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Sample records for system targeting tumor

  1. In vivo tumor targeting and anti-tumor effects of 5-fluororacil loaded, folic acid targeted quantum dot system.

    Science.gov (United States)

    Bwatanglang, Ibrahim Birma; Mohammad, Faruq; Yusof, Nor Azah; Abdullah, Jaafar; Alitheen, Noorjahan Banu; Hussein, Mohd Zubir; Abu, Nadiah; Mohammed, Nurul Elyani; Nordin, Noraini; Zamberi, Nur Rizi; Yeap, Swee Keong

    2016-10-15

    In this study, we modulated the anti-cancer efficacy of 5-Fluorouracil (5-FU) using a carrier system with enhanced targeting efficacy towards folate receptors (FRs) expressing malignant tissues. The 5-FU drug was loaded onto Mn-ZnS quantum dots (QDs) encapsulated with chitosan (CS) biopolymer and conjugated with folic acid (FA) based on a simple wet chemical method. The formation of 5-FU drug loaded composite was confirmed using Fourier transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Furthermore, the in vivo biodistribution and tumor targeting specificity of the 5-FU@FACS-Mn:ZnS in the tumor-bearing mice was conducted based on the Zn(2+) tissue bioaccumulation using inductively coupled plasma (ICP) spectroscopy. In addition to the characterization, the in vitro release profile of 5-FU from the conjugates investigated under diffusion controlled method demonstrated a controlled release behaviour as compared against the release behaviour of free 5-FU drug. The as-synthesized 5-FU@FACS-Mn:ZnS nanoparticle (NP) systemically induced higher level of apoptosis in breast cancer cells in vitro as compared to cells treated with free 5-FU drug following both cell cycle and annexin assays, respectively. Also, the in vivo toxicity assessment of the 5-FU@FACS-Mn:ZnS NPs as compared to the control did not cause any significant increase in the activities of the liver and kidney function biomarkers, malondialdehyde (MDA) and nitric oxide (NO) levels. However, based on the FA-FRs chemistry, the 5-FU@FACS-Mn:ZnS NPs specifically accumulated in the tumor of the tumor-bearing mice and thus contributed to the smaller tumor size and less event of metastasis was observed in the lungs when compared to the tumor-bearing mice groups treated with the free 5-FU drug. In summary, the results demonstrated that the 5-FU@FACS-Mn:ZnS QDs exhibits selective anti-tumor effect in MDA-MB231 breast cancer cells in vitro and 4TI breast

  2. Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

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    Han-Chung Wu

    2010-01-01

    Full Text Available Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

  3. Magnetic nanoparticle drug delivery systems for targeting tumor

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    Mody, Vicky V.; Cox, Arthur; Shah, Samit; Singh, Ajay; Bevins, Wesley; Parihar, Harish

    2014-04-01

    Tumor hypoxia, or low oxygen concentration, is a result of disordered vasculature that lead to distinctive hypoxic microenvironments not found in normal tissues. Many traditional anti-cancer agents are not able to penetrate into these hypoxic zones, whereas, conventional cancer therapies that work by blocking cell division are not effective to treat tumors within hypoxic zones. Under these circumstances the use of magnetic nanoparticles as a drug delivering agent system under the influence of external magnetic field has received much attention, based on their simplicity, ease of preparation, and ability to tailor their properties for specific biological applications. Hence in this review article we have reviewed current magnetic drug delivery systems, along with their application and clinical status in the field of magnetic drug delivery.

  4. Nanobody-Based Delivery Systems for Diagnosis and Targeted Tumor Therapy

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    Yaozhong Hu

    2017-11-01

    Full Text Available The development of innovative targeted therapeutic approaches are expected to surpass the efficacy of current forms of treatments and cause less damage to healthy cells surrounding the tumor site. Since the first development of targeting agents from hybridoma’s, monoclonal antibodies (mAbs have been employed to inhibit tumor growth and proliferation directly or to deliver effector molecules to tumor cells. However, the full potential of such a delivery strategy is hampered by the size of mAbs, which will obstruct the targeted delivery system to access the tumor tissue. By serendipity, a new kind of functional homodimeric antibody format was discovered in camelidae, known as heavy-chain antibodies (HCAbs. The cloning of the variable domain of HCAbs produces an attractive minimal-sized alternative for mAbs, referred to as VHH or nanobodies (Nbs. Apart from their dimensions in the single digit nanometer range, the unique characteristics of Nbs combine a high stability and solubility, low immunogenicity and excellent affinity and specificity against all possible targets including tumor markers. This stimulated the development of tumor-targeted therapeutic strategies. Some autonomous Nbs have been shown to act as antagonistic drugs, but more importantly, the targeting capacity of Nbs has been exploited to create drug delivery systems. Obviously, Nb-based targeted cancer therapy is mainly focused toward extracellular tumor markers, since the membrane barrier prevents antibodies to reach the most promising intracellular tumor markers. Potential strategies, such as lentiviral vectors and bacterial type 3 secretion system, are proposed to deliver target-specific Nbs into tumor cells and to block tumor markers intracellularly. Simultaneously, Nbs have also been employed for in vivo molecular imaging to diagnose diseased tissues and to monitor the treatment effects. Here, we review the state of the art and focus on recent developments with Nbs as

  5. Targeting the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

    2006-11-07

    Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.

  6. An intelligent re-shieldable targeting system for enhanced tumor accumulation.

    Science.gov (United States)

    Hu, Zhenpeng; Ma, Jinlong; Fu, Fei; Cui, Chen; Li, Xiaomin; Wang, Xinyu; Wang, Wei; Wan, Yeda; Yuan, Zhi

    2017-12-28

    Programmed ligand targeting strategy promotes the blood circulation stability of nanoparticles by shielding the ligand. However, the irreversible shielding causes the deshielded nanoparticles to be easily recognized and cleared by the reticuloendothelial system (RES), impeding their further retention in the tumor. Here, we for the first time prove the superiority of the intelligent re-shieldable targeting system that is based on the pH-responsive self-assembly/disassembly of gold nanoparticles. The system can enhance the stability of gold nanoparticles in the blood circulation (2.6-fold at 24h), reduce uptake by the RES (35% lower) and improve tumor accumulation (41% higher by analysis of gold content in tumor) effectively compared with the conventional irreversible system. Furthermore, preliminary study indicates that the system could be applied as computed tomography contrast agent in tumor imaging. The in vivo validity of the intelligent re-shieldable targeting system provides inspiration for the design of nanomaterials for cancer diagnosis and treatment. Copyright © 2017. Published by Elsevier B.V.

  7. 3D cell culture systems modeling tumor growth determinants in cancer target discovery.

    Science.gov (United States)

    Thoma, Claudio R; Zimmermann, Miriam; Agarkova, Irina; Kelm, Jens M; Krek, Wilhelm

    2014-04-01

    Phenotypic heterogeneity of cancer cells, cell biological context, heterotypic crosstalk and the microenvironment are key determinants of the multistep process of tumor development. They sign responsible, to a significant extent, for the limited response and resistance of cancer cells to molecular-targeted therapies. Better functional knowledge of the complex intra- and intercellular signaling circuits underlying communication between the different cell types populating a tumor tissue and of the systemic and local factors that shape the tumor microenvironment is therefore imperative. Sophisticated 3D multicellular tumor spheroid (MCTS) systems provide an emerging tool to model the phenotypic and cellular heterogeneity as well as microenvironmental aspects of in vivo tumor growth. In this review we discuss the cellular, chemical and physical factors contributing to zonation and cellular crosstalk within tumor masses. On this basis, we further describe 3D cell culture technologies for growth of MCTS as advanced tools for exploring molecular tumor growth determinants and facilitating drug discovery efforts. We conclude with a synopsis on technological aspects for on-line analysis and post-processing of 3D MCTS models. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Tumor targeting via integrin ligands

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    Udaya Kiran eMarelli

    2013-08-01

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

  9. An aptamer ligand based liposomal nanocarrier system that targets tumor endothelial cells.

    Science.gov (United States)

    Ara, Mst Naznin; Matsuda, Takashi; Hyodo, Mamoru; Sakurai, Yu; Hatakeyama, Hiroto; Ohga, Noritaka; Hida, Kyoko; Harashima, Hideyoshi

    2014-08-01

    The objective of this study was to construct our recently developed aptamer-modified targeted liposome nano-carrier (Apt-PEG-LPs) system to target primary cultured mouse tumor endothelial cells (mTEC), both in vitro and in vivo. We first synthesized an aptamer-polyethylene glycol 2000-distearoyl phosphoethanolamine (Apt-PEG2000-DSPE). The conjugation of the Apt-PEG2000-DSPE was confirmed by MALDI-TOF mass spectroscopy. A lipid hydration method was used to prepare Apt-PEG-LPs, in which the outer surface of the PEG-spacer was decorated with the aptamer. Apt-PEG-LPs were significantly taken up by mTECs. Cellular uptake capacity was observed both quantitatively and qualitatively using spectrofluorometry, and confocal laser scanning microscopy (CLSM), respectively. In examining the extent of localization of aptamer-modified liposomes that entered the cells, approximately 39% of the Apt-PEG-LPs were not co-localized with lysotracker, indicating that they had escaped from endosomes. The uptake route involved a receptor mediated pathway, followed by clathrin mediated endocytosis. This Apt-PEG-LP was also applied for in vivo research whether this system could target tumor endothelial cells. Apt-PEG-LP and PEG5000-DSPE modified Apt-PEG-LP (Apt/PEG5000-LP) were investigated by human renal cell carcinoma (OS-RC-2 cells) inoculating mice using CLSM. Apt-PEG-LP and Apt/PEG5000-LP showed higher accumulation on tumor vasculature compared to PEG-LP and the co-localization efficacy of Apt-PEG-LP and Apt/PEG5000-LP on TEC were quantified 16% and 25% respectively, which was also better than PEG-LP (3%). The findings suggest that this system is considerable promise for targeting tumor endothelial cells to deliver drugs or genes in vitro and in vivo. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. A Tumor-Targeted Nanodelivery System to Improve Early MRI Detection of Cancer

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    Kathleen F. Pirollo

    2006-01-01

    Full Text Available The development of improvements in magnetic resonance imaging (MRI that would enhance sensitivity, leading to earlier detection of cancer and visualization of metastatic disease, is an area of intense exploration. We have devised a tumor-targeting, liposomal nanodelivery platform for use in gene medicine. This systemically administered nanocomplex has been shown to specifically and efficiently deliver both genes and oligonucleotides to primary and metastatic tumor cells, resulting in significant tumor growth inhibition and even tumor regression. Here we examine the effect on MRI of incorporating conventional MRI contrast agent Magnevist® into our anti-transferrin receptor single-chain antibody (TfRscFv liposomal complex. Both in vitro and in an in vivo orthotopic mouse model of pancreatic cancer, we show increased resolution and image intensity with the complexed Magnevist®. Using advanced microscopy techniques (scanning electron microscopy and scanning probe microscopy, we also established that the Magnevist® is in fact encapsulated by the liposome in the complex and that the complex still retains its nanodimensional size. These results demonstrate that this TfRscFv-liposome-Magnevist® nanocomplex has the potential to become a useful tool in early cancer detection.

  11. The ubiquitin–proteasome system as a molecular target in solid tumors: an update on bortezomib

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    A Milano

    2009-06-01

    Full Text Available A Milano,1 F Perri,2 F Caponigro21Sandro Pitigliani Medical Oncology Unit, Department of Oncology, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy; 2Head and Neck Medical Oncology Unit, National Tumour institute of Naples, Naples, ItalyAbstract: The ubiquitin–proteasome system has become a promising molecular target in cancer therapy due to its critical role in cellular protein degradation, interaction with cell cycle and apoptosis regulation, and unique mechanism of action. Bortezomib (PS-341 is a potent and specific reversible proteasome inhibitor, which has shown strong in vitro antitumor activity as single agent and in combination with other cytotoxic drugs in a broad spectrum of hematological and solid malignancies. In preclinical studies, bortezomib induced apoptosis of malignant cells through the inhibition of NF-κB and stabilization of pro-apoptotic proteins. Bortezomib also promotes chemo- and radiosensitization of malignant cells in vitro and inhibits tumor growth in murine xenograft models. The proteasome has been established as a relevant target in hematologic malignancies and bortezomib has been approved for the treatment of multiple myeloma. This review summarizes recent data from clinical trials in solid tumors. Keywords: proteasome, bortezomib, NF-κB, clinical studies, solid tumors

  12. Targeting thapsigargin towards tumors

    DEFF Research Database (Denmark)

    Christensen, Søren Brøgger; Doan, Thi Quynh Nhu; Paulsen, Eleonora Sandholdt

    2015-01-01

    substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) prodrugs were created, which selectively affect prostate cancer cells or neovascular tissue in tumors. One of the prodrug is currently tested in clinical phase II. The prodrug under clinical trial has been...

  13. Tumor targeted gene therapy

    International Nuclear Information System (INIS)

    Kang, Joo Hyun

    2006-01-01

    Knowledge of molecular mechanisms governing malignant transformation brings new opportunities for therapeutic intervention against cancer using novel approaches. One of them is gene therapy based on the transfer of genetic material to an organism with the aim of correcting a disease. The application of gene therapy to the cancer treatment had led to the development of new experimental approaches such as suicidal gene therapy, inhibition of oncogenes and restoration of tumor-suppressor genes. Suicidal gene therapy is based on the expression in tumor cells of a gene encoding an enzyme that converts a prodrug into a toxic product. Representative suicidal genes are Herpes simplex virus type 1 thymidine kinase (HSV1-tk) and cytosine deaminase (CD). Especially, physicians and scientists of nuclear medicine field take an interest in suicidal gene therapy because they can monitor the location and magnitude, and duration of expression of HSV1-tk and CD by PET scanner

  14. Advances in Tumor Targeted Liposomes.

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    Jain, A; Jain, S K

    2018-04-15

    Cancer remains a deadly disease for effective treatment. Although anomalous tumor microenvironment is now widely exploited for targeted chemotherapy, safe and efficacious drug delivery to tumor cells is not still warranted. Liposomes are promising biodegradable and biocompatible nanocarriers having potential amenability for surface and internal modifications, and extraordinary capability to carry both hydrophilic as well as hydrophobhic drugs. Meticulous fabrication of liposomes with tumor selective ligand(s) and PEGylation reduces immunogenicity and increase target-specificity. This chapter focuses on critical developmental aspects of liposomes to target cancer cells exploiting Enhanced Permeability and Retention (EPR) effect and tumor-selective ligands such as folate, transferrin, peptides etc. Moreover, stimuli-responsive smart liposomes (triggers: pH, temperature, enzymes, magnetic field, ultrasound, and redox potential etc.) are also investigated for enhancement of drug delivery to tumors. This review summarizes advances in tumor-targeted liposomes via various means of targeting. This knowledgeable assemblage of advances in liposomal approaches will render new insights to formulators and budding scientists to design cancer targeted liposomes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. Impact of fluid-structure interaction on direct tumor-targeting in a representative hepatic artery system.

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    Childress, Emily M; Kleinstreuer, Clement

    2014-03-01

    Direct targeting of solid tumors with chemotherapeutic drugs and/or radioactive microspheres can be a treatment option which minimizes side-effects and reduces cost. Briefly, computational analysis generates particle release maps (PRMs) which visually link upstream particle injection regions in the main artery with associated exit branches, some connected to tumors. The overall goal is to compute patient-specific PRMs realistically, accurately, and cost-effectively, which determines the suitable radial placement of a micro-catheter for optimal particle injection. Focusing in this paper on new steps towards realism and accuracy, the impact of fluid-structure interaction on direct drug-targeting is evaluated, using a representative hepatic artery system with liver tumor as a test bed. Specifically, the effect of arterial wall motion was demonstrated by modeling a two-way fluid-structure interaction analysis with Lagrangian particle tracking in the bifurcating arterial system. Clearly, rapid computational evaluation of optimal catheter location for tumor-targeting in a clinical application is very important. Hence, rigid-wall cases were also compared to the flexible scenario to establish whether PRMs generated when based on simplifying assumptions could provide adequate guidance towards ideal catheter placement. It was found that the best rigid (i.e., time-averaged) geometry is the physiological one that occurs during the diastolic targeting interval.

  16. A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice.

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    Liechtenstein, Therese; Perez-Janices, Noemi; Gato, Maria; Caliendo, Fabio; Kochan, Grazyna; Blanco-Luquin, Idoia; Van der Jeught, Kevin; Arce, Frederick; Guerrero-Setas, David; Fernandez-Irigoyen, Joaquin; Santamaria, Enrique; Breckpot, Karine; Escors, David

    2014-09-15

    Myeloid-derived suppressor cells (MDSCs) exhibit potent immunosuppressive activities in cancer. MDSCs infiltrate tumors and strongly inhibit cancer-specific cytotoxic T cells. Their mechanism of differentiation and identification of MDSC-specific therapeutic targets are major areas of interest. We have devised a highly efficient and rapid method to produce very large numbers of melanoma-infiltrating MDSCs ex vivo without inducing tumors in mice. These MDSCs were used to study their differentiation, immunosuppressive activities and were compared to non-neoplastic counterparts and conventional dendritic cells using unbiased systems biology approaches. Differentially activated/deactivated pathways caused by cell type differences and by the melanoma tumor environment were identified. MDSCs increased the expression of trafficking receptors to sites of inflammation, endocytosis, changed lipid metabolism, and up-regulated detoxification pathways such as the expression of P450 reductase. These studies uncovered more than 60 potential novel therapeutic targets. As a proof of principle, we demonstrate that P450 reductase is the target of pro-drugs such as Paclitaxel, which depletes MDSCs following chemotherapy in animal models of melanoma and in human patients. Conversely, P450 reductase protects MDSCs against the cytotoxic actions of other chemotherapy drugs such as Irinotecan, which is ineffective for the treatment of melanoma.

  17. Targeted Radionuclide Therapy of Human Tumors

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    Sergey V. Gudkov

    2015-12-01

    Full Text Available Targeted radionuclide therapy is one of the most intensively developing directions of nuclear medicine. Unlike conventional external beam therapy, the targeted radionuclide therapy causes less collateral damage to normal tissues and allows targeted drug delivery to a clinically diagnosed neoplastic malformations, as well as metastasized cells and cellular clusters, thus providing systemic therapy of cancer. The methods of targeted radionuclide therapy are based on the use of molecular carriers of radionuclides with high affinity to antigens on the surface of tumor cells. The potential of targeted radionuclide therapy has markedly grown nowadays due to the expanded knowledge base in cancer biology, bioengineering, and radiochemistry. In this review, progress in the radionuclide therapy of hematological malignancies and approaches for treatment of solid tumors is addressed.

  18. Construction of a Novel Magnetic Targeting Anti-Tumor Drug Delivery System: Cytosine Arabinoside-Loaded Bacterial Magnetosome

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    Wenguo Wu

    2013-09-01

    Full Text Available To ease the side effects triggered by cytosine arabinoside (Ara-C for acute leukemia treatment, a novel magnetic targeting anti-tumor drug delivery system was constructed through bacterial magnetosomes (BMs from Magnetospirillum magneticum AMB-1 combined with Ara-C by crosslinking of genipin (GP. The results showed that Ara-C could be bonded onto the membrane surface of BMs effectively through chemical crosslinking induced by dual hand reagents GP. The average diameters of BMs and Ara-C-coupled BMs (ABMs were 42.0 ± 8.6 and 72.7 ± 6.0 nm respectively, and the zeta potentials (−38.1 ± 9.1 revealed that these systems were stable, confirming the stability of the system. The optimal encapsulation efficiency and drug loading were 89.05% ± 2.33% and 47.05% ± 0.64% respectively when crosslinking reaction lasted for 72 h. The system also presented long-term stability and release behaviors without initial burst release (Ara-C could be released 80% within three months. Our results indicate that BMs have great potential in biomedical and clinical fields as a novel anti-tumor drug carrier.

  19. Targeting Therapy Resistant Tumor Vessels

    National Research Council Canada - National Science Library

    Ruoslahti, Erkki

    2007-01-01

    .... To achieve this, we have developed tumor models for vascular normalization and are using in vivo phage display and isolation of peptides that specifically home to normalized tumor vessels resistant...

  20. Targeting Therapy Resistant Tumor Vessels

    National Research Council Canada - National Science Library

    Ruoslahti, Erkki

    2008-01-01

    .... To achieve this, we have developed tumor models for vascular normalization and are using in vivo phage display and isolation of peptides that specifically home to normalized tumor vessels resistant...

  1. Targeting the tumor microenvironment for cancer therapy.

    Science.gov (United States)

    Sounni, Nor Eddine; Noel, Agnès

    2013-01-01

    With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic. The malignant features of cancer cells cannot be manifested without an important interplay between cancer cells and their local environment. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblastic cells contributes actively to cancer progression. The ability to change these surroundings is an important property by which tumor cells are able to acquire some of the hallmark functions necessary for tumor growth and metastatic dissemination. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. The variety of stromal cells, the complexity of the molecular components of the tumor stroma, and the similarity with normal tissue present huge challenges for therapies targeting the tumor microenvironment. These issues and their interplay are addressed in this review. After a decade of intensive clinical trials targeting cellular components of the tumor microenvironment, more recent investigations have shed light on the important role in cancer progression played by the noncellular stromal compartment composed of the extracellular matrix. A better understanding of how the tumor environment affects cancer progression should provide new targets for the isolation and destruction of cancer cells via interference with the complex crosstalk established between cancer cells, host cells, and their surrounding extracellular matrix. © 2012 American Association for Clinical Chemistry

  2. Development and optimization of a tumor targeting system based on microbial synthesized PHA biopolymers and PhaP mediated functional modification.

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    Fan, Fan; Wang, Leilei; Ouyang, Zhenlin; Wen, Yurong; Lu, Xiaoyun

    2018-04-01

    Polyhydroxyalkanoate (PHA) is a class of microbial synthesized biodegradable and biocompatible aliphatic polymer which has been developed into nanoparticles (NPs) for sustained release of hydrophobic compounds. Taking advantage of the natural PHA binding protein PhaP which could be steadily adsorbed onto PHA NPs through hydrophobic interaction, a tumor targeting system was developed in this study by presenting an epidermal growth factor receptor (EGFR)-targeting peptide (ETP) on the surface of PHA NPs, via PhaP mediated adsorption. To reveal the effects of residual emulsifiers on PhaP mediated ETP modification and optimize the tumor targeting capacity of the system, a novel emulsifier-free PHA NPs (EF-NPs) was fabricated together with other two kinds of conventional emulsifier-required PHA NPs (PVA-NPs and P68-NPs, which were prepared with poly(vinyl alcohol) (PVA) and Pluronic F68 as emulsifiers, respectively). By analyzing the surface hydrophobicity, the amount of adsorbed fusion protein, and the cellular uptake of all kinds of PHA NPs, our results demonstrated that EF-NPs with stronger surface hydrophobicity were the most proper formulation for further PhaP mediated ETP functionalization. The residual PVA and Pluronic F68 affected the modification efficiency and secondary structure of ETP-PhaP fusion protein, and finally obstructed the targeting effect of ETP-PhaP modified PVA-NPs and P68-NPs to EGFR over-expressed tumor cells. The animal experiment further confirmed the effectiveness and feasibility of in vivo application of ETP-PhaP functionalized EF-NPs, indicating that it could be served as a promising tumor targeting system with satisfactory EGFR targeting ability. This PhaP mediated bio-modification process also opens a wide way for developing various PHA-based targeting systems by presenting different tumor or other tissue-specific targeting peptides.

  3. Targeted Brain Tumor Treatment: Current Perspectives

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    Ningaraj N.S

    2007-01-01

    Full Text Available Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefly discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with over-expression of calcium-dependent potassium (KCa channels, and high grade glioma express specific KCa channel gene (gBK splice variants, and mutant epidermal growth factor receptors (EGFRvIII. These specific genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifically microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed.

  4. Targeted Brain Tumor Treatment-Current Perspectives

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    N.S. Ningaraj

    2007-01-01

    Full Text Available Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefly discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with over-expression of calcium-dependent potassium (K Ca channels, and high grade glioma express specific K Ca channel gene (gBK splice variants, and mutant epidermal growth factor receptors (EGFRvIII. These specific genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifically microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed.

  5. Computationally efficient particle release map determination for direct tumor-targeting in a representative hepatic artery system.

    Science.gov (United States)

    Childress, E M; Kleinstreuer, C

    2014-01-01

    Implementation of a novel direct tumor-targeting technique requires a computer modeling stage to generate particle release maps (PRMs) which allow for optimal catheter positioning and selection of best injection intervals for drug-particles. This simulation task for a patient-specific PRM may require excessive computational resources and a relatively long turn-around time for a fully transient analysis. Hence, steady-state conditions were sought which generates PRMs equivalent to the pulsatile arterial flow environment. Fluid-particle transport in a representative hepatic artery system was simulated under fully transient and steady-state flow conditions and their corresponding PRMs were analyzed and compared. Comparisons of the transient PRMs from ten equal intervals of the cardiac pulse revealed that the diastolic phase produced relatively constant PRMs due to its semisteady flow conditions. Furthermore, steady-state PRMs, which best matched the transient particle release maps, were found for each interval and over the entire cardiac pulse. From these comparisons, the flow rate and outlet pressure differences proved to be important parameters for estimating the PRMs. The computational times of the fully transient and steady simulations differed greatly, i.e., about 10 days versus 0.5 to 1 h, respectively. The time-averaged scenario may provide the best steady conditions for estimating the transient particle release maps. However, given the considerable changes in the PRMs due to the accelerating and decelerating phases of the cardiac cycle, it may be better to model several steady scenarios, which encompass the wide range of flows and pressures experienced by the arterial system in order to observe how the PRMs may change throughout the pulse. While adding more computation time, this method is still significantly faster than running the full transient case. Finally, while the best steady PRMs provide a qualitative guide for best catheter placement, the final

  6. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress

    NARCIS (Netherlands)

    Lammers, Twan Gerardus Gertudis Maria; Kiessling, F.; Hennink, W.E.; Storm, Gerrit

    2012-01-01

    Abstract Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells,

  7. Targeting Malignant Brain Tumors with Antibodies

    Directory of Open Access Journals (Sweden)

    Rok Razpotnik

    2017-09-01

    Full Text Available Antibodies have been shown to be a potent therapeutic tool. However, their use for targeting brain diseases, including neurodegenerative diseases and brain cancers, has been limited, particularly because the blood–brain barrier (BBB makes brain tissue hard to access by conventional antibody-targeting strategies. In this review, we summarize new antibody therapeutic approaches to target brain tumors, especially malignant gliomas, as well as their potential drawbacks. Many different brain delivery platforms for antibodies have been studied such as liposomes, nanoparticle-based systems, cell-penetrating peptides (CPPs, and cell-based approaches. We have already shown the successful delivery of single-chain fragment variable (scFv with CPP as a linker between two variable domains in the brain. Antibodies normally face poor penetration through the BBB, with some variants sufficiently passing the barrier on their own. A “Trojan horse” method allows passage of biomolecules, such as antibodies, through the BBB by receptor-mediated transcytosis (RMT. Such examples of therapeutic antibodies are the bispecific antibodies where one binding specificity recognizes and binds a BBB receptor, enabling RMT and where a second binding specificity recognizes an antigen as a therapeutic target. On the other hand, cell-based systems such as stem cells (SCs are a promising delivery system because of their tumor tropism and ability to cross the BBB. Genetically engineered SCs can be used in gene therapy, where they express anti-tumor drugs, including antibodies. Different types and sources of SCs have been studied for the delivery of therapeutics to the brain; both mesenchymal stem cells (MSCs and neural stem cells (NSCs show great potential. Following the success in treatment of leukemias and lymphomas, the adoptive T-cell therapies, especially the chimeric antigen receptor-T cells (CAR-Ts, are making their way into glioma treatment as another type of cell

  8. [Immune system and tumors].

