of siRNA and docetaxel for the synergistic treatment of lung cancer.

    Qu, Mei-Hua; Zeng, Rui-Fang; Fang, Shi; Dai, Qiang-Sheng; Li, He-Ping; Long, Jian-Ting

    2014-10-20

    Combination of more than one therapeutic strategy is the standard treatment in clinics. Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a nanoparticulate system will suppress the tumor growth. In the present study, docetaxel (DTX) and BCL-2 siRNA was incorporated in a PEGylated liposome to systemically deliver in a lung cancer model (A549). The resulting nanoparticle (lipo-DTX/siRNA) was stable and exhibited a sustained release profile. The co-delivery of therapeutic moieties inhibited the cell proliferation (A549 and H226) in a time-dependent manner. Moreover, the co-delivery system of DTX and siRNA exhibited a remarkable apoptosis of cancer cells with elevated levels of caspase 3/7 activity (apoptosis markers). Cell cycle analysis further showed remarkable increase in sub-G0/G1 phase, indicating increasing hypodiploids or apoptotic cells. Pharmacokinetic study showed a long circulating profile for DTX from lipo-DTX/siRNA system facilitating the passive tumor targeting. In vivo antitumor study on A549 cell bearing xenograft tumor model exhibited a remarkable tumor regression profile for lipo-DTX/siRNA with 100% survival rate. The favorable tumor inhibition response was attributed to the synergistic effect of DTX potency and MDR reversing ability of BCL-2 siRNA in the tumor mass. Overall, experimental results suggest that co-delivery of DTX and siRNA could be promising approach in the treatment of lung cancers. PMID:25138252

  10. A multi-functional nanoplatform for tumor synergistic phototherapy

    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.

  11. BACTERIA IN CANCER THERAPY: AN EMERGING ROBUST STRATEGY

    Preenu P Sen

    2013-06-01

    Full Text Available Cancer is one of the leading causes of death in the world. Solid tumors account for 90% of all cancers. Despite rapid developments in the conventional modalities of cancer treatment (chemotherapy and radiotherapy there is still no definitive “cure” for cancer. The present observation aims to an eye on alternative cancer therapies. The search for alternative therapies dates back to early 1800’s when a patient was observed to recover spontaneously following an infection. This resulted in the birth of Coley’s toxin for the treatment of sarcomas and use of live Bacillus Calmette – Guerin (BCG for bladder cancer. The same provoked for a series of researches in this field, but was heralded due to lack of specificity, lack of complete tumor lyses and ineffectiveness against small tumors. However with the advent of recombinant DNA technology and its developments, it has paved the way for a new era for a tumor- targeted bacterial vector system for gene therapy of solid tumors. In this review we will discuss the potential of genetically manipulated bacteria that will usher in the new era of bacterial therapy for solid tumors.

  12. Protective Effect of HSP25 on Radiation Induced Tissue Damage

    Control of cancer by irradiation therapy alone or in conjunction with combination chemotherapy is often limited by organ specific toxicity. Ionizing irradiation toxicity is initiated by damage to normal tissue near the tumor target and within the transit volume of radiotherapy beams. Irradiation-induced cellular, tissue, and organ damage is mediated by acute effects, which can be dose limiting. A latent period follows recovery from the acute reaction, then chronic irradiation fibrosis (late effects) pose a second cause of organ failure. HSP25/27 has been suggested to protect cells against apoptotic cell death triggered by hyperthermia, ionizing radiation, oxidative stress, Fas ligand, and cytotoxic drugs. And several mechanisms have been proposed to account for HSP27-mediated apoptotic protection. However radioprotective effect of HSP25/27 in vivo system has not yet been evaluated. The aim of this study was to evaluate the potential of exogenous HSP25 expression, as delivered by adenoviral vectors, to protect animal from radiation induced tissue damage

  13. Gd(III)-DOTA-modified sonosensitive liposomes for ultrasound-triggered release and MR imaging

    Jung, Suk Hyun; Na, Kyunga; Lee, Seul A.; Cho, Sun Hang; Seong, Hasoo; Shin, Byung Cheol

    2012-08-01

    Ultrasound-sensitive (sonosensitive) liposomes for tumor targeting have been studied in order to increase the antitumor efficacy of drugs and decrease the associated severe side effects. Liposomal contrast agents having Gd(III) are known as a nano-contrast agent system for the efficient and selective delivery of contrast agents into pathological sites. The objective of this study was to prepare Gd(III)-DOTA-modified sonosensitive liposomes (GdSL), which could deliver a model drug, doxorubicin (DOX), to a specific site and, at the same time, be capable of magnetic resonance (MR) imaging. The GdSL was prepared using synthesized Gd(III)-DOTA-1,2-distearoyl- sn-glycero-3-phosphoethanolamine lipid. Sonosensitivity of GdSL to 20-kHz ultrasound induced 33% to 40% of DOX release. The relaxivities ( r 1) of GdSL were 6.6 to 7.8 mM-1 s-1, which were higher than that of MR-bester®. Intracellular uptake properties of GdSL were evaluated according to the intensity of ultrasound. Intracellular uptake of DOX for ultrasound-triggered GdSL was higher than that for non-ultrasound-triggered GdSL. The results of our study suggest that the paramagnetic and sonosensitive liposomes, GdSL, may provide a versatile platform for molecular imaging and targeted drug delivery.