    Science.gov (United States)

    Terme, Magali; Tanchot, Corinne

    2017-02-01

    Despite having been much debated, it is now well established that the immune system plays an essential role in the fight against cancer. In this article, we will highlight the implication of the immune system in the control of tumor growth and describe the major components of the immune system involved in the antitumoral immune response. The immune system, while exerting pressure on tumor cells, also will play a pro-tumoral role by sculpting the immunogenicity of tumors cells as they develop. Finally, we will illustrate the numerous mechanisms of immune suppression that take place within the tumoral microenvironment which allow tumor cells to escape control from the immune system. The increasingly precise knowledge of the brakes to an effective antitumor immune response allows the development of immunotherapy strategies more and more innovating and promising of hope. Copyright © 2016. Published by Elsevier Masson SAS.

  9. High efficiency diffusion molecular retention tumor targeting.

    Directory of Open Access Journals (Sweden)

    Yanyan Guo

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

  10. Central nervous system tumors

    International Nuclear Information System (INIS)

    Curran, W.J. Jr.

    1991-01-01

    Intrinsic tumors of the central nervous system (CNS) pose a particularly challenging problem to practicing oncologists. These tumors rarely metastasize outside the CNS, yet even histologically benign tumors can be life-threatening due to their local invasiveness and strategic location. The surrounding normal tissues of the nervous system is often incapable of full functional regeneration, therefore prohibiting aggressive attempts to use either complete surgical resection or high doses of irradiation. Despite these limitations, notable achievements have recently been recorded in the management of these tumors

  11. Carbohydrate plasma expanders for passive tumor targeting

    DEFF Research Database (Denmark)

    Hoffmann, Stefan; Caysa, Henrike; Kuntsche, Judith

    2013-01-01

    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 characterized in human colon carcinoma xenograft bearing nude mice. A tumor specific accumulation of HES 450 was observed, which proves it’s potential as carrier for passive tumor targeting....

  12. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress.

    Science.gov (United States)

    Lammers, Twan; Kiessling, Fabian; Hennink, Wim E; Storm, Gert

    2012-07-20

    Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells, active drug targeting to endothelial cells and triggered drug delivery. Significant progress has been made in this area of research both at the preclinical and at the clinical level, and a number of (primarily passively tumor-targeted) nanomedicine formulations have been approved for clinical use. Significant progress has also been made with regard to better understanding the (patho-) physiological principles of drug targeting to tumors. This has led to the identification of several important pitfalls in tumor-targeted drug delivery, including I) overinterpretation of the EPR effect; II) poor tumor and tissue penetration of nanomedicines; III) misunderstanding of the potential usefulness of active drug targeting; IV) irrational formulation design, based on materials which are too complex and not broadly applicable; V) insufficient incorporation of nanomedicine formulations in clinically relevant combination regimens; VI) negligence of the notion that the highest medical need relates to metastasis, and not to solid tumor treatment; VII) insufficient integration of non-invasive imaging techniques and theranostics, which could be used to personalize nanomedicine-based therapeutic interventions; and VIII) lack of (efficacy analyses in) proper animal models, which are physiologically more relevant and more predictive for the clinical situation. These insights strongly suggest that besides making ever more nanomedicine formulations, future efforts should also address some of the conceptual drawbacks of drug targeting to tumors, and that strategies should be developed to overcome these shortcomings. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Tumor-targeted nanomedicines for cancer theranostics

    Science.gov (United States)

    Lammers, Twan; Shi, Yang

    2017-01-01

    Chemotherapeutic drugs have multiple drawbacks, including severe side effects and suboptimal therapeutic efficacy. Nanomedicines assist in improving the biodistribution and the target accumulation of chemotherapeutic drugs, and are therefore able to enhance the balance between efficacy and toxicity. Multiple different types of nanomedicines have been evaluated over the years, including liposomes, polymer-drug conjugates and polymeric micelles, which rely on strategies such as passive targeting, active targeting and triggered release for improved tumor-directed drug delivery. Based on the notion that tumors and metastases are highly heterogeneous, it is important to integrate imaging properties in nanomedicine formulations in order to enable non-invasive and quantitative assessment of targeting efficiency. By allowing for patient pre-selection, such next generation nanotheranostics are useful for facilitating clinical translation and personalizing nanomedicine treatments. PMID:27865762

  14. Modeling and Targeting MYC Genes in Childhood Brain Tumors

    Science.gov (United States)

    Hutter, Sonja; Bolin, Sara; Weishaupt, Holger; Swartling, Fredrik J.

    2017-01-01

    Brain tumors are the second most common group of childhood cancers, accounting for about 20%–25% of all pediatric tumors. Deregulated expression of the MYC family of transcription factors, particularly c-MYC and MYCN genes, has been found in many of these neoplasms, and their expression levels are often correlated with poor prognosis. Elevated c-MYC/MYCN initiates and drives tumorigenesis in many in vivo model systems of pediatric brain tumors. Therefore, inhibition of their oncogenic function is an attractive therapeutic target. In this review, we explore the roles of MYC oncoproteins and their molecular targets during the formation, maintenance, and recurrence of childhood brain tumors. We also briefly summarize recent progress in the development of therapeutic approaches for pharmacological inhibition of MYC activity in these tumors. PMID:28333115

  15. Central nervous system tumors

    International Nuclear Information System (INIS)

    Gavin, P.R.; Fike, J.R.; Hoopes, P.J.

    1995-01-01

    Central nervous system (CNS) tumors are relatively common in veterinary medicine, with most diagnoses occurring in the canine and feline species. Numerous tumor types from various cells or origins have been identified with the most common tumors being meningiomas and glial cell tumors. Radiation therapy is often used as an aid to control the clinical signs associated with these neoplasms. In general, these tumors have a very low metastatic potential, such that local control offers substantial benefit. Experience in veterinary radiation oncology would indicate that many patients benefit from radiation treatment. Current practice indicates the need for computed tomography or magnetic resonance imaging studies. These highly beneficial studies are used for diagnosis, treatment planning, and to monitor treatment response. Improvements in treatment planning and radiation delivered to the tumor, while sparing the normal tissues, should improve local control and decrease potential radiation related problems to the CNS. When possible, multiple fractions of 3 Gy or less should be used. The tolerance dose to the normal tissue with this fractionation schedule is 50 to 55 Gy. The most common and serious complications of radiation for CNS tumors is delayed radiation myelopathy and necrosis. Medical management of the patient during radiation therapy requires careful attention to anesthetic protocols, and medications to reduce intracranial pressure that is often elevated in these patients. Canine brain tumors have served as an experimental model to test numerous new treatments. Increased availability of advanced imaging modalities has spawned increased detection of these neoplasms. Early detection of these tumors with appropriate aggressive therapy should prove beneficial to many patients

  16. Tumor cells and neovasculature dual targeting delivery for glioblastoma treatment.

    Science.gov (United States)

    Gao, Huile; Yang, Zhi; Cao, Shijie; Xiong, Yang; Zhang, Shuang; Pang, Zhiqing; Jiang, Xinguo

    2014-02-01

    Glioblastoma multiforme (GBM), one of the most common primary malignant brain tumors, was characterized by angiogenesis and tumor cells proliferation. Antiangiogenesis and antitumor combination treatment gained much attention because of the potency in dual inhibition of both the tumor proliferation and the tumor invasion. In this study, a neovasculature and tumor cell dual targeting delivery system was developed through modification of nanoparticles with interleukin-13 peptide and RGD (IRNPs), in which interleukin-13 peptide was targeting GBM cells and RGD was targeting neovasculature. To evaluate the potency in GBM treatment, docetaxel was loaded into IRNPs. In vitro, interleukin-13 peptide and RGD could enhance the corresponding cells (C6 and human umbilical vein endothelial cells) uptake and cytotoxicity. In combination, IRNPs showed high uptake in both cells and increased the cytotoxicity on both cells. In vivo, IRNPs could effectively deliver cargoes to GBM with higher intensity than mono-modified nanoparticles. Correspondingly, docetaxel-IRNPs displayed best anti-tumor effect with a median survival time of 35 days, which was significantly longer than that of mono-modified and unmodified nanoparticles. Importantly, treatment with docetaxel-IRNPs could avoid the accumulation of HIF1α in GBM site, which was crucial for the tumor invasion. After the treatment, there was no obvious change in normal organs of mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2015-03-01

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

  18. Tumor Evolution as a Therapeutic Target.

    Science.gov (United States)

    Amirouchene-Angelozzi, Nabil; Swanton, Charles; Bardelli, Alberto

    2017-07-20

    Recent technological advances in the field of molecular diagnostics (including blood-based tumor genotyping) allow the measurement of clonal evolution in patients with cancer, thus adding a new dimension to precision medicine: time. The translation of this new knowledge into clinical benefit implies rethinking therapeutic strategies. In essence, it means considering as a target not only individual oncogenes but also the evolving nature of human tumors. Here, we analyze the limitations of targeted therapies and propose approaches for treatment within an evolutionary framework. Significance: Precision cancer medicine relies on the possibility to match, in daily medical practice, detailed genomic profiles of a patient's disease with a portfolio of drugs targeted against tumor-specific alterations. Clinical blockade of oncogenes is effective but only transiently; an approach to monitor clonal evolution in patients and develop therapies that also evolve over time may result in improved therapeutic control and survival outcomes. Cancer Discov; 7(8); 1-13. ©2017 AACR. ©2017 American Association for Cancer Research.

  19. Targeted Radionuclide Therapy of Human Tumors

    OpenAIRE

    Gudkov, Sergey V.; Shilyagina, Natalya Yu.; Vodeneev, Vladimir A.; Zvyagin, Andrei V.

    2015-01-01

    Targeted radionuclide therapy is one of the most intensively developing directions of nuclear medicine. Unlike conventional external beam therapy, the targeted radionuclide therapy causes less collateral damage to normal tissues and allows targeted drug delivery to a clinically diagnosed neoplastic malformations, as well as metastasized cells and cellular clusters, thus providing systemic therapy of cancer. The methods of targeted radionuclide therapy are based on the use of molecular carrier...

  20. Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers.

    Science.gov (United States)

    Kebebe, Dereje; Liu, Yuanyuan; Wu, Yumei; Vilakhamxay, Maikhone; Liu, Zhidong; Li, Jiawei

    2018-01-01

    Cancer has become one of the leading causes of mortality globally. The major challenges of conventional cancer therapy are the failure of most chemotherapeutic agents to accumulate selectively in tumor cells and their severe systemic side effects. In the past three decades, a number of drug delivery approaches have been discovered to overwhelm the obstacles. Among these, nanocarriers have gained much attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. In order to enhance targeting efficiency further and reduce limitations of nanocarriers, nanoparticle surfaces are functionalized with different ligands. Several kinds of ligand-modified nanomedicines have been reported. Cell-penetrating peptides (CPPs) are promising ligands, attracting the attention of researchers due to their efficiency to transport bioactive molecules intracellularly. However, their lack of specificity and in vivo degradation led to the development of newer types of CPP. Currently, activable CPP and tumor-targeting peptide (TTP)-modified nanocarriers have shown dramatically superior cellular specific uptake, cytotoxicity, and tumor growth inhibition. In this review, we discuss recent advances in tumor-targeting strategies using CPPs and their limitations in tumor delivery systems. Special emphasis is given to activable CPPs and TTPs. Finally, we address the application of CPPs and/or TTPs in the delivery of plant-derived chemotherapeutic agents.

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

    International Nuclear Information System (INIS)

    Hosseinkhani, Hossein; Chen Yiru; He Wenjie; Hong Poda; Yu, Dah-Shyong; Domb, Abraham J.

    2013-01-01

    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 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-01-15

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

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

    Science.gov (United States)

    Hosseinkhani, Hossein; Chen, Yi-Ru; He, Wenjie; Hong, Po-Da; Yu, Dah-Shyong; Domb, Abraham J.

    2013-01-01

    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.

  4. Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration

    Directory of Open Access Journals (Sweden)

    Hong Shen

    2016-09-01

    Full Text Available To assess targeting of an epothilone folate conjugate (BMS-753493 to the folate receptor (FR-overexpressed tumor in mice bearing both FR+ and FR– tumors, a series of experiments were conducted by quantitative whole-body autoradiography (QWBA and LC–MS/MS following i.v. administration of BMS-753493 or its active moiety, BMS-748285 in mice bearing FR+ (98M109 and FR– (M109 tumors. QWBA showed [3H]BMS-753493–derived radioactivity was extensively distributed to various tissues. The FR over-expressing 98M109 tumors showed consistently higher level of radioactivity than FR-negative tumors (i.e., M109 tumors up to 48 h post dose of [3H]BMS-753493, despite the magnitude of difference between the tumors is relatively small (generally 3~5-fold. The radioactivity level in 98M109 tumors was 2~12-fold of normal tissues except intestine/content at 48 h post dose. No selective radioactivity uptake into 98M109 tumors over M109 or normal tissues was observed after i.v. administration of the active epothilone, [3H]BMS-748285. LC–MS/MS measurements demonstrated that the concentrations of BMS-748285, presumably from hydrolysis of the folate conjugate, in 98M109 tumors were greater than those in M109 tumors after i.v. administration of BMS-753493 (2–3-fold whereas no differential uptake in the tumors following BMS-748285 administration. Those data were consistent with radioactivity determinations. Those results demonstrated that the folate conjugation in BMS-753493 enabled moderately preferential distribution of the active epothilone to FR over-expressing 98M109 tumors, thereby supporting targeted delivery of cytotoxics through the folate receptor.

  5. Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery.

    Science.gov (United States)

    Gao, Ning; Bozeman, Erica N; Qian, Weiping; Wang, Liya; Chen, Hongyu; Lipowska, Malgorzata; Staley, Charles A; Wang, Y Andrew; Mao, Hui; Yang, Lily

    2017-01-01

    The major obstacles in intraperitoneal (i.p.) chemotherapy of peritoneal tumors are fast absorption of drugs into the blood circulation, local and systemic toxicities, inadequate drug penetration into large tumors, and drug resistance. Targeted theranostic nanoparticles offer an opportunity to enhance the efficacy of i.p. therapy by increasing intratumoral drug delivery to overcome resistance, mediating image-guided drug delivery, and reducing systemic toxicity. Herein we report that i.p. delivery of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (IONPs) led to intratumoral accumulation of 17% of total injected nanoparticles in an orthotopic mouse pancreatic cancer model, which was three-fold higher compared with intravenous delivery. Targeted delivery of near infrared dye labeled IONPs into orthotopic tumors could be detected by non-invasive optical and magnetic resonance imaging. Histological analysis revealed that a high level of uPAR targeted, PEGylated IONPs efficiently penetrated into both the peripheral and central tumor areas in the primary tumor as well as peritoneal metastatic tumor. Improved theranostic IONP delivery into the tumor center was not mediated by nonspecific macrophage uptake and was independent from tumor blood vessel locations. Importantly, i.p. delivery of uPAR targeted theranostic IONPs carrying chemotherapeutics, cisplatin or doxorubicin, significantly inhibited the growth of pancreatic tumors without apparent systemic toxicity. The levels of proliferating tumor cells and tumor vessels in tumors treated with the above theranostic IONPs were also markedly decreased. The detection of strong optical signals in residual tumors following i.p. therapy suggested the feasibility of image-guided surgery to remove drug-resistant tumors. Therefore, our results support the translational development of i.p. delivery of uPAR-targeted theranostic IONPs for image-guided treatment of peritoneal tumors.

  6. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    International Nuclear Information System (INIS)

    Pagan, Jonathan; Przybyla, Beata; Jamshidi-Parsian, Azemat; Gupta, Kalpna; Griffin, Robert J.

    2013-01-01

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm 3 ) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

  7. BONE TUMOR ENVIRONMENT AS POTENTIAL THERAPEUTIC TARGET IN EWING SARCOMA

    Directory of Open Access Journals (Sweden)

    Françoise eREDINI

    2015-12-01

    Full Text Available Ewing sarcoma is the second most common pediatric bone tumor, with three cases per million worldwide. In clinical terms, ES is an aggressive, rapidly fatal malignancy that mainly develops in osseous sites (85%, but also in extraskeletal soft tissue. It spreads naturally to the lungs, bones and bone marrow with poor prognosis in the two latter cases. Bone lesions from primary or secondary (metastases tumors are characterized by extensive bone remodeling, more often due to osteolysis. Osteoclast activation and subsequent bone resorption is responsible for the clinical features of bone tumors including pain, vertebral collapse and spinal cord compression. Based on the vicious cycle concept of tumor cells and bone resorbing cells, drugs which target osteoclasts may be promising agents as adjuvant setting for treating bone tumors, including Ewing sarcoma. There is also increasing evidence that cellular and molecular protagonists present in the bone microenvironment play a part in establishing a favorable niche for tumor initiation and progression. The purpose of this review is to discuss the potential therapeutic value of drugs targeting the bone tumor microenvironment in Ewing Sarcoma. The first part of the review will focus on targeting the bone resorbing function of osteoclasts by means of bisphosphonates (BPs or drugs blocking the pro-resorbing cytokine Receptor Activator of NF-kappa B Ligand (RANKL. Second, the role of this peculiar hypoxic microenvironment will be discussed in the context of resistance to chemotherapy, escape from the immune system, or neo-angiogenesis. Therapeutic interventions based on these specificities could be then proposed in the context of Ewing sarcoma.

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

    Science.gov (United States)

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

    2017-01-01

    A nanosized drug delivery platform with a combination of rational components and tumor targeting is significant for enhancement of anticancer therapy and reduction of side effects. In this study, we developed a octanoyl galactose ester-modified microemulsion system self-assembled by coix seed components (Gal(oct)-C-MEs), which improved the tumor accumulation through asialoglycoprotein receptor-mediated endocytosis and promoted the antitumor efficacy through multicomponent-mediated synergistic effect. Octanoyl galactose ester (Gal(oct)) with a yield of 82.3% was synthesized through a green enzymatic reaction and multidimensional characterization. Gal(oct)-C-MEs with a spherical shape had a small and uniform particle size (58.49±1.03 nm), narrow polydispersity index (0.09±0.01) and neutral surface charge (−5.82±0.57 mV). In the cellular uptake studies, the internalized Gal(oct)-C-ME was 2.28-fold higher relative to that of coix seed component-based microemulsions (C-MEs). The half-maximal inhibitory concentration of Gal(oct)-C-MEs against HepG2 cells was 46.5±2.4 μg/mL, which was notably higher than that of C-MEs. Importantly, the intratumor fluorescence of HepG2 xenograft-bearing nude mice treated with Cy5/Gal(oct)-C-MEs was 1.9-fold higher relative to treatment with Cy5/C-MEs. In the study of antitumor efficacy in vivo, HepG2 xenograft-bearing nude mice intragastrically administered Gal(oct)-C-MEs for 14 days exhibited the strongest inhibition of tumor growth and the lowest toxicity against liver and kidney among all the treatments. In summary, Gal(oct)-C-ME, as a highly effective and safe anticancer drug delivery system, showed promising potential for hepatoma therapy. PMID:28352174

  9. Glycan Markers as Potential Immunological Targets in Circulating Tumor Cells.

    Science.gov (United States)

    Wang, Denong; Wu, Lisa; Liu, Xiaohe

    2017-01-01

    We present here an experimental approach for exploring a new class of tumor biomarkers that are overexpressed by circulating tumor cells (CTCs) and are likely targetable in immunotherapy against tumor metastasis. Using carbohydrate microarrays, anti-tumor monoclonal antibodies (mAbs) were scanned against a large panel of carbohydrate antigens to identify potential tumor glycan markers. Subsequently, flow cytometry and fiber-optic array scanning technology (FAST) were applied to determine whether the identified targets are tumor-specific cell-surface markers and are, therefore, likely suitable for targeted immunotherapy. Finally, the tumor glycan-specific antibodies identified were validated using cancer patients' blood samples for their performance in CTC-detection and immunotyping analysis. In this article, identifying breast CTC-specific glycan markers and targeting mAbs serve as examples to illustrate this tumor biomarker discovery strategy.

  10. Targeting tumors with nanobodies for cancer imaging and therapy.

    Science.gov (United States)

    Oliveira, Sabrina; Heukers, Raimond; Sornkom, Jirawas; Kok, Robbert J; van Bergen En Henegouwen, Paul M P

    2013-12-28

    The use of monoclonal antibodies has revolutionized both cancer therapy and cancer imaging. Antibodies have been used to directly inhibit tumor cell proliferation or to target drugs to tumors. Also in molecular imaging, monoclonal antibodies have found their way to the clinic. Nevertheless, distribution within tumors is hampered by their size, leading to insufficient efficacy of cancer treatment and irregular imaging. An attractive alternative for monoclonal antibodies are nanobodies or VHHs. These are the variable domain of heavy-chain antibodies from animals from the Camelidae family that were first discovered in 1993. Stimulated by the ease of nanobody selection, production, and low immunogenicity potential, a number of nanobodies specific to different disease-related targets have been developed. For cancer therapy, nanobodies have been employed as antagonistic drugs, and more recently, as targeting moieties of effector-domaINS and of drug delivery systems. In parallel, nanobodies have also been employed for molecular imaging with modalities such as nuclear and optical imaging. In this review, we discuss recent developments in the application of nanobodies as targeting moieties in cancer therapy and cancer imaging. With such a wide range of successful applications, nanobodies have become much more than simple antagonists. © 2013.

  11. Patient-Derived Antibody Targets Tumor Cells

    Science.gov (United States)

    An NCI Cancer Currents blog on an antibody derived from patients that killed tumor cells in cell lines of several cancer types and slowed tumor growth in mouse models of brain and lung cancer without evidence of side effects.

  12. Target tumor hypoxia with 2-nitroimidazole-ICG dye conjugates

    Science.gov (United States)

    Xu, Yan; Zanganeh, Saeid; Mohammad, Innus; Aguirre, Andres; Wang, Tianheng; Yang, Yi; Kuhn, Liisa; Smith, Michael; Zhu, Quing

    2013-03-01

    In this paper, we have synthesized a second generation tumor hypoxia targeted 2-nitroimidazole-ICG conjugate using piperazine linker (2-nitro-ICG-p) and validated its performance in in vivo tumor targeting. The results have shown that tumor hypoxia can be targeted with twice higher signal strength beyond three hours post-injection while the un-targeted ICG has completely washed out. The improvement of the second generation 2-nitro-ICG-p dyes is 1.2-1.3 times over the first generation 2-nitro-ICG dyes using ethanol linker beyond 3 hours post-injection which is the optimal time-window for evaluating tumor hypoxia.

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

    Directory of Open Access Journals (Sweden)

    Chadwick L. Wright

    2016-06-01

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

  14. Systemic co-delivery of doxorubicin and siRNA using nanoparticles conjugated with EGFR-specific targeting peptide to enhance chemotherapy in ovarian tumor bearing mice

    Energy Technology Data Exchange (ETDEWEB)

    Liu, C. W.; Lin, W. J., E-mail: wjlin@ntu.edu.tw [National Taiwan University, Graduate Institute of Pharmaceutical Sciences, School of Pharmacy (China)

    2013-10-15

    This aim of this study was to develop peptide-conjugated nanoparticles (NPs) for systemic co-delivery of siRNA and doxorubicin to enhance chemotherapy in epidermal growth factor receptor (EGFR) high-expressed ovarian tumor bearing mice. The active targeting NPs were prepared using heptapeptide-conjugated poly(d,l-lactic-co-glycolic acid)-poly(ethylene glycol). The particle sizes of peptide-free and peptide-conjugated NPs were 159.3 {+-} 32.5 and 184.0 {+-} 52.9 nm, respectively, with zeta potential -21.3 {+-} 3.8 and -15.3 {+-} 2.8 mV. The peptide-conjugated NPs uptake were more efficient in EGFR high-expressed SKOV3 cells than in EGFR low-expressed HepG2 cells due to heptapeptide specificity. The NPs were used to deliver small molecule anticancer drug (e.g., doxorubicin) and large molecule genetic agent (e.g., siRNA). The IC{sub 50} of doxorubicin-loaded peptide-conjugated NPs (0.09 {+-} 0.06 {mu}M) was significantly lower than peptide-free NPs (5.72 {+-} 2.64 {mu}M). The similar result was observed in siRNA-loaded NPs. The peptide-conjugated NPs not only served as a nanocarrier to efficiently deliver doxorubicin and siRNA to EGFR high-expressed ovarian cancer cells but also increased the intracellular accumulation of the therapeutic agents to induce assured anti-tumor growth effect in vivo.

  15. Systemic co-delivery of doxorubicin and siRNA using nanoparticles conjugated with EGFR-specific targeting peptide to enhance chemotherapy in ovarian tumor bearing mice

    Science.gov (United States)

    Liu, C. W.; Lin, W. J.