  14. Mechanism and energetics for complexation of 90Y with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a model for cancer radioimmunotherapy

    A promising cancer therapy involves the use of the macrocyclic polyaminoacetate DOTA (1,4,6,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) attached to a tumor-targeting antibody complexed with the β emitter 90Y3+. However, incorporation of the 90Y into the DOTA conjugate is too slow. To identify the origins of this problem, ab initio quantum chemistry methods (B3LYP/:ACVP* and HF/LACVP*) were used to predict structures and energetics. The authors find that the initial complex YH2(DOTA)+ is 4-coordinate (the four equivalent carboxylate oxygens), which transforms to YH(DOTA) (5-coordinate with one ring N and four carboxylate oxygens), and finally to Y(DOTA)-, which is 8-coordinate (four oxygens and four nitrogens). The rate-determining step is the conversion of YH(DOTA) to Y(DOTA)-, which was calculated to have an activation free energy (aqueous phase) of 8.4 kcal/mol, in agreement with experimental results (8.1--9.3 kcal/mol) for various metals to DOTA [Kumar, K.; Tweedle, M.F. Inorg. Chem. 1993, 32, 4193--4199; Wu, S.L.; Horrocks, W.D., Jr., Inorg. Chem. 1995, 34, 3724--2732]. On the basis of this mechanism the authors propose a modified chelate, DO3AlPr, which has calculated at a much faster rate of incorporation

  15. Diversity of radioprobes targeted to tumor angiogenesis on molecular functional imaging

    Molecular functional imaging could visualize, characterize, and measure the bio- logical processes including tumor angiogenesis at the molecular and cellular levels in humans and other living systems. The molecular probes labeled by a variety of radionuclide used in the field of the nuclear medicine play pivotal roles in molecular imaging of tumor angiogenesis. However, the regulatory role of different probes in tumor angiogenesis has not been systematically illustrated. The current status of tumor angiogenesis imaging with radiolabeled probes of peptide, monoclonal antibody as well as its fragment, especially nanoparticle-based probes to gain insights into the robust tumor angiogenesis development were summarized. It was recognized that only the probes such as nanoparticle-based probes, which truly target the tumor vasculature rather than tumor cells because of poor extravasation, are really tumor angiogenesis imaging agent. The research of molecular probe targeted to angiogenesis would meet its flourish just after the outstanding improvements in the in vivo stability and biocompatibility, tumor-targeting efficacy, and pharmacokinetics of tumor angiogenesis imaging probes are made. Translation to clinical applications will also be critical for the maximize benefits of these novel agents. The future of tumor angiogenesis imaging lies in liable imaging probes and multiple imaging modalities, imaging of protein-protein interactions, and quantitative molecular imaging. (authors)

  16. Activated Charge-Reversal Polymeric Nano-System: The Promising Strategy in Drug Delivery for Cancer Therapy

    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.

  17. Aptamer-conjugated gold nanorod for photothermal ablation of epidermal growth factor receptor-overexpressed epithelial cancer

    Choi, Jihye; Park, Yeonji; Choi, Eun Bi; Kim, Hyun-Ouk; Kim, Dong Joo; Hong, Yoochan; Ryu, Sung-Ho; Lee, Jung Hwan; Suh, Jin-Suck; Yang, Jaemoon; Huh, Yong-Min; Haam, Seungjoo

    2014-05-01

    Biomarker-specific photothermal nanoparticles that can efficiently sense markers that are overexpressed in distinguished adenocarcinomas have attracted much interest in an aspect of efficacy increase of cancer treatment. We demonstrated a promising prospect of a smart photothermal therapy agent employing anti-epidermal growth factor receptor aptamer (AptEGFR)-conjugated polyethylene glycol (PEG) layted gold nanorods (AptEGFR-PGNRs). The cetyltrimethylammonium bromide bilayer on GNRs was replaced with heterobifunctional PEG (COOH-PEG-SH) not only to serve as a biocompatible stabilizer and but also to conjugate Apt. Subsequently, to direct photothermal therapy agent toward epithelial cancer cells, the carboxylated PEGylated GNRs (PGNRs) were further functionalized with Apt using carbodiimide chemistry. Then, to assess the potential as biomarker-specific photothermal therapy agent of synthesized Apt-PGNRs, the optical properties, biocompatibility, colloidal stability, binding affinity, and epicellial cancer cell killing efficacy in vitro/in vivo under near-infrared laser irradiation were investigated. As a result, Apt-PGNRs exhibit excellent tumor targeting ability and feasibility of effective photothermal ablation cancer therapy.