    2013-10-01

    This aim of this study was to develop peptide-conjugated nanoparticles (NPs) for systemic co-delivery of siRNA and doxorubicin to enhance chemotherapy in epidermal growth factor receptor (EGFR) high-expressed ovarian tumor bearing mice. The active targeting NPs were prepared using heptapeptide-conjugated poly( d, l-lactic-co-glycolic acid)-poly(ethylene glycol). The particle sizes of peptide-free and peptide-conjugated NPs were 159.3 ± 32.5 and 184.0 ± 52.9 nm, respectively, with zeta potential -21.3 ± 3.8 and -15.3 ± 2.8 mV. The peptide-conjugated NPs uptake were more efficient in EGFR high-expressed SKOV3 cells than in EGFR low-expressed HepG2 cells due to heptapeptide specificity. The NPs were used to deliver small molecule anticancer drug (e.g., doxorubicin) and large molecule genetic agent (e.g., siRNA). The IC50 of doxorubicin-loaded peptide-conjugated NPs (0.09 ± 0.06 μM) was significantly lower than peptide-free NPs (5.72 ± 2.64 μM). The similar result was observed in siRNA-loaded NPs. The peptide-conjugated NPs not only served as a nanocarrier to efficiently deliver doxorubicin and siRNA to EGFR high-expressed ovarian cancer cells but also increased the intracellular accumulation of the therapeutic agents to induce assured anti-tumor growth effect in vivo.

  16. Targeted Cancer Therapy with Tumor Necrosis Factor-Alpha

    Directory of Open Access Journals (Sweden)

    Weibo Cai Ph.D.

    2008-01-01

    Full Text Available Tumor necrosis factor-alpha (TNF-α, a member of the TNF superfamily, was the first cytokine to be evaluated for cancer biotherapy. However, the clinical use of TNF-α is severely limited by its toxicity. Currently, TNF-α is administered only through locoregional drug delivery systems such as isolated limb perfusion and isolated hepatic perfusion. To reduce the systemic toxicity of TNF-α, various strategies have been explored over the last several decades. This review summarizes current state-of-the-art targeted cancer therapy using TNF-α. Passive targeting, cell-based therapy, gene therapy with inducible or tissue-specific promoters, targeted polymer-DNA complexes, tumor pre-targeting, antibody-TNF-α conjugate, scFv/TNF-α fusion proteins, and peptide/TNF-α fusion proteins have all been investigated to combat cancer. Many of these agents are already in advanced clinical trials. Molecular imaging, which can significantly speed up the drug development process, and nanomedicine, which can integrate both imaging and therapeutic components, has the potential to revolutionize future cancer patient management. Cooperative efforts from scientists within multiple disciplines, as well as close partnerships among many organizations/entities, are needed to quickly translate novel TNF-α-based therapeutics into clinical investigation.

  17. Uncertainces in tumor target definition using PET

    International Nuclear Information System (INIS)

    Kirov, A.

    2013-01-01

    Full text: Introduction: PET entered into the clinics for radiation therapy as a means of displaying the metabolically active part of the tumor. However this advantage, PET has a number of shortcomings that prevent its use for precise determination of the tumor boundaries. What you will learn: The aim of the lecture is to present: the requirements for the accuracy of the determination of tumor boundaries in radiation therapy; the main phenomena which bring uncertainty using PET and a brief overview of methods for segmentation of tumors and their problems

  18. Targeting Nanomedicine to Brain Tumors: Latest Progress and Achievements.

    Science.gov (United States)

    Van't Root, Moniek; Lowik, Clemens; Mezzanotte, Laura

    2017-01-01

    Targeting nanomedicine to brain tumors is hampered by the heterogeneity of brain tumors and the blood brain barrier. These represent the main reasons of unsuccessful treatments. Nanomedicine based approaches hold promise for improved brain tissue distribution of drugs and delivery of combination therapies. In this review, we describe the recent advancements and latest achievements in the use of nanocarriers, virus and cell-derived nanoparticles for targeted therapy of brain tumors. We provide successful examples of nanomedicine based approaches for direct targeting of receptors expressed in brain tumor cells or modulation of pathways involved in cell survival as well as approaches for indirect targeting of cells in the tumor stroma and immunotherapies. Although the field is at its infancy, clinical trials involving nanomedicine based approaches for brain tumors are ongoing and many others will start in the near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Targeted liposomes for cytosolic drug delivery to tumor cells

    NARCIS (Netherlands)

    Mastrobattista, E.

    2001-01-01

    In this thesis, a Trojan horse strategy with antibody-targeted liposomes has been followed to obtain cytosolic delivery of biotherapeutics to tumor cells in vitro. This strategy involves targeting of immunoliposomes to specific receptors on tumor cells that result in receptor-mediated uptake of the

  20. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature

    NARCIS (Netherlands)

    Huang, XM; Molema, G; King, S; Watkins, L; Edgington, TS; Thorpe, PE

    1997-01-01

    Selective occlusion of tumor vasculature was tested as a therapy for solid tumors in a mouse model. The formation of blood clots (thrombosis) within the tumor Vessels was initiated by targeting the cell surface domain of human tissue factor, by means of a bispecific antibody, to an experimentally

  1. Design of planning target volume margin using an active breathing control and Varian image-guided radiotherapy (IGRT) system in unresectable liver tumor

    International Nuclear Information System (INIS)

    Yue Jinbo; Yu Jinming; Liu Jing; Liu Tonghai; Yin Yong; Shi Xuetao; Song Jinlong

    2007-01-01

    Objective: To define the planning target volume(PTV) margin with an active breathing control (ABC) and the Varian image-guided radiotherapy (IGRT) system. Methods: Thirteen patients with liver cancer were treated with radiotherapy from May 2006 to September 2006. Prior to radiotherapy, all patients had undergone transarterial chemoembolization (TACE) by infusing a mixture of iodized oil contrast medium and chemotherapeutic agents, kV fluoroscopy was used to measure the potential motion of lipiodol spot positions during ABC breath-holds. ABC was used for planning CT scan and radiation delivery, with the breath held at the same phase of the respiratory cycle (near end-exhalation). Cone beam CT (CBCT) was taken using Varian IGRT system, which was then compared online with planning CT using a 3 D-3 D matching tool. Analysis relied on lipiodol spots on planning CT and CBCT manually. The treatment table was moved to produce acceptable setup before treatment delivery. Repeated CBCT image and another analysis were obtained after irradiation. Results: No motion of the intrahepatic tumor was observed on fluoroscopy during ABC breath-holds. The estimated required PTV margins, calculated according to the Stroom formula, were 4.4 mm, 5.3 mm and 7.8 mm in the x, y and z axis directions before radiotherapy. The corresponding parameters were 2.5m, 2.6 mm and 3.9 mm after radiotherapy. Conclusions: We have adopted a PTV margin of 5 mm, 6 mm and 8 mm in the x, y and z axis directions with ABC, and 3,3 and 4 mm with ABC and on-line kilovoltage CBCT. (authors)

  2. Characterization of Heterogeneous Prostate Tumors in Targeted Pten Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Hanneke Korsten

    Full Text Available Previously, we generated a preclinical mouse prostate tumor model based on PSA-Cre driven inactivation of Pten. In this model homogeneous hyperplastic prostates (4-5m developed at older age (>10m into tumors. Here, we describe the molecular and histological characterization of the tumors in order to better understand the processes that are associated with prostate tumorigenesis in this targeted mouse Pten knockout model. The morphologies of the tumors that developed were very heterogeneous. Different histopathological growth patterns could be identified, including intraductal carcinoma (IDC, adenocarcinoma and undifferentiated carcinoma, all strongly positive for the epithelial cell marker Cytokeratin (CK, and carcinosarcomas, which were negative for CK. IDC pattern was already detected in prostates of 7-8 month old mice, indicating that it could be a precursor stage. At more than 10 months IDC and carcinosarcoma were most frequently observed. Gene expression profiling discriminated essentially two molecular subtypes, denoted tumor class 1 (TC1 and tumor class 2 (TC2. TC1 tumors were characterized by high expression of epithelial markers like Cytokeratin 8 and E-Cadherin whereas TC2 tumors showed high expression of mesenchyme/stroma markers such as Snail and Fibronectin. These molecular subtypes corresponded with histological growth patterns: where TC1 tumors mainly represented adenocarcinoma/intraductal carcinoma, in TC2 tumors carcinosarcoma was the dominant growth pattern. Further molecular characterization of the prostate tumors revealed an increased expression of genes associated with the inflammatory response. Moreover, functional markers for senescence, proliferation, angiogenesis and apoptosis were higher expressed in tumors compared to hyperplasia. The highest expression of proliferation and angiogenesis markers was detected in TC2 tumors. Our data clearly showed that in the genetically well-defined PSA-Cre;Pten-loxP/loxP prostate tumor

  3. A comparison of prostate tumor targeting strategies using magnetic resonance imaging-targeted, transrectal ultrasound-guided fusion biopsy.

    Science.gov (United States)

    Martin, Peter R; Cool, Derek W; Fenster, Aaron; Ward, Aaron D

    2018-03-01

    Magnetic resonance imaging (MRI)-targeted, three-dimensional (3D) transrectal ultrasound (TRUS)-guided prostate biopsy aims to reduce the 21-47% false-negative rate of clinical two-dimensional (2D) TRUS-guided systematic biopsy, but continues to yield false-negative results. This may be improved via needle target optimization, accounting for guidance system errors and image registration errors. As an initial step toward the goal of optimized prostate biopsy targeting, we investigated how needle delivery error impacts tumor sampling probability for two targeting strategies. We obtained MRI and 3D TRUS images from 49 patients. A radiologist and radiology resident assessed these MR images and contoured 81 suspicious regions, yielding tumor surfaces that were registered to 3D TRUS. The biopsy system's root-mean-squared needle delivery error (RMSE) and systematic error were modeled using an isotropic 3D Gaussian distribution. We investigated two different prostate tumor-targeting strategies using (a) the tumor's centroid and (b) a ring in the lateral-elevational plane. For each simulation, targets were spaced at equal arc lengths on a ring with radius equal to the systematic error magnitude. A total of 1000 biopsy simulations were conducted for each tumor, with RMSE and systematic error magnitudes ranging from 1 to 6 mm. The difference in median tumor sampling probability and probability of obtaining a 50% core involvement was determined for ring vs centroid targeting. Our simulation results indicate that ring targeting outperformed centroid targeting in situations where systematic error exceeds RMSE. In these instances, we observed statistically significant differences showing 1-32% improvement in sampling probability due to ring targeting. Likewise, we observed statistically significant differences showing 1-39% improvement in 50% core involvement probability due to ring targeting. Our results suggest that the optimal targeting scheme for prostate biopsy depends on

  4. Balancing Passive and Active Targeting to Different Tumor Compartments Using Riboflavin-Functionalized Polymeric Nanocarriers.

    Science.gov (United States)

    Tsvetkova, Yoanna; Beztsinna, Nataliia; Baues, Maike; Klein, Dionne; Rix, Anne; Golombek, Susanne K; Al Rawashdeh, Wa'el; Gremse, Felix; Barz, Matthias; Koynov, Kaloian; Banala, Srinivas; Lederle, Wiltrud; Lammers, Twan; Kiessling, Fabian

    2017-08-09

    Riboflavin transporters (RFTs) and the riboflavin carrier protein (RCP) are highly upregulated in many tumor cells, tumor stem cells, and tumor neovasculature, which makes them attractive targets for nanomedicines. Addressing cells in different tumor compartments requires drug carriers, which are not only able to accumulate via the EPR effect but also to extravasate, target specific cell populations, and get internalized by cells. Reasoning that antibodies are among the most efficient targeting systems developed by nature, we consider their size (∼10-15 nm) to be ideal for balancing passive and active tumor targeting. Therefore, small, short-circulating (10 kDa, ∼7 nm, t 1/2 ∼ 1 h) and larger, longer-circulating (40 kDa, ∼13 nm, t 1/2 ∼ 13 h) riboflavin-targeted branched PEG polymers were synthesized, and their biodistribution and target site accumulation were evaluated in mice bearing angiogenic squamous cell carcinoma (A431) and desmoplastic prostate cancer (PC3) xenografts. The tumor accumulation of the 10 kDa PEG was characterized by rapid intercompartmental exchange and significantly improved upon active targeting with riboflavin (RF). The 40 kDa PEG accumulated in tumors four times more efficiently than the small polymer, but its accumulation did not profit from active RF-targeting. However, RF-targeting enhanced the cellular internalization in both tumor models and for both polymer sizes. Interestingly, the nanocarriers' cell-uptake in tumors was not directly correlated with the extent of accumulation. For example, in both tumor models the small RF-PEG accumulated much less strongly than the large passively targeted PEG but showed significantly higher intracellular amounts 24 h after iv administration. Additionally, the size of the polymer determined its preferential uptake by different tumor cell compartments: the 10 kDa RF-PEGs most efficiently targeted cancer cells, whereas the highest uptake of the 40 kDa RF-PEGs was observed in tumor

  5. Diversity of radioprobes targeted to tumor angiogenesis on molecular functional imaging

    International Nuclear Information System (INIS)

    Lu Xia; Zhang Huabei

    2013-01-01

    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)

  6. Toward integrative cancer immunotherapy: targeting the tumor microenvironment.

    Science.gov (United States)

    Emens, Leisha A; Silverstein, Samuel C; Khleif, Samir; Marincola, Francesco M; Galon, Jérôme

    2012-04-10

    The development of cancer has historically been attributed to genomic alterations of normal host cells. Accordingly, the aim of most traditional cancer therapies has been to destroy the transformed cells themselves. There is now widespread appreciation that the progressive growth and metastatic spread of cancer cells requires the cooperation of normal host cells (endothelial cells, fibroblasts, other mesenchymal cells, and immune cells), both local to, and at sites distant from, the site at which malignant transformation occurs. It is the balance of these cellular interactions that both determines the natural history of the cancer, and influences its response to therapy. This active tumor-host dynamic has stimulated interest in the tumor microenvironment as a key target for both cancer diagnosis and therapy. Recent data has demonstrated both that the presence of CD8⁺ T cells within a tumor is associated with a good prognosis, and that the eradication of all malignantly transformed cells within a tumor requires that the intra-tumoral concentration of cytolytically active CD8⁺ effector T cells remain above a critical concentration until every tumor cell has been killed. These findings have stimulated two initiatives in the field of cancer immunotherapy that focus on the tumor microenvironment. The first is the development of the immune score as part of the routine diagnostic and prognostic evaluation of human cancers, and the second is the development of combinatorial immune-based therapies that reduce tumor-associated immune suppression to unleash pre-existing or therapeutically-induced tumor immunity. In support of these efforts, the Society for the Immunotherapy of Cancer (SITC) is sponsoring a workshop entitled "Focus on the Target: The Tumor Microenvironment" to be held October 24-25, 2012 in Bethesda, Maryland. This meeting should support development of the immune score, and result in a position paper highlighting opportunities for the development of

  7. Active targeting of tumor cells using light emitting bacteria

    International Nuclear Information System (INIS)

    Moon, Sung Min; Min, Jung Joon; Hong, Yeong Jin; Kim, Hyun Ju; Le, Uuenchi N.; Rhee, Joon Haeng; Song, Ho Chun; Heo, Young Jun; Bom, Hee Seung; Choy, Hyon E

    2004-01-01

    The presence of bacteria and viruses in human tumors has been recognized for more than 50 years. Today, with the discovery of bacterial strains that specifically target tumors, and aided by genomic sequencing and genetic engineering, there is new interest in the use of bacteria as tumor vectors. Here, we show that bacteria injected intravenously into live animals entered and replicated in solid tumors and metastases using the novel imaging technology of biophotonics. Bioluminescence operon (LuxCDABE) or fluorescence protein, GFP) has been cloned into pUC19 plasmid to engineer pUC19lux or pUC19gfp. Engineered plasmid was transformed into different kinds of wild type (MG1655) or mutant E. coli (DH5, ppGpp, fnr, purE, crpA, flagella, etc.) strains to construct light emitting bacteria. Xenograft tumor model has been established using CT26 colon cancer cell line. Light emitting bacteria was injected via tail vein into tumor bearing mouse. In vivo bioluminescence imaging has been done after 20 min to 14 days of bacterial injection. We observed localization of tumors by light-emitting E. coli in tumor (CT-26) bearing mice. We confirmed the presence of light-emitting bacteria under the fluorescence microscope with E. coli expressing GFP. Althoug varying mutants strain with deficient invading function has been found in tumor tissues, mutant strains of movement (flagella) couldn't show any light signal from the tumor tissue under the cooled CCD camera, indicating bacteria may actively target the tumor cells. Based on their 'tumor-finding' nature, bacteria may be designed to carry multiple genes or drugs for detection and treatment of cancer, such as prodrug-converting enzymes, toxins, angiogenesis inhibitors and cytokines

  8. Targeting Killing of Breast Tumor Stem Cells

    National Research Council Canada - National Science Library

    Chen, Si-Yi

    2005-01-01

    .... Toward the goal, we have prepared HA molecules from human umbilical cord hyaluronic acid by hydrolysed by Bee venom. However, we have encountered the technical difficulty to produce CD44-targeted liposomes that are incorporated with HA molecules. Due to the technical problems, this proposed study has been extended for additional one year.

  9. Targeted Killing of Breast Tumor Stem Cells

    National Research Council Canada - National Science Library

    Chen, Si-Yi

    2004-01-01

    .... Toward the goal, we have prepared HA molecules from human umbilical cord hyaluronic acid by hydrolysed by Bee venom. However, we have encountered the technical difficulty to produce CD44-targeted liposomes that are incorporated with HA molecules. Due to the technical problems, this proposed study has been extended for additional one year.

  10. Tumor-Associated Macrophages: Therapeutic Targets for Skin Cancer

    Directory of Open Access Journals (Sweden)

    Taku Fujimura

    2018-01-01

    Full Text Available Tumor-associated macrophages (TAMs and regulatory T cells (Tregs are significant components of the microenvironment of solid tumors in the majority of cancers. TAMs sequentially develop from monocytes into functional macrophages. In each differentiation stage, TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment (e.g., expression of immune checkpoint molecules, production of Treg-related chemokines and cytokines, production of arginase I. Although the main population of TAMs is immunosuppressive M2 macrophages, TAMs can be modulated into M1-type macrophages in each differential stage, leading to the suppression of tumor growth. Because the administration of certain drugs or stromal factors can stimulate TAMs to produce specific chemokines, leading to the recruitment of various tumor-infiltrating lymphocytes, TAMs can serve as targets for cancer immunotherapy. In this review, we discuss the differentiation, activation, and immunosuppressive function of TAMs, as well as their benefits in cancer immunotherapy.

  11. Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery.

    Science.gov (United States)

    Fu, Xinping; Rivera, Armando; Tao, Lihua; Zhang, Xiaoliu

    2013-11-15

    Converting T cells into tumor cell killers by grafting them with a chimeric antigen receptor (CAR) has shown promise as a cancer immunotherapeutic. However, the inability of these cells to actively migrate and extravasate into tumor parenchyma has limited their effectiveness in vivo. Here we report the construction of a CAR containing an echistatin as its targeting moiety (eCAR). As echistatin has high binding affinity to αvβ3 integrin that is highly expressed on the surface of endothelial cells of tumor neovasculature, T cells engrafted with eCAR (T-eCAR) can efficiently lyse human umbilical vein endothelial cells and tumor cells that express αvβ3 integrin when tested in vitro. Systemic administration of T-eCAR led to extensive bleeding in tumor tissues with no evidence of damage to blood vessels in normal tissues. Destruction of tumor blood vessels by T-eCAR significantly inhibited the growth of established bulky tumors. Moreover, when T-eCAR was codelivered with nanoparticles in a strategically designed temporal order, it dramatically increased nanoparticle deposition in tumor tissues, pointing to the possibility that it may be used together with nanocarriers to increase their capability to selectively deliver antineoplastic drugs to tumor tissues. Copyright © 2013 UICC.

  12. Targeting Autophagy in the Tumor Microenvironment: New Challenges and Opportunities for Regulating Tumor Immunity

    Directory of Open Access Journals (Sweden)

    Bassam Janji

    2018-04-01

    Full Text Available Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Despite the remarkable and fairly rapid progress over the past two decades regarding our understanding of the role of the tumor microenvironment in cancer development, its precise contribution to cancer resistance is still fragmented. This is mainly related to the complexity of the “tumor ecosystem” and the diversity of the stromal cell types that constitute the tumor microenvironment. Emerging data indicate that several factors, such as hypoxic stress, activate a plethora of resistance mechanisms, including autophagy, in tumor cells. Hypoxia-induced autophagy in the tumor microenvironment also activates several tumor escape mechanisms, which effectively counteract anti-tumor immune responses mediated by natural killer and cytotoxic T lymphocytes. Therefore, strategies aiming at targeting autophagy in cancer cells in combination with other therapeutic strategies have inspired significant interest to overcome immunological tolerance and promote tumor regression. However, a number of obstacles still hamper the application of autophagy inhibitors in clinics. First, the lack of selectivity of the current pharmacological inhibitors of autophagy makes difficult to draw a clear statement about its effective contribution in cancer. Second, autophagy has been also described as an important mechanism in tumor cells involved in presentation of antigens to T cells. Third, there is a circumstantial evidence that autophagy activation in some innate immune cells may support the maturation of these cells, and it is required for their anti-tumor activity. In this review, we will address these aspects and discuss our current knowledge on the benefits and the drawbacks of targeting autophagy in the context of anti-tumor immunity. We believe that it is

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

    Directory of Open Access Journals (Sweden)

    Federico Perche

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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

  15. Balancing Passive and Active Targeting to Different Tumor Compartments Using Riboflavin-Functionalized Polymeric Nanocarriers

    NARCIS (Netherlands)

    Tsvetkova, Yoanna; Beztsinna, Nataliia; Baues, Maike; Klein, Dionne; Rix, Anne; Golombek, Susanne K.; Al Rawashdeh, Wa'el; Gremse, Felix; Barz, Matthias; Koynov, Kaloian; Banala, Srinivas; Lederle, Wiltrud; Lammers, Twan; Kiessling, Fabian

    2017-01-01

    Riboflavin transporters (RFTs) and the riboflavin carrier protein (RCP) are highly upregulated in many tumor cells, tumor stem cells, and tumor neovasculature, which makes them attractive targets for nanomedicines. Addressing cells in different tumor compartments requires drug carriers, which are

  16. Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization.

    Directory of Open Access Journals (Sweden)

    Daniel Y Joh

    Full Text Available Successful treatment of brain tumors such as glioblastoma multiforme (GBM is limited in large part by the cumulative dose of Radiation Therapy (RT that can be safely given and the blood-brain barrier (BBB, which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs. GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ~1.3. Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature.

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

    Science.gov (United States)

    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

  18. Targeted Imaging of Tumor-Associated Macrophages by Cyanine 7-Labeled Mannose in Xenograft Tumors

    Directory of Open Access Journals (Sweden)

    Chong Jiang MD

    2017-01-01

    Full Text Available Mannose receptor is considered as a hallmark of M2-oriented tumor-associated macrophages (TAMs, but its utility in TAMs was rarely reported. Therefore, deoxymannose (DM, a high-affinity ligand of mannose receptor, was labeled with near-infrared dye cyanine 7 (Cy7, and its feasibility of targeted imaging on TAMs was evaluated in vitro and in vivo. The Cy7-DM was synthesized, and its binding affinity with induced TAMs in vitro, whole-body imaging in xenograft tumor mouse model in vivo, and the cellular localization in dissected tissues were evaluated. We demonstrated a high uptake of Cy7-DM by induced M2 macrophages and TAMs in tumor tissues. In vivo near-infrared live imaging visualized abundant TAMs in tumor lesions instead of inflammatory sites by Cy7-DM imaging, and the quantity of Cy7-DM signals in tumors was significantly higher than that shown in inflammatory sites from 1 to 8 hours of imaging. Our results suggest that mannose could rapidly and specifically target TAMs and is a promising candidate for targeted diagnosis of tumor with rich TAMs.

  19. Preparation and Characterization of a Tumor-Targeting Dual-Image System Based on Iron Oxide Nanoparticles Functionalized with Folic Acid and Rhodamine

    Directory of Open Access Journals (Sweden)

    Alejandra Ancira-Cortez

    2017-01-01

    Full Text Available Cancer is one of the diseases with most deaths worldwide, around 8.2 million annually. For this reason, several treatments and diagnostic tools have been investigated and developed over the past decades. Among them, a dual-image system has been developed to achieve and enhance the detection of cancer, which has not been done with systems currently available. The present study describes the preparation of a dual-image targeting system composed of magnetic iron oxide nanoparticles functionalized with folic acid and rhodamine; nanoparticles synthesis was achieved by a coprecipitation method; the functionalization was carried out by a carbodiimide with folic acid and/or the rhodamine isothiocyanate; conjugates were characterized by spectrometric techniques; toxicity was measured by cell proliferation assay on HeLa cells using progressive concentrations of functionalized nanoparticles. Cellular uptake assay was carried out by competitive assay on HeLa cells. Iron oxide magnetite nanoparticles, modified with folic acid and rhodamine, were successfully synthetized with a particle size lower than 20 nm (TEM, EDS, HRTEM, and XDR showed highly crystalline Fe3O4 nanoparticles. Folic acid and rhodamine were conjugated with high efficiency. A significant selectivity and uptake, facilitated by surface modification of iron oxide nanoparticles with folic acid, were demonstrated. The multifunctional system showed suitable physicochemical and biological properties for cell targeting through folate receptors.

  20. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.

    Science.gov (United States)

    Schrader, Kasmintan A; Cheng, Donavan T; Joseph, Vijai; Prasad, Meera; Walsh, Michael; Zehir, Ahmet; Ni, Ai; Thomas, Tinu; Benayed, Ryma; Ashraf, Asad; Lincoln, Annie; Arcila, Maria; Stadler, Zsofia; Solit, David; Hyman, David M; Hyman, David; Zhang, Liying; Klimstra, David; Ladanyi, Marc; Offit, Kenneth; Berger, Michael; Robson, Mark

    2016-01-01

    Tumor genetic sequencing identifies potentially targetable genetic alterations with therapeutic implications. Analysis has concentrated on detecting tumor-specific variants, but recognition of germline variants may prove valuable as well. To estimate the burden of germline variants identified through routine clinical tumor sequencing. Patients with advanced cancer diagnoses eligible for studies of targeted agents at Memorial Sloan Kettering Cancer Center are offered tumor-normal sequencing with MSK-IMPACT, a 341-gene panel. We surveyed the germline variants seen in 187 overlapping genes with Mendelian disease associations in 1566 patients who had undergone tumor profiling between March and October 2014. The number of presumed pathogenic germline variants (PPGVs) and variants of uncertain significance per person in 187 genes associated with single-gene disorders and the proportions of individuals with PPGVs in clinically relevant gene subsets, in genes consistent with known tumor phenotypes, and in genes with evidence of second somatic hits in their tumors. The mean age of the 1566 patients was 58 years, and 54% were women. Presumed pathogenic germline variants in known Mendelian disease-associated genes were identified in 246 of 1566 patients (15.7%; 95% CI, 14.0%-17.6%), including 198 individuals with mutations in genes associated with cancer susceptibility. Germline findings in cancer susceptibility genes were concordant with the individual's cancer type in only 81 of 198 cases (40.9%; 95% CI, 34.3%-47.9%). In individuals with PPGVs retained in the tumor, somatic alteration of the other allele was seen in 39 of 182 cases (21.4%; 95% CI, 16.1%-28.0%), of which 13 cases did not show a known correlation of the germline mutation and a known syndrome. Mutations in non-cancer-related Mendelian disease genes were seen in 55 of 1566 cases (3.5%; 95% CI, 27.1%-45.4%). Almost every individual had more than 1 variant of uncertain significance (1565 of 1566 patients; 99

  1. Imaging and Targeting of Hypoxic Tumor Cells with Use of HIF-1-2

    International Nuclear Information System (INIS)

    Kizaka-Kondoh, Shinae; Harada, Hiroshi; Tanaka, Shotaro; Hiraoka, Masahiro

    2006-01-01

    This paper describes imaging (visualization) of transplanted tumor cells under hypoxia in vivo and molecular targeting to kill those cells by inducing their apoptosis. HIF (hypoxia inducible factor) concerned with angiogenesis is induced specifically in hypoxic tumor cells and its activity can be visualized by transfection of reporter vector construct of fluorescent protein GFP or luciferase. Authors established the transfected tumor cells with the plasmid p5HRE-luciferase and when transplanted in the nude mouse, those cells emitted light dependently to their hypoxic conditions, which could be visualized by in vivo imaging system (IVIS) with CCD camera. Authors prepared the oxygen-dependent degradation-procaspase 3-fusion protein (TOP3) to target the hypoxic tumor cells for enhancing their apoptotic signaling, whose apoptosis was actually observed by the IVIS. Reportedly, radiation transiently activates HIF-1 and combination treatment of radiation and TOP3 resulted in the enhanced death of tumor cells. Interestingly, the suppression of tumor growth lasted longer than expected, probably due to inhibition of angiogenesis. Authors called this anti-tumor strategy as the micro-environmental targeting. (T.I.)

  2. Targeting the epidermal growth factor receptor in solid tumor malignancies

    DEFF Research Database (Denmark)

    Nedergaard, Mette K; Hedegaard, Chris J; Poulsen, Hans S

    2012-01-01

    to the extracellular part of EGFR, blocking the binding sites for the EGFR ligands, and intracellular tyrosine kinase inhibitors (TKIs) that block the ATP binding site of the tyrosine kinase domain. Besides an EGFRvIII-targeted vaccine, conjugated anti-EGFR mAbs have been used in different settings to deliver lethal......The epidermal growth factor receptor (EGFR) is over-expressed, as well as mutated, in many types of cancers. In particular, the EGFR variant type III mutant (EGFRvIII) has attracted much attention as it is frequently and exclusively found on many tumor cells, and hence both EGFR and EGFRvIII have...... been proposed as valid targets in many cancer therapy settings. Different strategies have been developed in order to either inhibit EGFR/EGFRvIII activity or to ablate EGFR/EGFRvIII-positive tumor cells. Drugs that inhibit these receptors include monoclonal antibodies (mAbs) that bind...

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

    Science.gov (United States)

    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. Targeting Survivin Enhances Chemosensitivity in Retinoblastoma Cells and Orthotopic Tumors.

    Directory of Open Access Journals (Sweden)

    Angela Ferrario

    Full Text Available Treatments for retinoblastoma (Rb vary depending on the size and location of the intraocular lesions and include chemotherapy and radiation therapy. We examined whether agents used to treat Rb induce a pro-survival phenotype associated with increased expression of survivin, a member of the inhibitor of apoptosis family of proteins. We document that exposure to carboplatin, topotecan or radiation resulted in elevated expression of survivin in two human Rb cell lines but not in normal retinal pigmented epithelial (RPE cells. Cellular levels of survivin were attenuated in Rb cells exposed to an imidazolium-based survivin suppressant, Sepantronium bromide (YM155. Protein expression patterns of survivin in RPE cells were not altered following treatment protocols involving exposure to YM155. Including YM155 with chemotherapy or radiation increased levels of apoptosis in Rb cells but not in RPE cells. Intraocular luciferase expressing Rb tumors were generated from the Rb cell lines and used to evaluate the effects of carboplatin and YM155 on in-vivo survivin expression and tumor growth. Carboplatin induced expression of survivin while carboplatin combined with YM155 reduced survivin expression in tumor bearing eyes. The combination protocol was also most effective in reducing the rate of tumor regrowth. These results indicate that targeted inhibition of the anti-apoptotic protein survivin provides a therapeutic advantage for Rb cells and tumors treated with chemotherapy.

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

    Science.gov (United States)

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

    2012-01-01

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

  6. Guided molecular missiles for tumor-targeting chemotherapy--case studies using the second-generation taxoids as warheads.

    Science.gov (United States)

    Ojima, Iwao

    2008-01-01

    A long-standing problem in cancer chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, the development of innovative and efficacious tumor-specific drug delivery protocols or systems is urgently needed. A rapidly growing tumor requires various nutrients and vitamins. Thus, tumor cells overexpress many tumor-specific receptors, which can be used as targets to deliver cytotoxic agents into tumors. This Account presents our research program on the discovery and development of novel and efficient drug delivery systems, possessing tumor-targeting ability and efficacy against various cancer types, especially multidrug-resistant tumors. In general, a tumor-targeting drug delivery system consists of a tumor recognition moiety and a cytotoxic warhead connected directly or through a suitable linker to form a conjugate. The conjugate, which can be regarded as a "guided molecular missile", should be systemically nontoxic, that is, the linker must be stable in blood circulation, but upon internalization into the cancer cell, the conjugate should be readily cleaved to regenerate the active cytotoxic warhead. These novel "guided molecular missiles" are conjugates of the highly potent second-generation taxoid anticancer agents with tumor-targeting molecules through mechanism-based cleavable linkers. These conjugates are specifically delivered to tumors and internalized into tumor cells, and the potent taxoid anticancer agents are released from the linker into the cytoplasm. We have successfully used omega-3 polyunsaturated fatty acids, in particular DHA, and monoclonal antibodies (for EGFR) as tumor-targeting molecules for the conjugates, which exhibited remarkable efficacy against

  7. Temperature distribution in target tumor tissue and photothermal tissue destruction during laser immunotherapy

    Science.gov (United States)

    Doughty, Austin; Hasanjee, Aamr; Pettitt, Alex; Silk, Kegan; Liu, Hong; Chen, Wei R.; Zhou, Feifan

    2016-03-01

    Laser Immunotherapy is a novel cancer treatment modality that has seen much success in treating many different types of cancer, both in animal studies and in clinical trials. The treatment consists of the synergistic interaction between photothermal laser irradiation and the local injection of an immunoadjuvant. As a result of the therapy, the host immune system launches a systemic antitumor response. The photothermal effect induced by the laser irradiation has multiple effects at different temperature elevations which are all required for optimal response. Therefore, determining the temperature distribution in the target tumor during the laser irradiation in laser immunotherapy is crucial to facilitate the treatment of cancers. To investigate the temperature distribution in the target tumor, female Wistar Furth rats were injected with metastatic mammary tumor cells and, upon sufficient tumor growth, underwent laser irradiation and were monitored using thermocouples connected to locally-inserted needle probes and infrared thermography. From the study, we determined that the maximum central tumor temperature was higher for tumors of less volume. Additionally, we determined that the temperature near the edge of the tumor as measured with a thermocouple had a strong correlation with the maximum temperature value in the infrared camera measurement.

  8. Chemotherapy synergizes with radioimmunotherapy targeting La autoantigen in tumors.

    Directory of Open Access Journals (Sweden)

    Fares Al-Ejeh

    Full Text Available To date, inefficient delivery of therapeutic doses of radionuclides to solid tumors limits the clinical utility of radioimmunotherapy. We aim to test the therapeutic utility of Yttrium-90 ((90Y-radio-conjugates of a monoclonal antibody, which we showed previously to bind specifically to the abundant intracellular La ribonucleoprotein revealed in dead tumor cells after DNA-damaging treatment.Immunoconjugates of the DAB4 clone of the La-specific monoclonal antibody, APOMAB, were prepared using the metal chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA, and then radiolabeled with (90Y. Mice bearing established subcutaneous tumors were treated with (90Y-DOTA-DAB4 alone or after chemotherapy. Non-radiosensitizing cyclophosphamide/etoposide chemotherapy was used for the syngeneic EL4 lymphoma model. Radiosensitizing cisplatin/gemcitabine chemotherapy was used for the syngeneic Lewis Lung carcinoma (LL2 model, and for the xenograft models of LNCaP prostatic carcinoma and Panc-1 pancreatic carcinoma. We demonstrate the safety, specificity, and efficacy of (90Y-DOTA-DAB4-radioimmunotherapy alone or combined with chemotherapy. EL4 lymphoma-bearing mice either were cured at higher doses of radioimmunotherapy alone or lower doses of radioimmunotherapy in synergy with chemotherapy. Radioimmunotherapy alone was less effective in chemo- and radio-resistant carcinoma models. However, radioimmunotherapy synergized with radiosensitizing chemotherapy to retard significantly tumor regrowth and so prolong the survival of mice bearing LL2, LNCaP, or Panc-1 subcutaneous tumor implants.We report proof-of-concept data supporting a unique form of radioimmunotherapy, which delivers bystander killing to viable cancer cells after targeting the universal cancer antigen, La, created by DNA-damaging treatment in neighboring dead cancer cells. Subsequently we propose that DAB4-targeted ionizing radiation induces additional cycles of tumor cell death

  9. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy

    Directory of Open Access Journals (Sweden)

    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

  10. The tumor vasculature is a target for genetic radiotherapy

    International Nuclear Information System (INIS)

    Mauceri, Helena J.; Heimann, Ruth; Seetharam, Saraswathy; Beckett, Michael A.; Weichselbaum, Ralph R.

    1997-01-01

    Purpose: Tumor progression and metastasis require the growth of new capillaries from existing blood vessels. Tumor cells produce both activators and inhibitors of endothelial cell proliferation and migration. Changes in the balance between these regulators appear to govern an angiogenic switch which is activated during tumor development. Tumor necrosis factor-α (TNF-α) has a biphasic role in angiogenesis. It has been demonstrated that relatively low concentrations of TNF induce angiogenesis while high doses inhibit growth of blood vessels. In our previous studies, using the SQ-20B xenograft model system, we demonstrated increased tumor control when a virus containing the radiation-inducible promoter Egr-1 ligated to a cDNa for TNF-α was combined with radiation. The dominant histopathological feature of tumors receiving combined treatment with Ad.Egr-TNF and radiation was intratumoral vascular thrombosis. The present studies examine the role of TNF in tumor progression by investigating the effects of TNF on VEGF (vascular endothelial growth factor) production in vitro and on tumor vessel count in vivo. Methods: SQ-20B tumor cells in serum-free medium were exposed to hrTNF (10 ng/ml) 4 hours prior to a single dose of x-irradiation (10 Gy). 24 hrs. after treatment, the conditioned medium was harvested, centrifuged, diluted 1:10, and assayed for VEGF using a Quantikine TNF ELISA kit. For studies in vivo, female nude mice were injected sc in the right thigh with 10 6 SQ-20B cells. Xenografts were irradiated with four 5 Gy fractions (20 Gy) and injected twice with either Ad.Egr-TNF or Ad.null. Control tumors were injected with buffer. To highlight vessels, sections from paraffin embedded tissue were stained with anti-CD31 antibody using standard immunohistochemical techniques. Areas of high vascular density were identified and five high power fields (400X) were counted. Data are shown as the mean ± S.E.M. for each treatment group. Significance was evaluated using one

  11. Next Generation Target Control System

    National Research Council Canada - National Science Library

    1995-01-01

    Our objective was to evaluate the allegations concerning the Next Generation Target Control System Program and to determine whether the Program is the most cost effective solution to meet the target...

  12. The “Trojan Horse” Approach to Tumor Immunotherapy: Targeting the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Delia Nelson

    2014-01-01

    Full Text Available Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumors may be more effective, particularly those that overcome natural suppressive factors in the tumor microenvironment. The “Trojan Horse” approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more “full frontal” treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient “dangerous” tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients.

  13. Nova target diagnostics control system

    International Nuclear Information System (INIS)

    Severyn, J.R.

    1985-01-01

    During the past year the Nova target diagnostics control system was finished and put in service. The diagnostics loft constructed to the north of the target room provides the environmental conditions required to collect reliable target diagnostic data. These improvements include equipment cooling and isolation of the power source with strict control of instrumentation grounds to eliminate data corruption due to electromagnetic pulses from the laser power-conditioning system or from target implosion effects

  14. Direct binding of radioiodinated monoclonal antibody to tumor cells: significance of antibody purity and affinity for drug targeting or tumor imaging

    International Nuclear Information System (INIS)

    Kennel, S.J.; Foote, L.J.; Lankford, P.K.; Johnson, M.; Mitchell, T.; Braslawsky, G.R.

    1983-01-01

    For MoAb to be used efficiently for drug targeting and tumor imaging, the fraction of antibody binding to tumor cells must be maximized. The authors have studied the binding of 125 I MoAb in three different tumor systems. The fraction of antibody that could be bound to the cell surface was directly proportional to the antibody purity. The affinity constant also limits the fraction of antibody that can bind to cells at a given antigen concentration. Rearrangement of the standard expression for univalent equilibrium binding between two reactants shows that in antigen excess, the maximum fraction of antibody that can bind =Ka[Ag total]/1 + Ka[Ag total]. Binding data using four different MoAb with three cell systems confirm this relationship. Estimates for reasonable concentrations of tumor antigens in vivo indicate that antibodies with binding constants less than 10 8 M -1 are not likely to be useful for drug targeting or tumor imaging

  15. Direct binding of radioiodinated monoclonal antibody to tumor cells: significance of antibody purity and affinity for drug targeting or tumor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Kennel, S.J.; Foote, L.J.; Lankford, P.K.; Johnson, M.; Mitchell, T.; Braslawsky, G.R.

    1983-01-01

    For MoAb to be used efficiently for drug targeting and tumor imaging, the fraction of antibody binding to tumor cells must be maximized. We have studied the binding of 125I MoAb in three different tumor systems. The fraction of antibody that could be bound to the cell surface was directly proportional to the antibody purity. The affinity constant also limits the fraction of antibody that can bind to cells at a given antigen concentration. Rearrangement of the standard expression for univalent equilibrium binding between two reactants shows that in antigen excess, the maximum fraction of antibody that can bind (formula; see text). Binding data using four different MoAb with three cell systems confirm this relationship. Estimates for reasonable concentrations of tumor antigens in vivo indicate that antibodies with binding constants less than 10(8) M-1 are not likely to be useful for drug targeting or tumor imaging.

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

    Science.gov (United States)

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

    2014-01-01

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

  17. Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors.

    Science.gov (United States)

    Chester, Cariad; Marabelle, Aurelien; Houot, Roch; Kohrt, Holbrook E

    2015-04-01

    Cancer immunotherapy is a rapidly evolving field that offers a novel paradigm for cancer treatment: therapies focus on enhancing the immune system's innate and adaptive anti-tumor response. Early immunotherapeutics have achieved impressive clinical outcomes and monoclonal antibodies are now integral to therapeutic strategies in a variety of cancers. However, only recently have antibodies targeting innate immune cells entered clinical development. Innate immune effector cells play important roles in generating and maintaining antitumor immunity. Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important innate immune mechanisms for tumor eradication. These cytolytic processes are initiated by the detection of a tumor-targeting antibody and can be augmented by activating co-stimulatory pathways or blocking inhibitory signals on innate immune cells. The combination of FDA-approved monoclonal antibodies with innate effector-targeting antibodies has demonstrated potent preclinical therapeutic synergy and early-phase combinatorial clinical trials are ongoing. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Pericentriolar Targeting of the Mouse Mammary Tumor Virus GAG Protein.

    Directory of Open Access Journals (Sweden)

    Guangzhi Zhang

    Full Text Available The Gag protein of the mouse mammary tumor virus (MMTV is the chief determinant of subcellular targeting. Electron microscopy studies show that MMTV Gag forms capsids within the cytoplasm and assembles as immature particles with MMTV RNA and the Y box binding protein-1, required for centrosome maturation. Other betaretroviruses, such as Mason-Pfizer monkey retrovirus (M-PMV, assemble adjacent to the pericentriolar region because of a cytoplasmic targeting and retention signal in the Matrix protein. Previous studies suggest that the MMTV Matrix protein may also harbor a similar cytoplasmic targeting and retention signal. Herein, we show that a substantial fraction of MMTV Gag localizes to the pericentriolar region. This was observed in HEK293T, HeLa human cell lines and the mouse derived NMuMG mammary gland cells. Moreover, MMTV capsids were observed adjacent to centrioles when expressed from plasmids encoding either MMTV Gag alone, Gag-Pro-Pol or full-length virus. We found that the cytoplasmic targeting and retention signal in the MMTV Matrix protein was sufficient for pericentriolar targeting, whereas mutation of the glutamine to alanine at position 56 (D56/A resulted in plasma membrane localization, similar to previous observations from mutational studies of M-PMV Gag. Furthermore, transmission electron microscopy studies showed that MMTV capsids accumulate around centrioles suggesting that, similar to M-PMV, the pericentriolar region may be a site for MMTV assembly. Together, the data imply that MMTV Gag targets the pericentriolar region as a result of the MMTV cytoplasmic targeting and retention signal, possibly aided by the Y box protein-1 required for the assembly of centrosomal microtubules.

  19. Tumor imaging and targeting potential of an Hsp70-derived 14-mer peptide.

    Directory of Open Access Journals (Sweden)

    Mathias Gehrmann

    Full Text Available We have previously used a unique mouse monoclonal antibody cmHsp70.1 to demonstrate the selective presence of a membrane-bound form of Hsp70 (memHsp70 on a variety of leukemia cells and on single cell suspensions derived from solid tumors of different entities, but not on non-transformed cells or cells from corresponding 'healthy' tissue. This antibody can be used to image tumors in vivo and target them for antibody-dependent cellular cytotoxicity. Tumor-specific expression of memHsp70 therefore has the potential to be exploited for theranostic purposes. Given the advantages of peptides as imaging and targeting agents, this study assessed whether a 14-mer tumor penetrating peptide (TPP; TKDNNLLGRFELSG, the sequence of which is derived from the oligomerization domain of Hsp70 which is expressed on the cell surface of tumor cells, can also be used for targeting membrane Hsp70 positive (memHsp70+ tumor cells, in vitro.The specificity of carboxy-fluorescein (CF- labeled TPP (TPP to Hsp70 was proven in an Hsp70 knockout mammary tumor cell system. TPP specifically binds to different memHsp70+ mouse and human tumor cell lines and is rapidly taken up via endosomes. Two to four-fold higher levels of CF-labeled TPP were detected in MCF7 (82% memHsp70+ and MDA-MB-231 (75% memHsp70+ cells compared to T47D cells (29% memHsp70+ that exhibit a lower Hsp70 membrane positivity. After 90 min incubation, TPP co-localized with mitochondrial membranes in memHsp70+ tumors. Although there was no evidence that any given vesicle population was specifically localized, fluorophore-labeled cmHsp70.1 antibody and TPP preferentially accumulated in the proximity of the adherent surface of cultured cells. These findings suggest a potential association between membrane Hsp70 expression and cytoskeletal elements that are involved in adherence, the establishment of intercellular synapses and/or membrane reorganization.This study demonstrates the specific binding and rapid

  20. Fibrin-targeting peptide CREKA-conjugated multi-walled carbon nanotubes for self-amplified photothermal therapy of tumor.

    Science.gov (United States)

    Zhang, Bo; Wang, Huafang; Shen, Shun; She, Xiaojian; Shi, Wei; Chen, Jun; Zhang, Qizhi; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

    2016-02-01

    Inability of nanomedicine to efficiently home to tumor site still poses great challenge in tumor drug delivery. Inspired by the amplified formation of fibrin in clotting cascade, a self-amplified drug delivery system was developed for tumor photothermal therapy (CMWNTs-PEG) using multi-walled carbon nanotubes (MWNTs) with favorable photothermal effect as the vector, polyethylene glycol as the shelter, CREKA peptide with special affinity for fibrin as the targeting moiety and NIR illumination as the external power. The self-amplified targeting property was carefully characterized. The in vivo temperature monitoring experiment demonstrated that CMWNTs-PEG could significantly elevate the temperature in the tumor region than its counterpart 24 h post an initial NIR illumination. The in vivo imaging and biodistribution experiment showed IR783-labeled CMWNTs-PEG with illumination could accumulate in tumors tissues about 6.4-fold higher than control group, much stronger than other treatment groups. In vivo distribution experiments revealed Cy3-labeled CMWNTs-PEG could deposit on the wall of tumor vessels, intravascular and extravascular spaces, far more extensive than its counterpart in tumor slices. The pharmacodynamics experiment revealed that after four times of illumination, the CMWNTs-PEG almost totally eradiated the tumor xenografts. Altogether, the self-amplified targeting system CMWNTs-PEG showed strong tumor targeting capacity and powerful photothermal therapeutic efficacy. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2017-10-01

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

  2. Investigation of the effects of tumor size and type of radionuclide on tumor curability in targeted radiotherapy

    Directory of Open Access Journals (Sweden)

    Hassan Ranjbar

    2015-07-01

    Full Text Available Background: Targeted radiotherapy is one of the important methods of radiotherapy that involves the use of beta-emitting radionuclides to deliver a dose of radiation to tumor cells. An important feature of this method is the tumor size and the finite range of beta particles emitted as a result of radionuclide disintegration those have significant effects for the curability of tumors. Material and Methods: Monte Carlo simulations and mathematical models have been used to investigate the relationship of curability to tumors size for tumors treated with targeted 131I and 90Y. The model assumed that radionuclides are distributed uniformly throughout tumors. Results: The results show that there is an optimal tumor size for cure. For any given cumulated activity, cure probability is greatest for tumors whose diameter is close to the optimum value. There is a maximum value of curability that occurs at a diameter of approximately 3.5 mm for 131I. For 90Y maximum curability occurs at a tumor diameter of approximately 3.5 cm. Tumors smaller than the optimal size are less vulnerable to irradiation from radionuclides because a significant proportion of the disintegration energy escapes and is deposited outside the tumor volume. Tumors larger than the optimal size are less curable because of greater clonogenic cell number. Conclusion: With single radionuclide targeted radiotherapy, there is an optimal tumor size for tumor cure. It is suggested that single agent targeted radiotherapy should not be used for treatment of disseminated disease when multiple tumors of differing size may be present. The use of several radionuclides concurrently would be more effective than reliance on single radionuclide. This approach of using combination of radionuclides with complementary properties could hopefully prepare new measures and improve the efficiency of tumor therapy.

  3. Synergistic anti-tumor effects of bevacizumab and tumor targeted polymerized VEGF siRNA nanoparticles.

    Science.gov (United States)

    Kim, Myung Goo; Jo, Sung Duk; Yhee, Ji Young; Lee, Beom Suk; Lee, So Jin; Park, Sung Gurl; Kang, Sun-Woong; Kim, Sun Hwa; Jeong, Ji Hoon

    2017-07-15

    A variety of VEGF inhibitors have been reported to treat cancers by suppressing tumor angiogenesis. Bevacizumab, a monoclonal VEGF antibody, was the first FDA approved anti-angiogenic agent for cancer treatments. However, bevacizumab shows modest therapeutic efficiency and often cause resistant problem in significant populations of cancer patients. To solve these problem, we investigated the therapeutic efficacy of siRNA drugs targeting VEGF and combination of the RNAi drug with bevacizumab for cancer treatments. For efficient VEGF siRNA delivery, chemically polymerized siRNAs were complexed with thiolated-glycol chitosan (psi(VEGF)/tGC). The poly-VEGF siRNA and thiolated-glycol chitosan formed stable nanoparticles via electrostatic interaction and chemical crosslinking, and showed high accumulation in tumor tissues resulting in efficient gene silencing. Both VEGF siRNA nanoparticles and bevacizumab had efficient therapeutic effects in tumor xenograft mouse models. Interestingly, most pronounced therapeutic efficacy was observed when the two distinct VEGF inhibitors were treated in combination revealing synergistic effects. The results showed that the psi(VEGF)/tGC nanoparticle mediated knockdown of VEGF exerts anti-tumor effects and the combination treatments with bevacizumab can extend the treatments options to conventional bevacizumab treatments for cancer therapy. Copyright © 2017. Published by Elsevier Inc.

  4. Highly specific PET imaging of prostate tumors in mice with an iodine-124-labeled antibody fragment that targets phosphatidylserine.

    Directory of Open Access Journals (Sweden)

    Jason H Stafford

    Full Text Available Phosphatidylserine (PS is an attractive target for imaging agents that identify tumors and assess their response to therapy. PS is absent from the surface of most cell types, but becomes exposed on tumor cells and tumor vasculature in response to oxidative stresses in the tumor microenvironment and increases in response to therapy. To image exposed PS, we used a fully human PS-targeting antibody fragment, PGN635 F(ab'2, that binds to complexes of PS and β2-glycoprotein I. PGN635 F(ab'2 was labeled with the positron-emitting isotope iodine-124 ((124I and the resulting probe was injected into nude mice bearing subcutaneous or orthotopic human PC3 prostate tumors. Biodistribution studies showed that (124I-PGN635 F(ab'2 localized with remarkable specificity to the tumors with little uptake in other organs, including the liver and kidneys. Clear delineation of the tumors was achieved by PET 48 hours after injection. Radiation of the tumors with 15 Gy or systemic treatment of the mice with 10 mg/kg docetaxel increased localization in the tumors. Tumor-to-normal (T/N ratios were inversely correlated with tumor growth measured over 28 days. These data indicate that (124I-PGN635 F(ab'2 is a promising new imaging agent for predicting tumor response to therapy.

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

    Directory of Open Access Journals (Sweden)

    Chia-Che Wu

    2010-01-01

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

  6. Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth.

    Science.gov (United States)

    Pérez-Pérez, María-Jesús; Priego, Eva-María; Bueno, Oskía; Martins, Maria Solange; Canela, María-Dolores; Liekens, Sandra

    2016-10-13

    The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).