  18. Regulation of IL-2 induced proliferation and cytotoxicity in human natural killer cells by monoclonal antibodies

    Natural killer (NK) activity is mediated by a subpopulation of cells termed large granular lymphocytes (LGL), which exhibit cytotoxic activity against a variety of tumor targets. LGL express OKT8, OKT9, OKT10, OKT11, 3G8 (FcγR), OKM1, NKH1. The addition of recombinant IL-2 (rIL-2), increases cytotoxicity, induces IFN-γ production and leads to LGL proliferation. Since monoclonal antibodies (MoAb) represent highly specific probes to analyze possible surface molecules, they have studied the role of various MoAbs in the regulation of cytotoxicity, proliferation, and secretory function of purified LGL. LGL were isolated from nonadherent human peripheral blood leukocytes on discontinuous Percoll density gradients, followed by 290C E-rosette depletion of contaminating T cells. These preparations were ≥ 85% LGL and contained ≥ 5% OKT3+ cells. Using a limiting dilution assay, purified LGL were incubated with rIL-2 and the MoAbs (10 μg/ml) for 7 days. These cells were tested for cytotoxicity against K562 in a 51Cr- release assay, and for proliferation as determined by 3H-thymidine incorporation. Results indicate that the OKT9 antibody inhibited both the cytotoxicity and proliferation. MoAb against LGl markers (OKT11, OKT8, OKM1, 3G8, and NKH1) had no effect on cytotoxicity or proliferation. Unlike the T cell receptor complex (with OKT3), the surface molecules examined do not regulate LGL lysis or proliferation

  19. Use of the uteroglobin platform for the expression of a bivalent antibody against oncofetal fibronectin in Escherichia coli.

    Elisa Ventura

    Full Text Available Escherichia coli is a robust, economic and rapid expression system for the production of recombinant therapeutic proteins. However, the expression in bacterial systems of complex molecules such as antibodies and fusion proteins is still affected by several drawbacks. We have previously described a procedure based on uteroglobin (UG for the engineering of very soluble and stable polyvalent and polyspecific fusion proteins in mammalian cells (Ventura et al. 2009. J. Biol. Chem. 284∶26646-26654. Here, we applied the UG platform to achieve the expression in E. coli of a bivalent human recombinant antibody (L19 toward the oncofetal fibronectin (B-FN, a pan-tumor target. Purified bacterial L19-UG was highly soluble, stable, and, in all molecules, the L19 moiety maintained its immunoreactivity. About 50-70% of the molecules were covalent homodimer, however after refolding with the redox couple reduced-glutathione/oxidized-glutathione (GSH/GSSG, 100% of molecules were covalent dimers. Mass spectrometry studies showed that the proteins produced by E. coli and mammalian cells have an identical molecular mass and that both proteins are not glycosylated. L19-UG from bacteria can be freeze-dried without any loss of protein and immunoreactivity. In vivo, in tumor-bearing mice, radio-iodinated L19-UG selectively accumulated in neoplastic tissues showing the same performance of L19-UG from mammalian cells. The UG-platform may represent a general procedure for production of various biological therapeutics in E. coli.

  20. Octreotide-functionalized and resveratrol-loaded unimolecular micelles for targeted neuroendocrine cancer therapy

    Xu, Wenjin; Burke, Jocelyn F.; Pilla, Srikanth; Chen, Herbert; Jaskula-Sztul, Renata; Gong, Shaoqin

    2013-09-01

    Medullary thyroid cancer (MTC) is a neuroendocrine tumor (NET) that is often resistant to standard therapies. Resveratrol suppresses MTC growth in vitro, but it has low bioavailability in vivo due to its poor water solubility and rapid metabolic breakdown, as well as lack of tumor-targeting ability. A novel unimolecular micelle based on a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for NET-targeted delivery. The hyperbranched amphiphilic block copolymer consisted of a dendritic Boltorn® H40 core, a hydrophobic poly(l-lactide) (PLA) inner shell, and a hydrophilic poly(ethylene glycol) (PEG) outer shell. Octreotide (OCT), a peptide that shows strong binding affinity to somatostatin receptors, which are overexpressed on NET cells, was used as the targeting ligand. Resveratrol was physically encapsulated by the micelle with a drug loading content of 12.1%. The unimolecular micelles exhibited a uniform size distribution and spherical morphology, which were determined by both transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular uptake, cellular proliferation, and Western blot analyses demonstrated that the resveratrol-loaded OCT-targeted micelles suppressed growth more effectively than non-targeted micelles. Moreover, resveratrol-loaded NET-targeted micelles affected MTC cells similarly to free resveratrol in vitro, with equal growth suppression and reduction in NET marker production. These results suggest that the H40-based unimolecular micelle may offer a promising approach for targeted NET therapy.