  7. Short hairpin RNA targeting of fibroblast activation protein inhibits tumor growth and improves the tumor microenvironment in a mouse model

    Directory of Open Access Journals (Sweden)

    Fan Cai

    2013-05-01

    Full Text Available Fibroblast activation protein (FAP is a specific serine proteaseexpressed in tumor stroma proven to be a stimulatory factor inthe progression of some cancers. The purpose of this studywas to investigate the effects of FAP knockdown on tumorgrowth and the tumor microenvironment. Mice bearing 4T1subcutaneous tumors were treated with liposome-shRNAcomplexes targeting FAP. Tumor volumes and weights weremonitored, and FAP, collagen, microvessel density (MVD,and apoptosis were measured. Our studies showed thatshRNA targeting of FAP in murine breast cancer reduces FAPexpression, inhibits tumor growth, promotes collagenaccumulation (38%, and suppresses angiogenesis (71.7%, aswell as promoting apoptosis (by threefold. We suggest thatFAP plays a role in tumor growth and in altering the tumormicroenvironment. Targeting FAP may therefore represent asupplementary therapy for breast cancer. [BMB Reports 2013;46(5: 252-257

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

    Directory of Open Access Journals (Sweden)

    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

  9. Nanotechnology of emerging targeting systems.

    Science.gov (United States)

    Smith, S S

    2008-09-01

    Recent developments in the design and testing of complex nanoscale payload-carrying systems (i.e. systems with payloads that do not exceed 100 nm in size) are the focus of this brief review. Emerging systems include targeted single-walled nanotubes, viral capsids, dendrimers, gold nanoparticles, milled boron carbide nanoparticles, and protein nucleic acid assemblies. Significant advances are emerging with each of these bionanotechnological approaches to cellular targeting.

  10. Congenital tumors of the central nervous system

    International Nuclear Information System (INIS)

    Severino, Mariasavina; Schwartz, Erin S.; Thurnher, Majda M.; Rydland, Jana; Nikas, Ioannis; Rossi, Andrea

    2010-01-01

    Congenital tumors of the central nervous system (CNS) are often arbitrarily divided into ''definitely congenital'' (present or producing symptoms at birth), ''probably congenital'' (present or producing symptoms within the first week of life), and ''possibly congenital'' (present or producing symptoms within the first 6 months of life). They represent less than 2% of all childhood brain tumors. The clinical features of newborns include an enlarged head circumference, associated hydrocephalus, and asymmetric skull growth. At birth, a large head or a tense fontanel is the presenting sign in up to 85% of patients. Neurological symptoms as initial symptoms are comparatively rare. The prenatal diagnosis of congenital CNS tumors, while based on ultrasonography, has significantly benefited from the introduction of prenatal magnetic resonance imaging studies. Teratomas constitute about one third to one half of these tumors and are the most common neonatal brain tumor. They are often immature because of primitive neural elements and, rarely, a component of mixed malignant germ cell tumors. Other tumors include astrocytomas, choroid plexus papilloma, primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, and medulloblastomas. Less common histologies include craniopharyngiomas and ependymomas. There is a strong predilection for supratentorial locations, different from tumors of infants and children. Differential diagnoses include spontaneous intracranial hemorrhage that can occur in the presence of coagulation factor deficiency or underlying vascular malformations, and congenital brain malformations, especially giant heterotopia. The prognosis for patients with congenital tumors is generally poor, usually because of the massive size of the tumor. However, tumors can be resected successfully if they are small and favorably located. The most favorable outcomes are achieved with choroid plexus tumors, where aggressive surgical treatment leads to disease

  11. Congenital tumors of the central nervous system

    Energy Technology Data Exchange (ETDEWEB)

    Severino, Mariasavina [G. Gaslini Children' s Hospital, Department of Neuroradiology, Genoa (Italy); Schwartz, Erin S. [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); Thurnher, Majda M. [Medical University of Vienna, Department of Radiology, Vienna (Austria); Rydland, Jana [MR Center, St. Olav' s Hospital HF, Trondheim (Norway); Nikas, Ioannis [Agia Sophia Children' s Hospital, Imaging Department, Athens (Greece); Rossi, Andrea [G. Gaslini Children' s Hospital, Department of Neuroradiology, Genoa (Italy); G. Gaslini Children' s Hospital, Department of Pediatric Neuroradiology, Genoa (Italy)

    2010-06-15

    Congenital tumors of the central nervous system (CNS) are often arbitrarily divided into ''definitely congenital'' (present or producing symptoms at birth), ''probably congenital'' (present or producing symptoms within the first week of life), and ''possibly congenital'' (present or producing symptoms within the first 6 months of life). They represent less than 2% of all childhood brain tumors. The clinical features of newborns include an enlarged head circumference, associated hydrocephalus, and asymmetric skull growth. At birth, a large head or a tense fontanel is the presenting sign in up to 85% of patients. Neurological symptoms as initial symptoms are comparatively rare. The prenatal diagnosis of congenital CNS tumors, while based on ultrasonography, has significantly benefited from the introduction of prenatal magnetic resonance imaging studies. Teratomas constitute about one third to one half of these tumors and are the most common neonatal brain tumor. They are often immature because of primitive neural elements and, rarely, a component of mixed malignant germ cell tumors. Other tumors include astrocytomas, choroid plexus papilloma, primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, and medulloblastomas. Less common histologies include craniopharyngiomas and ependymomas. There is a strong predilection for supratentorial locations, different from tumors of infants and children. Differential diagnoses include spontaneous intracranial hemorrhage that can occur in the presence of coagulation factor deficiency or underlying vascular malformations, and congenital brain malformations, especially giant heterotopia. The prognosis for patients with congenital tumors is generally poor, usually because of the massive size of the tumor. However, tumors can be resected successfully if they are small and favorably located. The most favorable outcomes are achieved with choroid plexus tumors

  12. Tumor-targeted induction of oxystress for cancer therapy.

    Science.gov (United States)

    Fang, J; Nakamura, H; Iyer, A K

    2007-01-01

    Reactive oxygen species (ROS), such as superoxide anion radicals (O.-2) and hydrogen peroxide (H2O2) are potentially harmful by-products of normal cellular metabolism that directly affect cellular functions. ROS is generated by all aerobic organisms and it seems to be indispensable for signal transduction pathways that regulate cell growth and reduction-oxidation (redox) status. However, overproduction of these highly reactive oxygen metabolites can initiate lethal chain reactions, which involve oxidation and damage to structures that are crucial for cellular integrity and survival. In fact, many antitumor agents, such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, neocarzinostatin and many others exhibit antitumor activity via ROS-dependent activation of apoptotic cell death, suggesting potential use of ROS as an antitumor principle. Thus, a unique anticancer strategy named "oxidation therapy" has been developed by inducing cytotoxic oxystress for cancer treatment. This goal could be achieved mainly by two methods, namely, (i) inducing the generation of ROS directly to solid tumors and (ii) inhibiting the antioxidative enzyme (defense) system of tumor cells. Since 1950s, many strategies have been employed based on the first method, namely, administration of ROS per se (e.g. H2O2) or ROS generating enzyme to tumor bearing animals. However no successful and practical results were obtained probably because of the lack of tumor selective ROS delivery and hence resulting in subsequent induction of severe side effects. To overcome these obstacles, we developed polyethylene glycol (PEG) conjugated O.-2 or H2O2-generating enzymes, xanthine oxidase (XO) and D-amino acid oxidase (DAO) (PEG-DAO) respectively. More recently, a pegylated (PEG) zinc protoporphyrin (PEG-ZnPP) and a highly water soluble micellar formulation of ZnPP based on amphiphilic styrene maleic acid (SMA) copolymer, SMA-ZnPP, are prepared, which are potent inhibitors of heme

  13. Targeting doxorubicin encapsulated in stealth liposomes to solid tumors by non thermal diode laser.

    Science.gov (United States)

    Ghannam, Magdy M; El Gebaly, Reem; Fadel, Maha

    2016-04-05

    The use of liposomes as drug delivery systems is the most promising technique for targeting drug especially for anticancer therapy. In this study sterically stabilized liposomes was prepared from DPPC/Cholesterol/PEG-PE encapsulated doxorubicin. The effect of lyophilization on liposomal stability and hence expiration date were studied. Moreover, the effect of diode laser on the drug released from liposomesin vitro and in vivo in mice carrying implanted solid tumor were also studied. The results indicated that lyophilization of the prepared liposomes encapsulating doxorubicin led to marked stability when stored at 5 °C and it is possible to use the re-hydrated lyophilized liposomes within 12 days post reconstitution. Moreover, the use of low energy diode laser for targeting anticancer drug to the tumor cells is a promising method in cancer therapy. We can conclude that lyophilization of the liposomes encapsulating doxorubicin lead to marked stability for the liposomes when stored at 5 °C. Moreover, the use of low energy diode laser for targeting anticancer drug to the tumor cells through the use of photosensitive sterically stabilized liposomes loaded with doxorubicin is a promising method. It proved to be applicable and successful for treatment of Ehrlich solid tumors implanted in mice and eliminated toxic side effects of doxorubicin.

  14. Tumor-specific RNA interference targeting Pokemon suppresses tumor growth and induces apoptosis in prostate cancer.

    Science.gov (United States)

    Li, Yining; Xu, Shuxiong; Wang, Xiangwei; Shi, Hua; Sun, Zhaolin; Yang, Zhao

    2013-02-01

    To explore the exact mechanism of Pokemon in prostate cancer. Pokemon is a member of the POK family of transcriptional repressors. Its main function is suppression of the p14ARF (alternate reading frame) tumor suppressor gene. Although Pokemon expression has been found to be increased in various types of lymphoma, the exact mechanism of the gene in prostate cancer is not clear. In the present study, prostate cancer cells were transfected with the specific short hairpin ribonucleic acid (RNA) expression vector targeting Pokemon. The expression of Pokemon messenger RNA and its protein was detected by semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The cell growth and cell apoptosis were also examined using the methyl thiazolyl tetrazolium assay and flow cytometry. The results demonstrated that specific RNA interference (RNAi) could decrease the expression levels of Pokemon gene messenger RNA and protein in prostate cancer cells. In addition, that specific RNAi significantly inhibited the cell proliferation and increased the apoptotic rate. In vivo experiments showed that specific RNAi inhibited the tumorigenicity of prostate cancer cells and significantly suppressed tumor growth. Therefore, an RNAi-targeted Pokemon gene strategy could be a potential approach to prostate cancer therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Targeting doxorubicin encapsulated in stealth liposomes to solid tumors by non thermal diode laser

    OpenAIRE

    Ghannam, Magdy M.; El Gebaly, Reem; Fadel, Maha

    2016-01-01

    Background The use of liposomes as drug delivery systems is the most promising technique for targeting drug especially for anticancer therapy. Methods In this study sterically stabilized liposomes was prepared from DPPC/Cholesterol/PEG-PE encapsulated doxorubicin. The effect of lyophilization on liposomal stability and hence expiration date were studied. Moreover, the effect of diode laser on the drug released from liposomesin vitro and in vivo in mice carrying implanted solid tumor were also...

  16. Photosensitizer-Conjugated Hyaluronic Acid-Shielded Polydopamine Nanoparticles for Targeted Photomediated Tumor Therapy.

    Science.gov (United States)

    Han, Jieun; Park, Wooram; Park, Sin-Jung; Na, Kun

    2016-03-01

    Photodynamic therapy (PDT) is a widely used clinical option for tumor therapy. However, the clinical utilization of conventional small-molecule photosensitizers (PSs) for PDT has been limited by their low selectivity for disease sites, and undesirable photoactivation. To overcome these limitations, we demonstrated a tumor-specific and photoactivity-controllable nanoparticle photomedicine based on a combination of PS-biomacromolecule conjugates and polydopamine nanoparticles (PD-NP) for an effective tumor therapy. This novel photomedicine consisted of a PD-NP core and a PS-conjugated hyaluronic acid (PS-HA) shell. The PD-NP and the PS-HA play roles as a quencher for PSs and a cancer targeting moiety, respectively. The synthesized PS-HA-shielded PD-NPs (PHPD-NPs) had a relatively narrow size distribution (approximately 130 nm) with uniform spherical shapes. In response to cancer-specific intracellular enzymes (e.g., hyaluronidase), the PHPD-NPs exhibited an excellent singlet oxygen generation capacity for PDT. Furthermore, an efficient photothermal conversion ability for photothermal therapy (PTT) was also shown in the PHPD-NPs system. These properties provide superior therapeutic efficacy against cancer cells. In mice tumor model, the photoactive restorative effects of the PHPD-NPs were much higher in cancer microenvironments compared to that in the normal tissue. As a result, the PHPD-NPs showed a significant antitumor activity in in vivo mice tumor model. The nanoparticle photomedicine design is a novel strategy for effective tumor therapy.

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

    Science.gov (United States)

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

    2017-07-15

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

  18. Systemic Targeted Alpha Radiotherapy for Cancer

    Directory of Open Access Journals (Sweden)

    Allan B. J.

    2013-09-01

    Full Text Available Background: The fundamental principles of internal targeted alpha therapy for cancer were established many decades ago.The high linear energy transfer (LET of alpha radiation to the targeted cancer cellscauses double strand breaks in DNA. At the same time, the short range radiation spares adjacent normal tissues. This targeted approach complements conventional external beam radiotherapy and chemotherapy. Such therapies fail on several fronts, such as lack of control of some primary cancers (e.g.glioblastoma multiformeand to inhibit the development of lethal metastatic cancer after successful treatment of the primary cancer. Objective: This review charts the developing role of systemic high LET, internal radiation therapy. Method: Targeted alpha therapy is a rapidly advancing experimental therapy that holds promise to deliver high cytotoxicity to targeted cancer cells. Initially thought to be indicated for leukemia and micrometastases, there is now evidence that solid tumors can also be regressed. Results: Alpha therapy may be molecular or physiological in its targeting. Alpha emitting radioisotopes such as Bi-212, Bi-213, At-211 and Ac-225 are used to label monoclonal antibodies or proteins that target specifc cancer cells. Alternatively, Radium-233 is used for palliative therapy of breast and prostate cancers because of its bone seeking properties. Conclusion: Preclinical studies and clinical trials of alpha therapy are discussed for leukemia, lymphoma, melanoma, glioblastoma multiforme, bone metastases, ovarian cancer, pancreatic cancer and other cancers.

  19. Tumor angiogenesis--a new therapeutic target in gliomas

    DEFF Research Database (Denmark)

    Lund, E L; Spang-Thomsen, M; Skovgaard-Poulsen, H

    1998-01-01

    Tumor growth is critically dependent on angiogenesis, which is sprouting of new vessels from pre-existing vasculature. This process is regulated by inducers and inhibitors released from tumor cells, endothelial cells, and macrophages. Brain tumors, especially glioblastoma multiforme, have...... significant angiogenic activity primarily by the expression of the angiogenic factor VEGF Anti-angiogenic therapy represents a new promising therapeutic modality in solid tumors. Several agents are currently under evaluation in clinical trials. The present review describes the principal inducers...... and inhibitors of angiogenesis in tumors and summarizes what is known about their mechanisms of action in relation to CNS tumors. Potential areas for clinical use are also discussed....

  20. Pre-targeted tumor imaging with avidin-McAb and 99Tcm-DTPA-Biotin

    International Nuclear Information System (INIS)

    Zhang Jinming; Tian Jiahe; Wang Yuqi; Liu Xi; Sun Xin

    2002-01-01

    Objective: Biotin-avidin is used as pre-targeting system (BAS) in radioimmunoimaging in order to decrease radiation background and dose associated with the use of directly labelled McAb. The authors tried to use 99 Tc m to substitute 111 In to label DTPA-biotin to evaluate the value of the 99 Tc m -DTPA-biotin in BAS. Methods: DTPA-biotin solution was mixed with SnCl 2 and then fresh eluted 99 Tc m . The solution incubated for 10 min at room temperature. Mice bearing lung tumor (LA-795) with and without metastases in lung underwent 3-step pre-targeting test. Briefly, biotin-C50 was injected first, then avidin and 99 Tc m -DTPA-biotin was respectively given 1 day, 2 days later. Directly labelled C50 with 99 Tc m was used as control agent. Results: The labelling yield of 99 Tc m -DTPA-biotin was over 90%. The amount of SnCl 2 was the key feature in labelling. The tumor could be seen at 2 h after injection of 99 Tc m -DTPA-biotin with γ camera in 3- step groups. The tracer uptake in tumor was (1.35 +- 0.45)% ID/g at 2 h after injection, Tumor/Blood (T/B) was 5.86, T/Muscle (T/M) was 8.43. In control group which received 99 Tc m -DTPA-biotin only, the T/B was 0.85, T/M 1.1. For the directly labelled C50, the T/B was 1.65, T/M was 2.0 at 8 h after injection. Conclusion: Avidin-biotin pre-targeting system can be labelled with 99 Tc m , and the BAS can image the tumor as early as 2 h after injection

  1. Reduction sensitive nanosystems for tumor targeted imaging and therapy

    NARCIS (Netherlands)

    Zhu, Yaqin

    2017-01-01

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

  2. Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer

    NARCIS (Netherlands)

    Binnemars-Postma, Karin; Bansal, Ruchi; Storm, Gert; Prakash, Jai

    2017-01-01

    Tumor-associated macrophages (TAMs) are the key effector cells in the tumor microenvironment and induce neoangiogenesis, matrix remodeling, and metastasis while suppressing the tumor immune system. These protumoral macrophages display an M2 phenotype induced by IL-4 and IL-13 cytokines. In this

  3. Liposomal targeting of glucocorticoids to inhibit tumor angiogenesis

    NARCIS (Netherlands)

    Banciu, M.

    2007-01-01

    Glucocorticoids (GC) have inhibitory actions on solid tumor growth due to suppressive effects on tumor angiogenesis and inflammation. When evaluating the preclinical studies on solid tumor growth inhibition, it appears that GC-induced antitumor effects are achieved by using substantially higher

  4. Evaluation of molecular targeted cancer drug by changes in tumor marker doubling times.

    Science.gov (United States)

    Enooku, Kenichiro; Tateishi, Ryosuke; Kanai, Fumihiko; Kondo, Yuji; Masuzaki, Ryota; Goto, Tadashi; Shiina, Shuichiro; Yoshida, Haruhiko; Omata, Masao; Koike, Kazuhiko

    2012-01-01

    We evaluated the usefulness of tumor marker doubling time (DT) as an efficacy indicator of a molecular targeted anticancer agent. Twenty-five patients with advanced hepatocellular carcinoma (HCC) received TSU-68, a multiple tyrosine kinase inhibitor. Exponential increase in HCC-specific tumor marker levels (alpha-fetoprotein or des-gamma-carboxyprothrombin) was seen in 15 of them prior to TSU-68 administration. The relationship between tumor marker DT and tumor volume DT was evaluated. Next, tumor marker DT in the first 8 weeks of TSU-68 administration was compared with tumor marker DT before treatment. Efficacy evaluation based on changes in tumor marker DT was compared with Response Evaluation Criteria In Solid Tumors (RECIST). Tumor marker DT and tumor volume DT were almost identical (r(2) = 0.94, P tumor marker DT on TSU-68 administration was in accordance with RECIST in 12/15 cases. Discordance was observed in three cases, for which RECIST indicated disease progression in spite of elongated tumor marker DT. Those cases showed substantial tumor necrosis without volume shrinkage or appearance of new lesions in spite of apparent effects on target lesions. Serum tumor marker DT can be used to evaluate viable tumor burden irrespective of the presence of tumor necrosis which can compromise radiographic evaluation. This approach may be applicable to the evaluation of responses to chemotherapy, particularly to cytostatic agents (ClinicalTrials.gov number, NCT00784290).

  5. Development of targeted radiotherapy systems

    International Nuclear Information System (INIS)

    Ferro, Guillermina; Villarreal, Jose E.; Garcia, Laura; Tendilla, Jose I.; Paredes, Lydia; Murphy, Consuelo A.; Pedraza, Martha

    2001-01-01

    Conventional or external beam radiotherapy, has been a viable alternative for cancer treatment. Although this technique is effective, its use is limited if the patient has multiple malignant lesions (metastases). An alternative approach is based on the design of radiopharmaceuticals that, to be administered in the patient, are directed specifically toward the target cell producing a selective radiation delivery. This treatment is known as targeted radiotherapy. We have summarized and discussed some results related to our investigations on the development of targeted radiotherapy systems, including aspects of internal dosimetry

  6. Targeting Unique Metabolic Properties of Breast Tumor Initiating Cells

    Science.gov (United States)

    Feng, Weiguo; Gentles, Andrew; Nair, Ramesh V.; Huang, Min; Lin, Yuan; Lee, Cleo Y.; Cai, Shang; Scheeren, Ferenc A.; Kuo, Angera H.; Diehn, Maximilian

    2014-01-01

    Normal stem cells from a variety of tissues display unique metabolic properties compared to their more differentiated progeny. However, relatively little is known about heterogeneity of metabolic properties cancer stem cells, also called tumor initiating cells (TICs). In this study we show that, analogous to some normal stem cells, breast TICs have distinct metabolic properties compared to non-tumorigenic cancer cells (NTCs). Transcriptome profiling using RNA-Seq revealed TICs under-express genes involved in mitochondrial biology and mitochondrial oxidative phosphorylation and metabolic analyses revealed TICs preferentially perform glycolysis over oxidative phosphorylation compared to NTCs. Mechanistic analyses demonstrated that decreased expression and activity of pyruvate dehydrogenase (Pdh), a key regulator of oxidative phosphorylation, play a critical role in promoting the pro-glycolytic phenotype of TICs. Metabolic reprogramming via forced activation of Pdh preferentially eliminates TICs both in vitro and in vivo. Our findings reveal unique metabolic properties of TICs and demonstrate that metabolic reprogramming represents a promising strategy for targeting these cells. PMID:24497069

  7. A pretargeting system for tumor PET imaging and radioimmunotherapy.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Frampas, Eric; Faivre-Chauvet, Alain; Rauscher, Aurore; Sharkey, Robert M; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2015-01-01

    Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.

  8. A pretargeting system for tumor PET imaging and radioimmunotherapy

    Directory of Open Access Journals (Sweden)

    Françoise eKraeber-Bodéré

    2015-03-01

    Full Text Available Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.

  9. Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of VL and VH Domains Targeting CD123+ Tumors.

    Directory of Open Access Journals (Sweden)

    Radhika Thokala

    Full Text Available Adoptive immunotherapy infusing T cells with engineered specificity for CD19 expressed on B- cell malignancies is generating enthusiasm to extend this approach to other hematological malignancies, such as acute myelogenous leukemia (AML. CD123, or interleukin 3 receptor alpha, is overexpressed on most AML and some lymphoid malignancies, such as acute lymphocytic leukemia (ALL, and has been an effective target for T cells expressing chimeric antigen receptors (CARs. The prototypical CAR encodes a VH and VL from one monoclonal antibody (mAb, coupled to a transmembrane domain and one or more cytoplasmic signaling domains. Previous studies showed that treatment of an experimental AML model with CD123-specific CAR T cells was therapeutic, but at the cost of impaired myelopoiesis, highlighting the need for systems to define the antigen threshold for CAR recognition. Here, we show that CARs can be engineered using VH and VL chains derived from different CD123-specific mAbs to generate a panel of CAR+ T cells. While all CARs exhibited specificity to CD123, one VH and VL combination had reduced lysis of normal hematopoietic stem cells. This CAR's in vivo anti-tumor activity was similar whether signaling occurred via chimeric CD28 or CD137, prolonging survival in both AML and ALL models. Co-expression of inducible caspase 9 eliminated CAR+ T cells. These data help support the use of CD123-specific CARs for treatment of CD123+ hematologic malignancies.

  10. Tumor vascular endothelium : Barrier or target in tumor directed drug delivery and immunotherapy

    NARCIS (Netherlands)

    Molema, Ingrid; de Leij, Lou; Meijer, D.K F

    The therapy of solid tumors with conventional chemotherapeutics, drug delivery preparations and immunomodulatory agents directed against the tumor cells is corrupted by a major barrier presented by the tumor vasculature. Permeability of the tumor blood vessels for transport of small molecules and

  11. Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

    Energy Technology Data Exchange (ETDEWEB)

    Fillat, Cristina, E-mail: cristina.fillat@crg.es; Jose, Anabel; Ros, Xavier Bofill-De; Mato-Berciano, Ana; Maliandi, Maria Victoria; Sobrevals, Luciano [Programa Gens i Malaltia, Centre de Regulació Genòmica-CRG, UPF, Parc de Recerca Biomedica de Barcelona-PRBB and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona (Spain)

    2011-01-18

    The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed.

  12. Roles of F-box proteins in human digestive system tumors (Review).

    Science.gov (United States)

    Gong, Jian; Lv, Liang; Huo, Jirong

    2014-12-01

    F-box proteins (FBPs), the substrate-recognition subunit of E3 ubiquitin (Ub) ligase, are the important components of Ub proteasome system (UPS). FBPs are involved in multiple cellular processes through ubiquitylation and subsequent degradation of their target proteins. Many studies have described the roles of FBPs in human cancers. Digestive system tumors account for a large proportion of all the tumors, and their mortality is very high. This review summarizes for the first time the roles of FBPs in digestive system tumorige-nesis and tumor progression, aiming at finding new routes for the rational design of targeted anticancer therapies in digestive system tumors.

  13. Radiolabeled Probes Targeting Hypoxia-Inducible Factor-1-Active Tumor Microenvironments

    Directory of Open Access Journals (Sweden)

    Masashi Ueda

    2014-01-01

    Full Text Available Because tumor cells grow rapidly and randomly, hypoxic regions arise from the lack of oxygen supply in solid tumors. Hypoxic regions in tumors are known to be resistant to chemotherapy and radiotherapy. Hypoxia-inducible factor-1 (HIF-1 expressed in hypoxic regions regulates the expression of genes related to tumor growth, angiogenesis, metastasis, and therapy resistance. Thus, imaging of HIF-1-active regions in tumors is of great interest. HIF-1 activity is regulated by the expression and degradation of its α subunit (HIF-1α, which is degraded in the proteasome under normoxic conditions, but escapes degradation under hypoxic conditions, allowing it to activate transcription of HIF-1-target genes. Therefore, to image HIF-1-active regions, HIF-1-dependent reporter systems and injectable probes that are degraded in a manner similar to HIF-1α have been recently developed and used in preclinical studies. However, no probe currently used in clinical practice directly assesses HIF-1 activity. Whether the accumulation of 18F-FDG or 18F-FMISO can be utilized as an index of HIF-1 activity has been investigated in clinical studies. In this review, the current status of HIF-1 imaging in preclinical and clinical studies is discussed.

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

    Science.gov (United States)

    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”).

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

    Science.gov (United States)

    Fang, Jun; Liao, Long; Yin, Hongzhuan; Nakamura, Hideaki; Subr, Vladimir; Ulbrich, Karel; Maeda, Hiroshi

    2015-01-01

    Aim: To evaluate the potential of tumor-targeted nanoprobe, N-(2-hydroxypropyl)methacrylamide copolymer-conjugated zinc protoporphyrin (PZP) for photodynamic therapy (PDT) and tumor imaging. Materials & Methods: Different tumor models including carcinogen-induced cancer were used, PZP was intravenously injected followed by irradiation with xenon or blue fluorescent light on tumor. Results: One PZP 20 mg/kg (ZnPP equivalent) dose with two or three treatments of light at an intensity of ≥20 J/cm2 caused necrosis and disappearance of most tumors (>70%) in different tumor models. We also confirmed PZP-based tumor imaging in carcinogen-induced breast tumor and colon cancer models. Conclusion: These findings support the potential application of PZP as a tumor-selective nanoprobe for PDT as well as tumor imaging, by virtue of the enhanced permeability and retention effect. PMID:28031879

  16. Tumor-Shed Antigen Affects Antibody Tumor Targeting: Comparison of Two 89Zr-Labeled Antibodies Directed against Shed or Nonshed Antigens

    Directory of Open Access Journals (Sweden)

    Jae-Ho Lee

    2018-01-01

    Full Text Available We investigated the effect of shed antigen mesothelin on the tumor uptake of amatuximab, a therapeutic anti-mesothelin mAb clinically tested in mesothelioma patients. The B3 mAb targeting a nonshed antigen was also analyzed for comparison. The mouse model implanted with A431/H9 tumor, which expresses both shed mesothelin and nonshed Lewis-Y antigen, provided an ideal system to compare the biodistribution and PET imaging profiles of the two mAbs. Our study demonstrated that the tumor and organ uptakes of 89Zr-B3 were dose-independent when 3 doses, 2, 15, and 60 μg B3, were compared at 24 h after injection. In contrast, tumor and organ uptakes of 89Zr-amatuximab were dose-dependent, whereby a high dose (60 μg was needed to achieve tumor targeting comparable to the low dose (2 μg of 89Zr-B3, suggesting that shed mesothelin may affect amatuximab tumor targeting as well as serum half-life. The autoradiography analysis showed that the distribution of 89Zr-B3 was nonuniform with the radioactivity primarily localized at the tumor periphery independent of the B3 dose. However, the autoradiography analysis for 89Zr-amatuximab showed dose-dependent distribution profiles of the radiolabel; at 10 μg dose, the radiolabel penetrated toward the tumor core with its activity comparable to that at the tumor periphery, whereas at 60 μg dose, the distribution profile became similar to those of 89Zr-B3. These results suggest that shed antigen in blood may act as a decoy requiring higher doses of mAb to improve serum half-life as well as tumor targeting. Systemic mAb concentration should be at a severalfold molar excess to the shed Ag in blood to overcome the hepatic processing of mAb-Ag complexes. On the other hand, mAb concentration should remain lower than the shed Ag concentration in the tumor ECS to maximize tumor penetration by passing binding site barriers.

  17. Toward a siRNA-containing nanoparticle targeted to breast cancer cells and the tumor microenvironment.

    Science.gov (United States)

    Gomes-da-Silva, Lígia C; Santos, Adriana O; Bimbo, Luís M; Moura, Vera; Ramalho, José S; Pedroso de Lima, Maria C; Simões, Sérgio; Moreira, João N

    2012-09-15

    The present work aimed at designing a lipid-based nanocarrier for siRNA delivery toward two cell sub-populations within breast tumors, the cancer and the endothelial cells from angiogenic tumor blood vessels. To achieve such goal, the F3 peptide, which is specifically internalized by nucleolin overexpressed on both those sub-populations, was used as a targeting moiety. The developed F3-targeted stable nucleic acid lipid particles presented adequate features for systemic administration. In addition, the attachment of the F3 peptide onto the liposomal surface enabled an internalization by both cancer and endothelial cells from angiogenic blood vessels that was significantly higher than the one observed with non-cancer cells. Sequence-specific downregulation of enhanced green fluorescent protein (eGFP) in eGFP-overexpressing human cancer cell lines, both at the protein and mRNA levels, was further observed upon delivery of anti-eGFP siRNA by F3-targeted liposomes, in contrast with the non-targeted counterpart. This effect was highly dependent on the content of poly(ethylene glycol) (PEG), as evidenced by the co-localization studies between the siRNA and the lysosomes. Overall, the present work represents an important contribution toward a nanoparticle with multi-targeting capabilities in breast cancer, both at the cellular and molecular level. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. [Tumors of the central nervous system].

    Science.gov (United States)

    Alegría-Loyola, Marco Antonio; Galnares-Olalde, Javier Andrés; Mercado, Moisés

    2017-01-01

    Central nervous system (CNS) tumors constitute a heterogeneous group of neoplasms that share a considerable morbidity and mortality rate. Recent advances in the underlying oncogenic mechanisms of these tumors have led to new classification systems, which, in turn, allow for a better diagnostic approach and therapeutic planning. Most of these neoplasms occur sporadically and several risk factors have been found to be associated with their development, such as exposure to ionizing radiation or electromagnetic fields and the concomitant presence of conditions like diabetes, hypertension and Parkinson's disease. A relatively minor proportion of primary CNS tumors occur in the context of hereditary syndromes. The purpose of this review is to analyze the etiopathogenesis, clinical presentation, diagnosis and therapy of CNS tumors with particular emphasis in the putative risk factors mentioned above.

  19. Novel Simulation Device for Targeting Tumors in Laparoscopic Ablation: A Learning Curve Study.

    Science.gov (United States)

    Jutric, Zeljka; Grendar, Jan; Brown, William L; Cassera, Maria A; Wolf, Ronald F; Hansen, Paul D; Hammill, Chet W

    2017-10-01

    A novel 3-dimensional (3D) guidance system was developed to aid accurate needle placement during ablation. Five novices and 5 experienced hepatobiliary surgeons were recruited. Using an agar block with analog tumor, participants targeted under 4 conditions: in-line with the ultrasound plane using ultrasound, in-line using 3D guidance, 45° off-axis using ultrasound, and off-axis using 3D guidance. Time to target the tumor, number of withdrawals, and the National Aeronautics and Space Administration Task Load Index were collected. Initial and final parameters for each of the conditions were compared using a within-subjects paired t test. A significant reduction was seen in the number of required withdrawals in all situations when using the 3D guidance (0.75 vs 3.65 in-line and 0.25 vs 3.6 for off-axis). Mental workload was significantly lower when using 3D guidance compared with ultrasound both for novices (29.85 vs 41.03) and experts (31.98 vs 44.57), P mental workload after proficiency was achieved. Furthermore, novices without experience in ultrasound were able to learn targeting with the 3D guidance system at a faster pace than targeting with ultrasound alone.

  20. MicroRNA Signatures as Biomarkers and Therapeutic Target for CNS Embryonal Tumors: The Pros and the Cons

    Directory of Open Access Journals (Sweden)

    Tarek Shalaby

    2014-11-01

    Full Text Available Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients’ response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors and a group of primitive neuroectodermal tumors. All are aggressive tumors with the tendency to disseminate throughout the central nervous system. The large amount of genomic and molecular data generated over the last 5–10 years encourages optimism that new molecular targets will soon improve outcomes. Recent neurobiological studies have uncovered the key role of microRNAs (miRNAs in embryonal tumors biology and their potential use as biomarkers is increasingly being recognized and investigated. However the successful use of microRNAs as reliable biomarkers for the detection and management of pediatric brain tumors represents a substantial challenge. This review debates the importance of miRNAs in the biology of central nervous systemembryonal tumors focusing on medulloblastoma and atypical teratoid/rhabdoid tumors and highlights the advantages as well as the limitations of their prospective application as biomarkers and candidates for molecular therapeutic targets.

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

    Science.gov (United States)

    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.

  2. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment.

    Science.gov (United States)

    Hendry, Shona A; Farnsworth, Rae H; Solomon, Benjamin; Achen, Marc G; Stacker, Steven A; Fox, Stephen B

    2016-01-01

    Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host's immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

  3. Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization.

    Science.gov (United States)

    Wang, Sheng; Huang, Peng; Chen, Xiaoyuan

    2016-09-01

    Targeted delivery of therapeutic agents is an important way to improve the therapeutic index and reduce side effects. To design nanoparticles for targeted delivery, both enhanced tumor tissue accumulation/retention and enhanced cellular internalization should be considered simultaneously. So far, there have been very few nanoparticles with immutable structures that can achieve this goal efficiently. Hierarchical targeting, a novel targeting strategy based on stimuli responsiveness, shows good potential to enhance both tumor tissue accumulation/retention and cellular internalization. Here, the recent design and development of hierarchical targeting nanoplatforms, based on changeable particle sizes, switchable surface charges and activatable surface ligands, will be introduced. In general, the targeting moieties in these nanoplatforms are not activated during blood circulation for efficient tumor tissue accumulation, but re-activated by certain internal or external stimuli in the tumor microenvironment for enhanced cellular internalization. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Antibody or Antibody Fragments: Implications for Molecular Imaging and Targeted Therapy of Solid Tumors

    Directory of Open Access Journals (Sweden)

    Katerina T. Xenaki

    2017-10-01

    Full Text Available The use of antibody-based therapeutics has proven very promising for clinical applications in cancer patients, with multiple examples of antibodies and antibody–drug conjugates successfully applied for the treatment of solid tumors and lymphomas. Given reported recurrence rates, improvements are clearly still necessary. A major factor limiting the efficacy of antibody-targeted cancer therapies may be the incomplete penetration of the antibody or antibody–drug conjugate into the tumor. Incomplete tumor penetration also affects the outcome of molecular imaging, when using such targeting agents. From the injection site until they arrive inside the tumor, targeting molecules are faced with several barriers that impact intratumoral distribution. The primary means of antibody transport inside tumors is based on diffusion. The diffusive penetration inside the tumor is influenced by both antibody properties, such as size and binding affinity, as well as tumor properties, such as microenvironment, vascularization, and targeted antigen availability. Engineering smaller antibody fragments has shown to improve the rate of tumor uptake and intratumoral distribution. However, it is often accompanied by more rapid clearance from the body and in several cases also by inherent destabilization and reduction of the binding affinity of the antibody. In this perspective, we discuss different cancer targeting approaches based on antibodies or their fragments. We carefully consider how their size and binding properties influence their intratumoral uptake and distribution, and how this may affect cancer imaging and therapy of solid tumors.

  5. Estimation of lung tissue incompressibility variation throughout respiration for tumor targeting in lung radiotherapy

    Science.gov (United States)

    Shirzadi, Zahra; Samani, Abbas

    2013-03-01

    A novel technique is proposed to characterize lung tissue incompressibility variation during respiration. Lung tissue incompressibility variation stems from significant air content variation in the tissue throughout respiration. Estimating lung tissue incompressibility and its variation is critical for computer assisted tumor motion tracking. Continuous tumor motion during respiration is a major challenge in lung cancer treatment by external beam radiotherapy. If not accounted for, this motion leads to areas of radiation over dosage for the lung normal tissues. Since no effective imaging modality is available for real-time lung tumor tracking, computer based modeling which has the capability for accurate tissue deformation estimation can be a good alternative. Lung tissue deformation estimation can be made using the lung Finite Element (FE) model where its accuracy depends on input tissue biomechanical properties including incompressibility parameter. In this research, an optimization algorithm is proposed to estimate the incompressibility parameter function in terms of respiration cycle time. In this algorithm, the incompressibility parameter and lung pressure values are varied systematically until optimal values, which result in maximum similarity between acquired and simulated 4D CT images of the lung, are achieved for each respiration time point. The simulated images are constructed using a reference image in conjunction with the deformation field obtained from the lung's FE model in each respiration time increment. We demonstrated that utilizing the calculated function along with respiratory system FE modeling leads to accurate tumor targeting, hence potentially improving lung radiotherapy outcome.

  6. CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.

    Science.gov (United States)

    Zhou, You; Shan, Song; Li, Zhi-Bin; Xin, Li-Jun; Pan, De-Si; Yang, Qian-Jiao; Liu, Ying-Ping; Yue, Xu-Peng; Liu, Xiao-Rong; Gao, Ji-Zhou; Zhang, Jin-Wen; Ning, Zhi-Qiang; Lu, Xian-Ping

    2017-03-01

    Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC 50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R + cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  7. Trispecific antibodies for CD16A-directed NK cell engagement and dual-targeting of tumor cells.

    Science.gov (United States)

    Gantke, Thorsten; Weichel, Michael; Herbrecht, Carmen; Reusch, Uwe; Ellwanger, Kristina; Fucek, Ivica; Eser, Markus; Müller, Thomas; Griep, Remko; Molkenthin, Vera; Zhukovsky, Eugene A; Treder, Martin

    2017-09-01

    Bispecific antibodies that redirect the lytic activity of cytotoxic immune effector cells, such as T- and NK cells, onto tumor cells have emerged as a highly attractive and clinically validated treatment modality for hematological malignancies. Advancement of this therapeutic concept into solid tumor indications, however, is hampered by the scarcity of targetable antigens that are surface-expressed on tumor cells but demonstrate only limited expression on healthy tissues. To overcome this limitation, the concept of dual-targeting, i.e. the simultaneous targeting of two tumor-expressed surface antigens with limited co-expression on non-malignant cells, with multispecific antibodies has been proposed to increase tumor selectivity of antibody-induced effector cell cytotoxicity. Here, a novel CD16A (FcγRIIIa)-directed trispecific, tetravalent antibody format, termed aTriFlex, is described, that is capable of redirecting NK cell cytotoxicity to two surface-expressed antigens. Using a BCMA/CD200-based in vitro model system, the potential use of aTriFlex antibodies for dual-targeting and selective induction of NK cell-mediated target cell lysis was investigated. Bivalent bispecific target cell binding was found to result in significant avidity gains and up to 17-fold increased in vitro potency. These data suggest trispecific aTriFlex antibodies may support dual-targeting strategies to redirect NK cell cytotoxicity with increased selectivity to enable targeting of solid tumor antigens. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Epigenetics, Nervous System Tumors, and Cancer Stem Cells

    International Nuclear Information System (INIS)

    Qureshi, Irfan A.; Mehler, Mark F.

    2011-01-01

    Recent advances have begun to elucidate how epigenetic regulatory mechanisms are responsible for establishing and maintaining cell identity during development and adult life and how the disruption of these processes is, not surprisingly, one of the hallmarks of cancer. In this review, we describe the major epigenetic mechanisms (i.e., DNA methylation, histone and chromatin modification, non-coding RNA deployment, RNA editing, and nuclear reorganization) and discuss the broad spectrum of epigenetic alterations that have been uncovered in pediatric and adult nervous system tumors. We also highlight emerging evidence that suggests epigenetic deregulation is a characteristic feature of so-called cancer stem cells (CSCs), which are thought to be present in a range of nervous system tumors and responsible for tumor maintenance, progression, treatment resistance, and recurrence. We believe that better understanding how epigenetic mechanisms operate in neural cells and identifying the etiologies and consequences of epigenetic deregulation in tumor cells and CSCs, in particular, are likely to promote the development of enhanced molecular diagnostics and more targeted and effective therapeutic agents for treating recalcitrant nervous system tumors

  9. Epigenetics, Nervous System Tumors, and Cancer Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    Qureshi, Irfan A. [Rosyln and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Mehler, Mark F., E-mail: mark.mehler@einstein.yu.edu [Rosyln and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States)

    2011-09-13

    Recent advances have begun to elucidate how epigenetic regulatory mechanisms are responsible for establishing and maintaining cell identity during development and adult life and how the disruption of these processes is, not surprisingly, one of the hallmarks of cancer. In this review, we describe the major epigenetic mechanisms (i.e., DNA methylation, histone and chromatin modification, non-coding RNA deployment, RNA editing, and nuclear reorganization) and discuss the broad spectrum of epigenetic alterations that have been uncovered in pediatric and adult nervous system tumors. We also highlight emerging evidence that suggests epigenetic deregulation is a characteristic feature of so-called cancer stem cells (CSCs), which are thought to be present in a range of nervous system tumors and responsible for tumor maintenance, progression, treatment resistance, and recurrence. We believe that better understanding how epigenetic mechanisms operate in neural cells and identifying the etiologies and consequences of epigenetic deregulation in tumor cells and CSCs, in particular, are likely to promote the development of enhanced molecular diagnostics and more targeted and effective therapeutic agents for treating recalcitrant nervous system tumors.

  10. Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model.

    Science.gov (United States)

    MacDiarmid, Jennifer A; Langova, Veronika; Bailey, Dale; Pattison, Scott T; Pattison, Stacey L; Christensen, Neil; Armstrong, Luke R; Brahmbhatt, Vatsala N; Smolarczyk, Katarzyna; Harrison, Matthew T; Costa, Marylia; Mugridge, Nancy B; Sedliarou, Ilya; Grimes, Nicholas A; Kiss, Debra L; Stillman, Bruce; Hann, Christine L; Gallia, Gary L; Graham, Robert M; Brahmbhatt, Himanshu

    2016-01-01

    Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted

  11. Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model.

    Directory of Open Access Journals (Sweden)

    Jennifer A MacDiarmid

    Full Text Available Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers.EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT and magnetic resonance imaging (MRI. Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973. No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs.Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of

  12. Activity of Nanobins Targeted to the Urokinase Plasminogen Activator System

    Science.gov (United States)

    Hankins, Patrick Leon

    While innovations in nanotechnology have resulted in numerous medical advancements for the treatment of cancer, there remains an urgent unmet need for safe and efficient molecular platforms that facilitate the delivery of potent therapeutics to solid tumors. Nanoscale formulations help to overcome the poor bioavailability and systemic organ toxicity associated with many small molecule drugs. Of these nanoparticle drug delivery systems, the greatest clinical successes to date have employed simple nanoscale lipid bilayer assemblies which encase large payloads of chemotherapeutic. While the nanobin platform we have developed has seen initial success through the passive accumulation into tumors, actively targeting nanobins to tumor specific antigens has the potential to increase the therapeutic index of these nanoparticle drugs. We have identified the urokinase plasminogen activator (uPA) and its cell surface bound receptor (uPAR) as ideal targets for drug delivery due to their selective overexpression in metastatic cancers and their important role in tumor progression. From a panel of monoclonal antibodies targeted to uPA and uPAR, we have selected ATN291 and ATN658 as lead candidates for nanobin targeting based on their tumor cell binding and ability to be internalized by cells. A novel method of conjugating antibodies to liposomes was developed for our nanobin platform that preserves the high binding affinity and specificity of these antibodies. We evaluated these uPA- and uPAR-targeted nanobins in several xenograft tumor models and found that they were well-tolerated over a wide range of doses and demonstrated significantly increased antitumor efficacy over untargeted nanobins in multiple tumor types. Preliminary studies suggest that uPA-targeted nanobins are readily internalized by tumor cells, and we believe this is the mechanism for their increased antitumor effect. A method for radiolabeling nanobins with gallium-67 was developed, and preliminary SPECT

  13. Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas

    NARCIS (Netherlands)

    van Laarhoven, H. W. M.; Gambarota, G.; Heerschap, A.; Lok, J.; Verhagen, I.; Corti, A.; Toma, S.; Gallo Stampino, C.; van der Kogel, A.; Punt, C. J. A.

    2006-01-01

    TNF-alpha may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the

  14. Targeted tumor theranostics using folate-conjugated and camptothecin-loaded acoustic nanodroplets in a mouse xenograft model.

    Science.gov (United States)

    Chen, Wei-Tsung; Kang, Shih-Tsung; Lin, Jian-Liang; Wang, Chung-Hsin; Chen, Ran-Chou; Yeh, Chih-Kuang

    2015-01-01

    In this study, we aimed to validate the feasibility of receptor-targeted tumor theranostics with folate-conjugated (FA) and camptothecin-loaded (CPT) acoustic nanodroplets (NDs) (collectively termed FA-CPT-NDs). The ND formulation was based on lipid-stabilized low-boiling perfluorocarbon that can undergo acoustic droplet vaporization (ADV) under ultrasound (US) exposure. Conjugation of folate enhanced the selective delivery to tumors expressing high levels of folate receptor (FR) under mediation by the enhanced permeability and retention effect. In vitro and in vivo studies were performed using FR-positive KB and FR-negative HT-1080 cell lines and mouse xenograft tumor models. Simultaneous therapy and imaging were conducted with a clinical US imaging system at mechanical indices of up to 1.4 at a center frequency of 10 MHz. The results demonstrated that FA-CPT-NDs selectively attached to KB cells, but not HT-1080 cells. The targeted ADV caused instant and delayed damage via mechanical disruption and chemical toxicity to decrease the viability of KB cells by up to 45%, a much higher decrease than that achieved by the NDs without folate conjugation. The in vivo experiments showed that FR-mediated targeting successfully enhanced the EPR of FA-CPT-NDs in KB tumors mainly on the tumor periphery as indicated by immunofluorescence microscopy and US B-mode imaging. Treatments with FA-CPT-NDs at a CPT dose of 50 μg/kg inhibited the growth of KB tumors for up to six weeks, whereas treatment with NDs lacking folate produced a 4.6-fold increase in tumor volume. For HT-1080 tumors, neither the treatments with FA-CPT-NDs nor those with the NDs lacking folate presented tumor growth inhibition. In summary, FR-targeted tumor theranostics has been successfully implemented with FA-CPT-NDs and a clinical US unit. The ligand-directed and EPR-mediated accumulation provides active and passive targeting capabilities, permitting the antitumor effects of FA-CPT-NDs to be exerted

  15. Targeting EGFR with photodynamic therapy in combination with Erbitux enhances in vivo bladder tumor response

    Directory of Open Access Journals (Sweden)

    Soo Khee

    2009-11-01

    Full Text Available Abstract Background Photodynamic therapy (PDT is a promising cancer treatment modality that involves the interaction of the photosensitizer, molecular oxygen and light of specific wavelength to destroy tumor cells. Treatment induced hypoxia is one of the main side effects of PDT and efforts are underway to optimize PDT protocols for improved efficacy. The aim of this study was to investigate the anti-tumor effects of PDT plus Erbitux, an angiogenesis inhibitor that targets epidermal growth factor receptor (EGFR, on human bladder cancer model. Tumor-bearing nude mice were assigned to four groups that included control, PDT, Erbitux and PDT plus Erbitux and tumor volume was charted over 90-day period. Results Our results demonstrate that combination of Erbitux with PDT strongly inhibits tumor growth in the bladder tumor xenograft model when compared to the other groups. Downregulation of EGFR was detected using immunohistochemistry, immunofluorescence and western blotting. Increased apoptosis was associated with tumor inhibition in the combination therapy group. In addition, we identified the dephosphorylation of ErbB4 at tyrosine 1284 site to play a major role in tumor inhibition. Also, at the RNA level downregulation of EGFR target genes cyclin D1 and c-myc was observed in tumors treated with PDT plus Erbitux. Conclusion The combination therapy of PDT and Erbitux effectively inhibits tumor growth and is a promising therapeutic approach in the treatment of bladder tumors.

  16. Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response.

    Directory of Open Access Journals (Sweden)

    David S Terman

    Full Text Available Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs but not normal RBCs (NLRBCs to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2O(2 and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.

  17. Sickle Erythrocytes Target Cytotoxics to Hypoxic Tumor Microvessels and Potentiate a Tumoricidal Response

    Science.gov (United States)

    Zennadi, Rahima; Fels, Diane; Boruta, Richard J.; Yuan, Hong; Dreher, Mathew R.; Grant, Gerald; Rabbani, Zahid N.; Moon, Ejung; Lan, Lan; Eble, Joseph; Cao, Yiting; Sorg, Brian; Ashcraft, Kathleen; Palmer, Greg; Telen, Marilyn J.; Dewhirst, Mark W.

    2013-01-01

    Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H2O2 and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments. PMID:23326340

  18. Anti-tumoral effect of the mitochondrial target domain of Noxa delivered by an engineered Salmonella typhimurium.

    Directory of Open Access Journals (Sweden)

    Jae-Ho Jeong

    Full Text Available Bacterial cancer therapy relies on the fact that several bacterial species are capable of targeting tumor tissue and that bacteria can be genetically engineered to selectively deliver therapeutic proteins of interest to the targeted tumors. However, the challenge of bacterial cancer therapy is the release of the therapeutic proteins from the bacteria and entry of the proteins into tumor cells. This study employed an attenuated Salmonella typhimurium to selectively deliver the mitochondrial targeting domain of Noxa (MTD as a potential therapeutic cargo protein, and examined its anti-cancer effect. To release MTD from the bacteria, a novel bacterial lysis system of phage origin was deployed. To facilitate the entry of MTD into the tumor cells, the MTD was fused to DS4.3, a novel cell-penetrating peptide (CPP derived from a voltage-gated potassium channel (Kv2.1. The gene encoding DS4.3-MTD and the phage lysis genes were placed under the control of PBAD , a promoter activated by L-arabinose. We demonstrated that DS4.3-MTD chimeric molecules expressed by the Salmonellae were anti-tumoral in cultured tumor cells and in mice with CT26 colon carcinoma.

  19. Dual targeting and enhanced cytotoxicity to HER2-overexpressing tumors by immunoapoptotin-armored mesenchymal stem cells.

    Science.gov (United States)

    Cai, Yanhui; Xi, Yujing; Cao, Zhongyuan; Xiang, Geng; Ni, Qingrong; Zhang, Rui; Chang, Jing; Du, Xiao; Yang, Angang; Yan, Bo; Zhao, Jing

    2016-10-10

    Mesenchymal stem cells (MSCs) are promising vehicles for the delivery of anticancer agents in cancer therapy. However, the tumor targeting of loaded therapeutics is essential. Here, we explored a dual-targeting strategy to incorporate tumor-tropic MSC delivery with HER2-specific killing by the immunoapoptotin e23sFv-Fdt-tBid generated in our previous studies. The MSC engineering allowed simultaneous immunoapoptotin secretion and bioluminescence detection of the modified MSCs. Systemic administration of the immunoapoptotin-engineered MSCs was investigated in human HER2-reconstituted syngeneic mouse models of orthotopic and metastatic breast cancer, as well as in a xenograft nude mouse model of orthotopic gastric cancer. In vivo dual tumor targeting was confirmed by local accumulation of the bioluminescence-imaged MSCs and persistence of His-immunostained immunoapoptotins in tumor sites. The added tumor preference of MSC-secreted immunoapoptotins resulted in a significantly stronger antitumor effect compared with purified immunoapoptotins and Jurkat-delivered immunoapoptotins. This immunoapoptotin-armored MSC strategy provides a rationale for its use in extended malignancies by combining MSC mobility with redirected immunoapoptotins against a given tumor antigen. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

    Science.gov (United States)

    2006-04-01

    kinase inhibitors. Drug Discov.Today, 5: 344-353, 2000. 31. Solorzano , C. C., Baker, C. H., Bruns, C. J., Killion, J. J., Ellis, L. M., Wood, J...tumor angiogenesis by synthetic receptor tyrosine kinase inhibitors. Drug Discov Today 5, 344 – 353. [31] Solorzano CC, Baker CH, Bruns CJ, Killion JJ

  1. The anti-tumor activity of a neutralizing nanobody targeting leptin receptor in a mouse model of melanoma.

    Directory of Open Access Journals (Sweden)

    Travis McMurphy

    Full Text Available Environmental and genetic activation of a brain-adipocyte axis inhibits cancer progression. Leptin is the primary peripheral mediator of this anticancer effect in a mouse model of melanoma. In this study we assessed the effect of a leptin receptor antagonist on melanoma progression. Local administration of a neutralizing nanobody targeting the leptin receptor at low dose adjacent to tumor decreased tumor mass with no effects on body weight or food intake. In contrast, systemic administration of the nanobody failed to suppress tumor growth. Daily intraperitoneal injection of high-dose nanobody led to weight gain, hyperphagia, increased adiposity, hyperleptinemia, and hyperinsulinemia, and central effects mimicking leptin deficiency. The blockade of central actions of leptin by systemic delivery of nanobody may compromise its anticancer effect, underscoring the need to develop peripherally acting leptin antagonists coupled with efficient cancer-targeting delivery.

  2. The anti-tumor activity of a neutralizing nanobody targeting leptin receptor in a mouse model of melanoma.

    Science.gov (United States)

    McMurphy, Travis; Xiao, Run; Magee, Daniel; Slater, Andrew; Zabeau, Lennart; Tavernier, Jan; Cao, Lei

    2014-01-01

    Environmental and genetic activation of a brain-adipocyte axis inhibits cancer progression. Leptin is the primary peripheral mediator of this anticancer effect in a mouse model of melanoma. In this study we assessed the effect of a leptin receptor antagonist on melanoma progression. Local administration of a neutralizing nanobody targeting the leptin receptor at low dose adjacent to tumor decreased tumor mass with no effects on body weight or food intake. In contrast, systemic administration of the nanobody failed to suppress tumor growth. Daily intraperitoneal injection of high-dose nanobody led to weight gain, hyperphagia, increased adiposity, hyperleptinemia, and hyperinsulinemia, and central effects mimicking leptin deficiency. The blockade of central actions of leptin by systemic delivery of nanobody may compromise its anticancer effect, underscoring the need to develop peripherally acting leptin antagonists coupled with efficient cancer-targeting delivery.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    Shuang Sha

    2016-07-01

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

  6. Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors

    Science.gov (United States)

    Ganesh, Shanthi; Iyer, Arun K.; Morrissey, David V.; Amiji, Mansoor M.

    2013-01-01

    Anticancer therapeutics employing RNA interference mechanism holds promising potentials for sequence-specific silencing of target genes. However targeted delivery of siRNAs to tumor tissues and cells and more importantly, their intracellular release at sites of interest still remains a major challenge that needs to be addressed before this technique could become a clinically viable option. In the current study, we have engineered and screened a series of CD44 targeting hyaluronic acid (HA) based self-assembling nanosystems for targeted siRNA delivery. The HA polymer was functionalized with lipids of varying carbon chain lengths/nitrogen content, as well as polyamines for assessing siRNA encapsulation. From the screens, several HA-derivatives were identified that could stably encapsulate/complex siRNAs and form self-assembled nanosystems, as determined by gel retardation assays and dynamic light scattering. Many HA derivatives could transfect siRNAs into cancer cells overexpressing CD44 receptors. Interestingly, blocking the CD44 receptors on the cells using free excess soluble HA prior to incubation of cy3-labeled-siRNA loaded HA nano-assemblies resulted in >90% inhibition of the receptor mediated uptake, confirming target specificity. In addition, SSB/PLK1 siRNA encapsulated in HA-PEI/PEG nanosystems demonstrated dose dependent and target specific gene knockdown in both sensitive and resistant A549 lung cancer cells overexpressing CD44 receptors. More importantly, these siRNA encapsulated nanosystems demonstrated tumor selective uptake and target specific gene knock down in vivo in solid tumors as well as in metastatic tumors. The HA based nanosystems thus portend to be promising siRNA delivery vectors for systemic targeting of CD44 overexpressing cancers including tumor initiating (stem-) cells and metastatic lesions. PMID:23410679

  7. Amine-modified hyaluronic acid-functionalized porous silicon nanoparticles for targeting breast cancer tumors

    Science.gov (United States)

    Almeida, Patrick V.; Shahbazi, Mohammad-Ali; Mäkilä, Ermei; Kaasalainen, Martti; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A.

    2014-08-01

    Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA+) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA+ nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of UnTHCPSi-HA+ relies on the capability of the conjugated HA+ to bind and consequently target CD44 receptors expressed on the surface of breast cancer cells, thus making the HA+-functionalized UnTHCPSi nanoparticles a suitable and promising nanoplatform for the targeting of CD44-overexpressing breast tumors and for drug delivery.Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA+) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA+ nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of Un

  8. PRELIMINARY STRUCTURE–ACTIVITY RELATIONSHIP STUDY OF HEPTAMETHINE INDOCYANINE DYES FOR TUMOR-TARGETED IMAGING

    Directory of Open Access Journals (Sweden)

    QINYUAN GUO

    2013-01-01

    Full Text Available Our research has identified a couple of near-infrared (NIR heptamethine indocyanine dyes exhibiting preferential tumor accumulation property for in vivo imaging. On the basis of our foregoing work, we describe here a preliminary structure–activity relationship (SAR study of 11 related heptamethine indocyanine dyes and several essential requirements of these structures for in vivo tumor-targeted imaging.

  9. Relationships between tumor size and curablity for uniformly targeted therapy with beta-emitting radionuclides

    International Nuclear Information System (INIS)

    O'Donoghue, J.A.; Bardies, M.; Wheldon, T.E.

    1995-01-01

    Targeted radionuclide therapy is a new form of radiotherapy that differs in some important respects from external beam irradiation. One of the most important differences is due to the finite range of ionizing beta particles emitted as a result of radionuclide disintegration. The effects of particle range have important implications for the curability of tumors. We used a mathematical model to examine tumor curability and its relationship to tumor size for 22 beta-emitting radionuclides that may have therapeutic potential. The model assumed a uniform distribution of radionuclide throughout. For targeted radionuclide therapy, the relationship between tumor curability and tumor size is different from that for conventional external beam radiotherapy. With targeted radionuclides, there is an optimal tumor size for cure. Tumors smaller than the optimal size are less vulnerable to irradiation from radionuclides because a substantial proportion of the disintegration energy escapes and is deposited outside the tumor volume. We found an optimal tumor size for radiocurability by each of the 22 radionuclides considered. Optimal cure diameters range from less than 1 mm for short-range emitters such as 199 Au and 33 P to several centimeters for long-range emitters such as 90 Y and 188 Re. The energy emitted per disintegration may be used to predict optimal cure size for uniform distributions of radionuclide. 17 refs., 8 figs., 3 tabs

  10. Integrin α5β1, the Fibronectin Receptor, as a Pertinent Therapeutic Target in Solid Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Schaffner, Florence; Ray, Anne Marie; Dontenwill, Monique, E-mail: monique.dontenwill@unistra.fr [UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Tumoral signaling and therapeutic targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch (France)

    2013-01-15

    Integrins are transmembrane heterodimeric proteins sensing the cell microenvironment and modulating numerous signalling pathways. Changes in integrin expression between normal and tumoral cells support involvement of specific integrins in tumor progression and aggressiveness. This review highlights the current knowledge about α5β1 integrin, also called the fibronectin receptor, in solid tumors. We summarize data showing that α5β1 integrin is a pertinent therapeutic target expressed by tumoral neovessels and tumoral cells. Although mainly evaluated in preclinical models, α5β1 integrin merits interest in particular in colon, breast, ovarian, lung and brain tumors where its overexpression is associated with a poor prognosis for patients. Specific α5β1 integrin antagonists will be listed that may represent new potential therapeutic agents to fight defined subpopulations of particularly aggressive tumors.

  11. 3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions

    Energy Technology Data Exchange (ETDEWEB)

    Wenzel, Carsten; Riefke, Björn; Gründemann, Stephan; Krebs, Alice; Christian, Sven; Prinz, Florian; Osterland, Marc; Golfier, Sven; Räse, Sebastian [Bayer Pharma AG, Global Drug Discovery, Muellerstrasse 178, 13353 Berlin (Germany); Ansari, Nariman [Physical Biology Group, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt (Germany); Esner, Milan; Bickle, Marc [Max Planck Institute of Molecular Cell Biology and Genetics, High-Throughput Technology Development Studio (TDS), Dresden (Germany); Pampaloni, Francesco; Mattheyer, Christian; Stelzer, Ernst H. [Physical Biology Group, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt (Germany); Parczyk, Karsten; Prechtl, Stefan [Bayer Pharma AG, Global Drug Discovery, Muellerstrasse 178, 13353 Berlin (Germany); Steigemann, Patrick, E-mail: Patrick.Steigemann@bayer.com [Bayer Pharma AG, Global Drug Discovery, Muellerstrasse 178, 13353 Berlin (Germany)

    2014-04-15

    Cancer cells in poorly vascularized tumor regions need to adapt to an unfavorable metabolic microenvironment. As distance from supplying blood vessels increases, oxygen and nutrient concentrations decrease and cancer cells react by stopping cell cycle progression and becoming dormant. As cytostatic drugs mainly target proliferating cells, cancer cell dormancy is considered as a major resistance mechanism to this class of anti-cancer drugs. Therefore, substances that target cancer cells in poorly vascularized tumor regions have the potential to enhance cytostatic-based chemotherapy of solid tumors. With three-dimensional growth conditions, multicellular tumor spheroids (MCTS) reproduce several parameters of the tumor microenvironment, including oxygen and nutrient gradients as well as the development of dormant tumor regions. We here report the setup of a 3D cell culture compatible high-content screening system and the identification of nine substances from two commercially available drug libraries that specifically target cells in inner MCTS core regions, while cells in outer MCTS regions or in 2D cell culture remain unaffected. We elucidated the mode of action of the identified compounds as inhibitors of the respiratory chain and show that induction of cell death in inner MCTS core regions critically depends on extracellular glucose concentrations. Finally, combinational treatment with cytostatics showed increased induction of cell death in MCTS. The data presented here shows for the first time a high-content based screening setup on 3D tumor spheroids for the identification of substances that specifically induce cell death in inner tumor spheroid core regions. This validates the approach to use 3D cell culture screening systems to identify substances that would not be detectable by 2D based screening in otherwise similar culture conditions. - Highlights: • Establishment of a novel method for 3D cell culture based high-content screening. • First reported high

  12. 3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions

    International Nuclear Information System (INIS)

    Wenzel, Carsten; Riefke, Björn; Gründemann, Stephan; Krebs, Alice; Christian, Sven; Prinz, Florian; Osterland, Marc; Golfier, Sven; Räse, Sebastian; Ansari, Nariman; Esner, Milan; Bickle, Marc; Pampaloni, Francesco; Mattheyer, Christian; Stelzer, Ernst H.; Parczyk, Karsten; Prechtl, Stefan; Steigemann, Patrick

    2014-01-01

    Cancer cells in poorly vascularized tumor regions need to adapt to an unfavorable metabolic microenvironment. As distance from supplying blood vessels increases, oxygen and nutrient concentrations decrease and cancer cells react by stopping cell cycle progression and becoming dormant. As cytostatic drugs mainly target proliferating cells, cancer cell dormancy is considered as a major resistance mechanism to this class of anti-cancer drugs. Therefore, substances that target cancer cells in poorly vascularized tumor regions have the potential to enhance cytostatic-based chemotherapy of solid tumors. With three-dimensional growth conditions, multicellular tumor spheroids (MCTS) reproduce several parameters of the tumor microenvironment, including oxygen and nutrient gradients as well as the development of dormant tumor regions. We here report the setup of a 3D cell culture compatible high-content screening system and the identification of nine substances from two commercially available drug libraries that specifically target cells in inner MCTS core regions, while cells in outer MCTS regions or in 2D cell culture remain unaffected. We elucidated the mode of action of the identified compounds as inhibitors of the respiratory chain and show that induction of cell death in inner MCTS core regions critically depends on extracellular glucose concentrations. Finally, combinational treatment with cytostatics showed increased induction of cell death in MCTS. The data presented here shows for the first time a high-content based screening setup on 3D tumor spheroids for the identification of substances that specifically induce cell death in inner tumor spheroid core regions. This validates the approach to use 3D cell culture screening systems to identify substances that would not be detectable by 2D based screening in otherwise similar culture conditions. - Highlights: • Establishment of a novel method for 3D cell culture based high-content screening. • First reported high

  13. Targeting BRAF V600E and Autophagy in Pediatric Brain Tumors

    Science.gov (United States)

    2015-10-01

    for childhood central nervous system (CNS) tumors, they remain the leading cause of death in pediatric oncology . One potential therapeutic...clinical trial design for pediatric brain tumor patients harboring the mutation. Keywords: Autophagy BRAF Brain tumor Pediatric Resistance...I submitted an abstract of my most recent findings to the Society of Neuro- Oncology Pediatric Neuro- Oncology Basic and Translational Research

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

    Directory of Open Access Journals (Sweden)

    Oula Penate Medina

    2011-01-01

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

  15. Tumor microenvironment in invasive lobular carcinoma: possible therapeutic targets.

    Science.gov (United States)

    Nakagawa, Saki; Miki, Yasuhiro; Miyashita, Minoru; Hata, Shuko; Takahashi, Yayoi; Rai, Yoshiaki; Sagara, Yasuaki; Ohi, Yasuyo; Hirakawa, Hisashi; Tamaki, Kentaro; Ishida, Takanori; Watanabe, Mika; Suzuki, Takashi; Ohuchi, Noriaki; Sasano, Hironobu

    2016-01-01

    Invasive ductal and lobular carcinomas (IDC and ILC) are the two most common histological types of breast cancer, and have been considered to develop from terminal duct lobular unit but their molecular, pathological, and clinical features are markedly different between them. These differences could be due to different mechanisms of carcinogenesis and tumor microenvironment, especially cancer-associated fibroblasts (CAFs) but little has been explored in this aspect. Therefore, in this study, we evaluated the status of angiogenesis, maturation of intratumoral microvessels, and proliferation of CAFs using immunohistochemistry and PCR array analysis to explore the differences of tumor microenvironment between ILC and IDC. We studied grade- and age-matched, luminal-like ILC and IDC. We immunolocalized CD34 and αSMA for an evaluation of CAFs and CD31, Vasohibin-1, a specific marker of proliferative endothelial cells and nestin, a marker of pericytes for studying the status of proliferation and maturation of intratumoral microvessel. We also performed PCR array analysis to evaluate angiogenic factors in tumor stromal components. The number of CAFs, microvessel density, and vasohibin-1/CD31 positive ratio were all significantly higher in ILC than IDC but nestin immunoreactivity in intratumoral microvessel was significantly lower in ILC. These results did indicate that proliferation of CAFs and endothelial cells was more pronounced in ILC than IDC but newly formed microvessels were less mature than those in IDC. PCR array analysis also revealed that IGF-1 expression was higher in ILC than IDC. This is the first study to demonstrate the differences of tumor microenvironment including CAFs and proliferation and maturation of intratumoral vessels between ILC and IDC.

  16. Boronic acid-tethered amphiphilic hyaluronic acid derivative-based nanoassemblies for tumor targeting and penetration.

    Science.gov (United States)

    Jeong, Jae Young; Hong, Eun-Hye; Lee, Song Yi; Lee, Jae-Young; Song, Jae-Hyoung; Ko, Seung-Hak; Shim, Jae-Seong; Choe, Sunghwa; Kim, Dae-Duk; Ko, Hyun-Jeong; Cho, Hyun-Jong

    2017-04-15

    (3-Aminomethylphenyl)boronic acid (AMPB)-installed hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated for tumor-targeted delivery. The amine group of AMPB was conjugated to the carboxylic acid group of hyaluronic acid (HA) via amide bond formation, and synthesis was confirmed by spectroscopic methods. HACE-AMPB/MB NPs with a 239-nm mean diameter, narrow size distribution, negative zeta potential, and >90% drug encapsulation efficiency were fabricated. Exposed AMPB in the outer surface of HACE-AMPB NPs (in the aqueous environment) may react with sialic acid of cancer cells. The improved cellular accumulation efficiency, in vitro antitumor efficacy, and tumor penetration efficiency of HACE-AMPB/MB NPs, compared with HACE/MB NPs, in MDA-MB-231 cells (CD44 receptor-positive human breast adenocarcinoma cells) may be based on the CD44 receptor-mediated endocytosis and phenylboronic acid-sialic acid interaction. Enhanced in vivo tumor targetability, infiltration efficiency, and antitumor efficacies of HACE-AMPB NPs, compared with HACE NPs, were observed in a MDA-MB-231 tumor-xenografted mouse model. In addition to passive tumor targeting (based on an enhanced permeability and retention effect) and active tumor targeting (interaction between HA and CD44 receptor), the phenylboronic acid-sialic acid interaction can play important roles in augmented tumor targeting and penetration of HACE-AMPB NPs. STATEMENT OF SIGNIFICANCE: (3-Aminomethylphenyl)boronic acid (AMPB)-tethered hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated and their tumor targeting and penetration efficiencies were assessed in MDA-MB-231 (CD44 receptor-positive human adenocarcinoma) tumor models. MB, which exhibited antitumor efficacies via the inhibition of angiogenesis and hypoxia inducible factor (HIF)-1, was entrapped in HACE-AMPB NPs in this study. Phenylboronic acid located in the outer surface

  17. Targeting of Breast Tumors and Tumor Cells Using Inductive Magnetic Heating of Metallic Nanoparticles

    National Research Council Canada - National Science Library

    Rotello, Vincent M

    2004-01-01

    Our research in the first year has focused on the creation of nanoparticles designed for hyperthermic tumor ablation via magnetic field heating, and the development of equipment for genetic magnetic field generation...

  18. CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR

    Science.gov (United States)

    Wang, Tianxiao; Yang, Jingxuan; Xu, Jianwei; Li, Jian; Cao, Zhe; Zhou, Li; You, Lei; Shu, Hong; Lu, Zhaohui; Li, Huihua; Li, Min; Zhang, Taiping; Zhao, Yupei

    2014-01-01

    Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer. PMID:24722501

  19. TNYL peptide functional chitosan-g-stearate conjugate micelles for tumor specific targeting

    Directory of Open Access Journals (Sweden)

    Chen FY

    2014-09-01

    Full Text Available Feng-Ying Chen,1 Jing-Jing Yan,1 Han-Xi Yi,2 Fu-Qiang Hu,2 Yong-Zhong Du,2 Hong Yuan,2 Jian You,2 Meng-Dan Zhao1 1Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2College of Pharmaceutical Science, Zhejiang University, Hangzhou, People’s Republic of China Abstract: Nowadays, a real challenge in cancer therapy is to design drug delivery systems that can achieve high concentrations of drugs at the target site for improved therapeutic effect with reduced side effects. In this research, we designed and synthesized a homing peptide-(TNYLFSPNGPIA, TNYL modified chitosan-g-stearate (CS polymer micelle (named T-CS for targeting delivery. The peptide displayed specific binding affinity to EphB4 which is a member of the Eph family of receptor tyrosine protein kinases. The amphiphilic polymer T-CS can gather into micelles by themselves in an aqueous environment with a low critical micelle concentration value (91.2 µg/L and nano-scaled size (82.1±2.8 nm. The drug encapsulation efficiency reached 86.43% after loading the hydrophobic drug doxorubicin (DOX. The cytotoxicity of T-CS/DOX against SKOV3 cells was enhanced by approximately 2.3-fold when compared with CS/DOX. The quantitative and qualitative analysis for cellular uptake indicated that TNYL modification can markedly increase cellular internalization in the EphB4-overexpressing SKOV3 cell line, especially with a short incubation time. It is interesting that relatively higher uptake of the T-CS/DOX micelles by SKOV3 cells (positive-EphB4 than A549 cells (negative-EphB4 was observed when the two cells were co-incubated. Furthermore, in vivo distribution experiment using a bilateral-tumor model showed that there was more fluorescence accumulation in the SKOV3 tumor than in the A549 tumor over the whole experiment. These results suggest that TNYL-modified CS micelles may be promising drug carriers as targeting therapy for the EphB4-overexpressing

  20. Sindbis Virus-Pseudotyped Lentiviral Vectors Carrying VEGFR2-Specific Nanobody for Potential Transductional Targeting of Tumor Vasculature.

    Science.gov (United States)

    Ahani, Roshank; Roohvand, Farzin; Cohan, Reza Ahangari; Etemadzadeh, Mohammad Hossein; Mohajel, Nasir; Behdani, Mahdi; Shahosseini, Zahra; Madani, Navid; Azadmanesh, Kayhan

    2016-11-01

    Introduction of selectivity/specificity into viral-based gene delivery systems, such as lentiviral vectors (LVs), is crucial in their systemic administration for cancer gene therapy. The pivotal role of tumor-associated endothelial cells (TAECs) in tumor angiogenesis and overexpression of vascular endothelial growth factor receptor-2 (VEGFR2 or KDR) in TAECs makes them a potent target in cancer treatment. Herein, we report the development of VEGFR2-targeted LVs pseudotyped with chimeric sindbis virus E2 glycoprotein (cSVE2s). For this purpose, either sequence of a VEGFR2-specific nanobody or its natural ligand (VEGF 121 ) was inserted into the binding site of sindbis virus E2 glycoprotein. In silico modeling data suggested that the inserted targeting motifs were exposed in the context of cSVE2s. Western blot analysis of LVs indicated the incorporation of cSVE2s into viral particles. Capture ELISA demonstrated the specificity/functionality of the incorporated cSVE2s. Transduction of 293/KDR (expressing VEGFR2) or 293T cells (negative control) by constructed LVs followed by fluorescent microscopy and flow cytometric analyses indicated selective transduction of 293/KDR cells (30 %) by both targeting motifs compared to 293T control cells (1-2 %). These results implied similar targeting properties of VEGFR2-specific nanobody compared to the VEGF 121 and indicated the potential for transductional targeting of tumor vasculature by the nanobody displaying LVs.

  1. Targeted Therapy in Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    Murray Baron

    2016-10-01

    Full Text Available Targeted therapies use an understanding of the pathophysiology of a disease in an individual patient. Although targeted therapy for systemic sclerosis (SSc, scleroderma has not yet reached the level of patient-specific treatments, recent developments in the understanding of the global pathophysiology of the disease have led to new treatments based on the cells and pathways that have been shown to be involved in the disease pathogenesis. The presence of a B cell signature in skin biopsies has led to the trial of rituximab, an anti-CD20 antibody, in SSc. The well-known properties of transforming growth factor (TGF-β in promoting collagen synthesis and secretion has led to a small trial of fresolimumab, a human IgG4 monoclonal antibody capable of neutralizing TGF-β. Evidence supporting important roles for interleukin-6 in the pathogenesis of SSc have led to a large trial of tocilizumab in SSc. Soluble guanylate cyclase (sGC is an enzyme that catalyzes the production of cyclic guanosine monophosphate (cGMP upon binding of nitric oxide (NO to the sGC molecule. Processes such as cell growth and proliferation are regulated by cGMP. Evidence that sGC may play a role in SSc has led to a trial of riociguat, a molecule that sensitizes sGC to endogenous NO. Tyrosine kinases (TKs are involved in a wide variety of physiologic and pathological processes including vascular remodeling and fibrogenesis such as occurs in SSc. This has led to a trial of nintedanib, a next-generation tyrosine-kinase (TK inhibitor which targets multiple TKs, in SSc.

  2. Investigating the effect of tumor vascularization on magnetic targeting in vivo using retrospective design of experiment.

    Science.gov (United States)

    Mei, Kuo-Ching; Bai, Jie; Lorrio, Silvia; Wang, Julie Tzu-Wen; Al-Jamal, Khuloud T

    2016-11-01

    Nanocarriers take advantages of the enhanced permeability and retention (EPR) to accumulate passively in solid tumors. Magnetic targeting has shown to further enhance tumor accumulation in response to a magnetic field gradient. It is widely known that passive accumulation of nanocarriers varies hugely in tumor tissues of different tumor vascularization. It is hypothesized that magnetic targeting is likely to be influenced by such factors. In this work, magnetic targeting is assessed in a range of subcutaneously implanted murine tumors, namely, colon (CT26), breast (4T1), lung (Lewis lung carcinoma) cancer and melanoma (B16F10). Passively- and magnetically-driven tumor accumulation of the radiolabeled polymeric magnetic nanocapsules are assessed with gamma counting. The influence of tumor vasculature, namely, the tumor microvessel density, permeability and diameter on passive and magnetic tumor targeting is assessed with the aid of the retrospective design of experiment (DoE) approach. It is clear that the three tumor vascular parameters contribute greatly to both passive and magnetically targeted tumor accumulation but play different roles when nanocarriers are targeted to the tumor with different strategies. It is concluded that tumor permeability is a rate-limiting factor in both targeting modes. Diameter and microvessel density influence passive and magnetic tumor targeting, respectively. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  3. Impact of target reproducibility on tumor dose in stereotactic radiotherapy of targets in the lung and liver

    International Nuclear Information System (INIS)

    Wulf, Joern; Haedinger, Ulrich; Oppitz, Ulrich; Thiele, Wibke; Flentje, Michael

    2003-01-01

    Background and purpose: Previous analyses of target reproducibility in extracranial stereotactic radiotherapy have revealed standard security margins for planning target volume (PTV) definition of 5 mm in axial and 5-10 mm in longitudinal direction. In this study the reproducibility of the clinical target volume (CTV) of lung and liver tumors within the PTV over the complete course of hypofractionated treatment is evaluated. The impact of target mobility on dose to the CTV is assessed by dose-volume histograms (DVH). Materials and methods: Twenty-two pulmonary and 21 hepatic targets were treated with three stereotactic fractions of 10 Gy to the PTV-enclosing 100%-isodose with normalization to 150% at the isocenter. A conformal dose distribution was related to the PTV, which was defined by margins of 5-10 mm added to the CTV. Prior to each fraction a computed tomography (CT)-simulation over the complete target volume was performed resulting in a total of 60 CT-simulations for lung and 58 CT-simulations for hepatic targets. The CTV from each CT-simulation was segmented and matched with the CT-study used for treatment planning. A DVH of the simulated CTV was calculated for each fraction. The target coverage (TC) of dose to the simulated CTV was defined as the proportion of the CTV receiving at least the reference dose (100%). Results: A decrease of TC to 3 . Conclusions: Target reproducibility was precise within the reference isodose in 91% of lung and 81% of liver tumors with a TC of the complete CTV ≥95% at each fraction of treatment. Pulmonary targets with increased breathing mobility and liver tumors >100 cm 3 are at risk for target deviation exceeding the standard security margins for PTV-definition at least for one fraction and require individual evaluation of sufficient margins

  4. DNA repair systems as targets of cadmium toxicity

    International Nuclear Information System (INIS)

    Giaginis, Constantinos; Gatzidou, Elisavet; Theocharis, Stamatios

    2006-01-01

    Cadmium (Cd) is a heavy metal and a potent carcinogen implicated in tumor development through occupational and environmental exposure. Recent evidence suggests that proteins participating in the DNA repair systems, especially in excision and mismatch repair, are sensitive targets of Cd toxicity. Cd by interfering and inhibiting these DNA repair processes might contribute to increased risk for tumor formation in humans. In the present review, the information available on the interference of Cd with DNA repair systems and their inhibition is summarized. These actions could possibly explain the indirect contribution of Cd to mutagenic effects and/or carcinogenicity

  5. Targeted multidrug delivery system to overcome chemoresistance in breast cancer

    Directory of Open Access Journals (Sweden)

    Tang Y

    2017-01-01

    Full Text Available Yuan Tang,1 Fariborz Soroush,1 Zhaohui Tong,2 Mohammad F Kiani,1 Bin Wang1,3 1Department of Mechanical Engineering, Temple University, Philadelphia, PA, 2Department of Agricultural and Biological Engineering, University of Florida, Gainesville, FL, 3Department of Biomedical Engineering, Widener University, Chester, PA, USA Abstract: Chemotherapy has been widely used in breast cancer patients to reduce tumor size. However, most anticancer agents cannot differentiate between cancerous and normal cells, resulting in severe systemic toxicity. In addition, acquired drug resistance during the chemotherapy treatment further decreases treatment efficacy. With the proper treatment strategy, nanodrug carriers, such as liposomes/immunoliposomes, may be able to reduce undesired side effects of chemotherapy, to overcome the acquired multidrug resistance, and to further improve the treatment efficacy. In this study, a novel combinational targeted drug delivery system was developed by encapsulating antiangiogenesis drug bevacizumab into liposomes and encapsulating chemotherapy drug doxorubicin (DOX into immunoliposomes where the human epidermal growth factor receptor 2 (HER2 antibody was used as a targeting ligand. This novel combinational system was tested in vitro using a HER2 positive and multidrug resistant breast cancer cell line (BT-474/MDR, and in vivo using a xenograft mouse tumor model. In vitro cell culture experiments show that immunoliposome delivery led to a high cell nucleus accumulation of DOX, whereas free DOX was observed mostly near the cell membrane and in cytoplasm due to the action of P-gp. Combining liposomal bevacizumab with immunoliposomal DOX achieved the best tumor growth inhibition and the lowest toxicity. Tumor size decreased steadily within a 60-day observation period indicating a potential synergistic effect between DOX and bevacizumab through the targeted delivery. Our findings clearly indicate that tumor growth was significantly

  6. Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers

    International Nuclear Information System (INIS)

    Cho, Nancy L.; Lin, Chi-Iou; Du, Jinyan; Whang, Edward E.; Ito, Hiromichi; Moore, Francis D.; Ruan, Daniel T.

    2012-01-01

    Highlights: ► Kinome profiling is a novel technique for identifying activated kinases in human cancers. ► Src activity is increased in invasive thyroid cancers. ► Inhibition of Src activity decreased proliferation and invasion in vitro. ► Further investigation of Src targeted therapies in thyroid cancer is warranted. -- Abstract: Background: Novel therapies are needed for the treatment of invasive thyroid cancers. Aberrant activation of tyrosine kinases plays an important role in thyroid oncogenesis. Because current targeted therapies are biased toward a small subset of tyrosine kinases, we conducted a study to reveal novel therapeutic targets for thyroid cancer using a bead-based, high-throughput system. Methods: Thyroid tumors and matched normal tissues were harvested from twenty-six patients in the operating room. Protein lysates were analyzed using the Luminex immunosandwich, a bead-based kinase phosphorylation assay. Data was analyzed using GenePattern 3.0 software and clustered according to histology, demographic factors, and tumor status regarding capsular invasion, size, lymphovascular invasion, and extrathyroidal extension. Survival and invasion assays were performed to determine the effect of Src inhibition in papillary thyroid cancer (PTC) cells. Results: Tyrosine kinome profiling demonstrated upregulation of nine tyrosine kinases in tumors relative to matched normal thyroid tissue: EGFR, PTK6, BTK, HCK, ABL1, TNK1, GRB2, ERK, and SRC. Supervised clustering of well-differentiated tumors by histology, gender, age, or size did not reveal significant differences in tyrosine kinase activity. However, supervised clustering by the presence of invasive disease showed increased Src activity in invasive tumors relative to non-invasive tumors (60% v. 0%, p < 0.05). In vitro, we found that Src inhibition in PTC cells decreased cell invasion and proliferation. Conclusion: Global kinome analysis enables the discovery of novel targets for thyroid cancer

  7. Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.

    Science.gov (United States)

    Bahia, Malkeet S; Silakari, Om

    2010-05-01

    Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.

  8. Immunological tumor destruction in a murine melanoma model by targeted LTalpha independent of secondary lymphoid tissue

    DEFF Research Database (Denmark)

    Schrama, D.; Voigt, H.; Eggert, A.O.

    2008-01-01

    BACKGROUND: We previously demonstrated that targeting lymphotoxin alpha (LTalpha) to the tumor evokes its immunological destruction in a syngeneic B16 melanoma model. Since treatment was associated with the induction of peritumoral tertiary lymphoid tissue, we speculated that the induced immune...... of specific T-cell responses even in the absence of secondary lymphoid organs. In addition, this effect is accompanied by the initiation of tertiary lymphoid tissue at the tumor site in which B and T lymphocytes are compartmentalized in defined areas and which harbor expanded numbers of tumor specific T cells...... as demonstrated by in situ TRP-2/K(b) tetramer staining. Mechanistically, targeted LTalpha therapy seems to induce changes at the tumor site which allows a coordinated interaction of immune competent cells triggering the induction of tertiary lymphoid tissue. CONCLUSION: Thus, our data demonstrate that targeted...

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

    Directory of Open Access Journals (Sweden)

    Akira Makino

    2014-01-01

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

  10. Curcumin targets fibroblast–tumor cell interactions in oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Dudás, József; Fullár, Alexandra; Romani, Angela; Pritz, Christian; Kovalszky, Ilona; Hans Schartinger, Volker; Mathias Sprinzl, Georg; Riechelmann, Herbert

    2013-01-01

    Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of OSCC tumor cells. We hypothesized that Curcumin targets this dynamic mutual interaction between CAFs and tumor cells. Normal and 2 μM Curcumin-treated co-culture were performed for 4 days, followed by analysis of tumor cell invasivity, mRNA/protein expression of EMT-markers and mediators, activity measure of matrix metalloproteinase 9 (MMP-9), and western blot analysis of signal transduction in tumor cells and fibroblasts. In Curcumin-treated co-culture, in tumor cells, the levels of nuclear factor κB (NFκBα) and early response kinase (ERK)—decreased, in fibroblasts, integrin αv protein synthesis decreased compared to corresponding cells in normal co-culture. The signal modulatory changes induced by Curcumin caused decreased release of EMT-mediators in CAFs and reversal of EMT in tumor cells, which was associated with decreased invasion. These data confirm the palliative potential of Curcumin in clinical application. - Graphical abstract: Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of tumor cells. Curcumin targets this dynamic mutual interaction between CAFs and tumor cells by inhibiting the production of EMT mediators in CAFs and by modification of intracellular signaling in tumor cells. This causes less invasivity and reversal of EMT in tumor cells. Highlights: ► Curcumin targets tumor–fibroblast interaction in head and neck cancer. ► Curcumin suppresses mediators of epithelial–mesenchymal transition. ► Curcumin decreases the invasivity of tumor cells

  11. Curcumin targets fibroblast–tumor cell interactions in oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Dudás, József, E-mail: jozsef.dudas@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Fullár, Alexandra, E-mail: fullarsz@gmail.com [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, 1085 Budapest (Hungary); Romani, Angela, E-mail: angela.romani@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Pritz, Christian, E-mail: christian.pritz@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Kovalszky, Ilona, E-mail: koval@korb1.sote.hu [1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, 1085 Budapest (Hungary); Hans Schartinger, Volker, E-mail: volker.schartinger@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Mathias Sprinzl, Georg, E-mail: georg.sprinzl@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Riechelmann, Herbert, E-mail: herbert.riechelmann@i-med.ac.at [Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria)

    2013-04-01

    Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of OSCC tumor cells. We hypothesized that Curcumin targets this dynamic mutual interaction between CAFs and tumor cells. Normal and 2 μM Curcumin-treated co-culture were performed for 4 days, followed by analysis of tumor cell invasivity, mRNA/protein expression of EMT-markers and mediators, activity measure of matrix metalloproteinase 9 (MMP-9), and western blot analysis of signal transduction in tumor cells and fibroblasts. In Curcumin-treated co-culture, in tumor cells, the levels of nuclear factor κB (NFκBα) and early response kinase (ERK)—decreased, in fibroblasts, integrin αv protein synthesis decreased compared to corresponding cells in normal co-culture. The signal modulatory changes induced by Curcumin caused decreased release of EMT-mediators in CAFs and reversal of EMT in tumor cells, which was associated with decreased invasion. These data confirm the palliative potential of Curcumin in clinical application. - Graphical abstract: Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of tumor cells. Curcumin targets this dynamic mutual interaction between CAFs and tumor cells by inhibiting the production of EMT mediators in CAFs and by modification of intracellular signaling in tumor cells. This causes less invasivity and reversal of EMT in tumor cells. Highlights: ► Curcumin targets tumor–fibroblast interaction in head and neck cancer. ► Curcumin suppresses mediators of epithelial–mesenchymal transition. ► Curcumin decreases the invasivity of tumor cells.

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

    Science.gov (United States)

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

    2010-12-01

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

  13. Two novel approaches targeting cancer cell membrane for tumor therapy.

    Science.gov (United States)

    Feng, Yingzhu; Wang, Bochu; Cao, Yang; He, Rui

    2013-04-01

    Disruption of normal cell function by chemicals, UV radiation or viruses can cause various cancer. Drugs that have been developed for cancer therapy bind to various targets to correct disorder cell behavior, repair damaged DNA or promote cell apoptosis. However, there is rare study that focuses on cancer cell membrane as target. We propose two approaches for achieving our goal. One is to use phospholipase A2 (PLA2) to cleave phospholipid heads of the bilayer of cancer cells. Because PLA2 has unique Ca(2+) catalytic site and the pH of healthy tissue cells should be slightly alkaline at 7.2-7.5, it can be easily protected by CO3(2-) in the form of PLA2-CaCO3. While PLA2-CaCO3 accumulate in cancer cells in the acidic microenvironment of which the pH is below 7, it could be converted to active state (PLA2-Ca(2+)) which can intensively damage the cancer cell membrane. The other one is to use both monoclonal antibodies and dimethylsulfoxide (DMSO). The internalization of targeted cancer cell antibodies could change the curvature of cell membrane from order state to disorder state, therefore strong detergent DMSO can destroy cancer cells at extreme low concentration. These two approaches present no harm for normal cells, therefore, drugs targeted cancer cell membrane might become a new and high effective clinical cancer therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Specific targeting of tumor cells by lyophilisomes functionalized with antibodies

    NARCIS (Netherlands)

    van Bracht, Etienne; Stolle, Sarah; Hafmans, Theo G.; Boerman, Otto C.; Oosterwijk, Egbert; van Kuppevelt, Toin H.; Daamen, Willeke F.

    Lyophilisomes are a novel class of proteinaceous biodegradable nano/micro drug delivery capsules prepared by freezing, annealing and Iyophilization. In the present study, lyophilisomes were functionalized for active targeting by antibody conjugation in order to obtain a selective drug-carrier

  15. Targeted two-photon photodynamic therapy for the treatment of subcutaneous tumors

    Science.gov (United States)

    Spangler, Charles W.; Starkey, Jean R.; Meng, Fanqing; Gong, Aijun; Drobizhev, Mikhail; Rebane, Aleksander; Moss, B.

    2005-04-01

    Photodynamic therapy (PDT) has developed into a mature technology over the past several years, and is currently being exploited for the treatment of a variety of cancerous tumors, and more recently for age-related wet macular degeneration of the eye. However, there are still some unresolved problems with PDT that are retarding a more general acceptance in clinical settings, and thus, for the most part, the treatment of most cancerous rumors still involves some combination of invasive surgery, chemotherapy and radiation treatment, particularly subcutaneous tumors. Currently approved PDT agents are activated in the Visible portion of the spectrum below 700 nm, Laser light in this spectral region cannot penetrate the skin more than a few millimeters, and it would be more desirable if PDT could be initiated deep in the Near-infrared (NIR) in the tissue transparency window (700-1000 nm). MPA Technologies, Inc. and Rasiris, Inc. have been co-developing new porphyrin PDT designed to have greatly enhanced intrinsic two-photon cross-sections (>800 GM units) whose two-photon absorption maxima lie deep in the tissue transparency window (ca. 780-850 nm), and have solubility characteristics that would allow for direct IV injection into animal models. Classical PDT also suffers from the lengthy time necessary for accumulation at the tumor site, a relative lack of discrimination between healthy and diseased tissue, particularly at the tumor margins, and difficulty in clearing from the system in a reasonable amount of time post-PDT. We have recently discovered a new design paradigm for the delivery of our two-photon activated PDT agents by incorporating the porphyrins into a triad ensemble that includes a small molecule targeting agent that directs the triad to over-expressed tumor receptor sites, and a NIR one-photon imaging agent that allows the tracking of the triad in terms of accumulation and clearance rates. We are currently using these new two-photon PDT triads in efficacy

  16. Enhancing the Efficacy of Drug-loaded Nanocarriers against Brain Tumors by Targeted Radiation Therapy

    Science.gov (United States)

    Baumann, Brian C.; Kao, Gary D.; Mahmud, Abdullah; Harada, Takamasa; Swift, Joe; Chapman, Christina; Xu, Xiangsheng; Discher, Dennis E.; Dorsey, Jay F.

    2013-01-01

    Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only ~15 months. It has proven resistant in clinical trials to chemotherapeutic agents such as paclitaxel that are highly effective in vitro, presumably because of impaired drug delivery across the tumor's blood-brain barrier (BBB). In an effort to increase paclitaxel delivery across the tumor BBB, we linked the drug to a novel filomicelle nanocarrier made with biodegradable poly(ethylene-glycol)-block-poly(ε-caprolactone-r-D,L-lactide) and used precisely collimated radiation therapy (RT) to disrupt the tumor BBB's permeability in an orthotopic mouse model of GBM. Using a non-invasive bioluminescent imaging technique to assess tumor burden and response to therapy in our model, we demonstrated that the drug-loaded nanocarrier (DLN) alone was ineffective against stereotactically implanted intracranial tumors yet was highly effective against GBM cells in culture and in tumors implanted into the flanks of mice. When targeted cranial RT was used to modulate the tumor BBB, the paclitaxel-loaded nanocarriers became effective against the intracranial tumors. Focused cranial RT improved DLN delivery into the intracranial tumors, significantly improving therapeutic outcomes. Tumor growth was delayed or halted, and survival was extended by >50% (p<0.05) compared to the results obtained with either RT or the DLN alone. Combinations of RT and chemotherapeutic agents linked to nanocarriers would appear to be an area for future investigations that could enhance outcomes in the treatment of human GBM. PMID:23296073

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

    Science.gov (United States)

    Ko, Joshua K; Auyeung, Kathy K

    2014-01-01

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

  18. Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment

    Science.gov (United States)

    ... teratoid/rhabdoid tumor. There is no standard staging system for central nervous system atypical teratoid/rhabdoid tumor. The extent or spread ... are different types of treatment for patients with central nervous system atypical teratoid/rhabdoid tumor. Different types of treatment ...

  19. Targeting antisense mitochondrial ncRNAs inhibits murine melanoma tumor growth and metastasis through reduction in survival and invasion factors.

    Science.gov (United States)

    Lobos-González, Lorena; Silva, Verónica; Araya, Mariela; Restovic, Franko; Echenique, Javiera; Oliveira-Cruz, Luciana; Fitzpatrick, Christopher; Briones, Macarena; Villegas, Jaime; Villota, Claudio; Vidaurre, Soledad; Borgna, Vincenzo; Socias, Miguel; Valenzuela, Sebastián; Lopez, Constanza; Socias, Teresa; Varas, Manuel; Díaz, Jorge; Burzio, Luis O; Burzio, Verónica A

    2016-09-06

    We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro-survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy.

  20. Simulations of effusion from ISOL target/ion source systems

    International Nuclear Information System (INIS)

    Mustapha, B.; Nolen, J.A.

    2004-01-01

    Monte Carlo simulations of the low- and high-conductivity Target/Ion Source systems used at Oak Ridge National Laboratory for effusion measurements are performed. Comparisons with the corresponding experimental data for the different geometries are presented and discussed. Independent checks of the simulation using data for simple geometries and using the conductance approach well known in vacuum technology are performed. A simulation-based comparison between the low- and high-conductivity systems is also presented

  1. Tumorer

    DEFF Research Database (Denmark)

    Prause, J.U.; Heegaard, S.

    2005-01-01

    oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer......oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer...

  2. Transcriptional targeting of primary and metastatic tumor neovasculature by an adenoviral type 5 roundabout4 vector in mice.

    Directory of Open Access Journals (Sweden)

    Zhi Hong Lu

    Full Text Available New approaches targeting metastatic neovasculature are needed. Payload capacity, cellular transduction efficiency, and first-pass cellular uptake following systemic vector administration, motivates persistent interest in tumor vascular endothelial cell (EC adenoviral (Ad vector targeting. While EC transductional and transcriptional targeting has been accomplished, vector administration approaches of limited clinical utility, lack of tumor-wide EC expression quantification, and failure to address avid liver sequestration, challenged prior work. Here, we intravenously injected an Ad vector containing 3 kb of the human roundabout4 (ROBO4 enhancer/promoter transcriptionally regulating an enhanced green fluorescent protein (EGFP reporter into immunodeficient mice bearing 786-O renal cell carcinoma subcutaneous (SC xenografts and kidney orthotopic (KO tumors. Initial experiments performed in human coxsackie virus and adenovirus receptor (hCAR transgenic:Rag2 knockout mice revealed multiple ECs with high-level Ad5ROBO4-EGFP expression throughout KO and SC tumors. In contrast, Ad5CMV-EGFP was sporadically expressed in a few tumor vascular ECs and stromal cells. As the hCAR transgene also facilitated Ad5ROBO4 and control Ad5CMV vector EC expression in multiple host organs, follow-on experiments engaged warfarin-mediated liver vector detargeting in hCAR non-transgenic mice. Ad5ROBO4-mediated EC expression was undetectable in most host organs, while the frequencies of vector expressing intratumoral vessels and whole tumor EGFP protein levels remained elevated. In contrast, AdCMV vector expression was only detectable in one or two stromal cells throughout the whole tumor. The Ad5ROBO4 vector, in conjunction with liver detargeting, provides tractable genetic access for in-vivo EC genetic engineering in malignancies.

  3. Targeting the Adipocyte Tumor Cell Interaction in Prostate Cancer Treatment

    Science.gov (United States)

    2015-10-01

    performed in task 4.1. Task 7. 3D Organotypic cultures to study the adipocyte-PCa cell interaction in vitro (Months 30-36; Diaz-Meco & Moscat). This...Targeting Metabolic Reprograming in Cancer” Centro Nacional de Biotecnologia, Madrid, Spain, 2015. Speaker (Moscat) “Cell Death and Survival Networks...PCa, we profited from a recently devel- oped technology for creating 3D prostate organoid cultures (Gao et al., 2014; Karthaus et al., 2014). Murine

  4. Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors

    Science.gov (United States)

    Cani, Andi K.; Hovelson, Daniel H.; McDaniel, Andrew S.; Sadis, Seth; Haller, Michaela J.; Yadati, Venkata; Amin, Anmol M.; Bratley, Jarred; Bandla, Santhoshi; Williams, Paul D.; Rhodes, Kate; Liu, Chia-Jen; Quist, Michael J.; Rhodes, Daniel R.; Grasso, Catherine S.; Kleer, Celina G.; Tomlins, Scott A.

    2016-01-01

    Phyllodes tumors are rare fibroepithelial tumors with variable clinical behavior accounting for a small subset of all breast neoplasms, yet little is known about the genetic alterations that drive tumor initiation and/or progression. Here targeted next generation sequencing (NGS) was used to identify somatic alterations in formalin fixed paraffin embedded (FFPE) patient specimens from malignant, borderline and benign cases. NGS revealed mutations in mediator complex subunit 12 (MED12) affecting the G44 hotspot residue in the majority (67%) of cases spanning all three histological grades. In addition, loss-of-function mutations in p53 (TP53) as well as deleterious mutations in the tumor suppressors retinoblastoma (RB1) and neurofibromin 1 (NF1) were identified exclusively in malignant tumors. High-level copy number alterations (CNAs) were nearly exclusively confined to malignant tumors, including potentially clinically actionable gene amplifications in IGF1R and EGFR. Taken together, this study defines the genomic landscape underlying phyllodes tumor development, suggests potential molecular correlates to histologic grade, expands the spectrum of human tumors with frequent recurrent MED12 mutations, and identifies IGF1R and EGFR as potential therapeutic targets in malignant cases. PMID:25593300

  5. Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast.

    Science.gov (United States)

    Gatalica, Zoran; Vranic, Semir; Ghazalpour, Anatole; Xiu, Joanne; Ocal, Idris Tolgay; McGill, John; Bender, Ryan P; Discianno, Erin; Schlum, Aaron; Sanati, Souzan; Palazzo, Juan; Reddy, Sandeep; Pockaj, Barbara

    2016-01-12

    Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.

  6. A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment

    Science.gov (United States)

    Nör, Jacques Eduardo

    2018-01-01

    Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth. PMID:29351275

  7. Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors.

    Science.gov (United States)

    Pincez, Thomas; Clément, Nathalie; Lapouble, Eve; Pierron, Gaëlle; Kamal, Maud; Bieche, Ivan; Bernard, Virginie; Fréneaux, Paul; Michon, Jean; Orbach, Daniel; Aerts, Isabelle; Pacquement, Hélène; Bourdeaut, Franck; Jiménez, Irene; Thébaud, Estelle; Oudot, Caroline; Vérité, Cécile; Taque, Sophie; Owens, Cormac; Doz, François; Le Tourneau, Christophe; Delattre, Olivier; Schleiermacher, Gudrun

    2017-06-01

    The role of tumor molecular profiling in directing targeted therapy utilization remains to be defined for pediatric tumors. We aimed to evaluate the feasibility of a sequencing and molecular biology tumor board (MBB) program, and its clinical impact on children with solid tumors. We report on a single-center MBB experience of 60 pediatric patients with a poor prognosis or relapsed/refractory solid tumors screened between October 2014 and November 2015. Tumor molecular profiling was performed with panel-based next-generation sequencing and array comparative genomic hybridization. Mean age was 12 ± 5.7 years (range 0.1-21.5); main tumor types were high-grade gliomas (n = 14), rare sarcomas (n = 9), and neuroblastomas (n = 8). The indication was a poor prognosis tumor at diagnosis for 16 patients and relapsed (n = 26) or refractory disease (n = 18) for the remaining 44 patients. Molecular profiling was feasible in 58 patients. Twenty-three patients (40%) had a potentially actionable finding. Patients with high-grade gliomas had the highest number of targetable alterations (57%). Six of the 23 patients subsequently received a matched targeted therapy for a period ranging from 16 days to 11 months. The main reasons for not receiving targeted therapy were poor general condition (n = 5), pursuit of conventional therapy (n = 6), or lack of pediatric trial (n = 4). Pediatric molecular profiling is feasible, with more than a third of patients being eligible to receive targeted therapy, yet only a small proportion were treated with these therapies. Analysis at diagnosis may be useful for children with very poor prognosis tumsors. © 2016 Wiley Periodicals, Inc.

  8. Overcoming the hurdles of multi-step targeting (MST) for effective radioimmunotherapy of solid tumors

    International Nuclear Information System (INIS)

    Larson, Steven M.; Cheung, Nai-Kong

    2009-01-01

    The 4 specific aims of this project are: (1) Optimization of MST to increase tumor uptake; (2) Antigen heterogeneity; (3) Characterization and reduction of renal uptake; and (4) Validation in vivo of optimized MST targeted therapy. This proposal focussed upon optimizing multistep immune targeting strategies for the treatment of cancer. Two multi-step targeting constructs were explored during this funding period: (1) anti-Tag-72 and (2) anti-GD2.

  9. BMI-1 targeting interferes with patient-derived tumor-initiating cell survival and tumor growth in prostate cancer

    Science.gov (United States)

    Yusuff, Shamila; Davis, Stephani; Flaherty, Kathleen; Huselid, Eric; Patrizii, Michele; Jones, Daniel; Cao, Liangxian; Sydorenko, Nadiya; Moon, Young-Choon; Zhong, Hua; Medina, Daniel J.; Kerrigan, John; Stein, Mark N.; Kim, Isaac Y.; Davis, Thomas W.; DiPaola, Robert S.; Bertino, Joseph R.; Sabaawy, Hatem E.

    2016-01-01

    Purpose Current prostate cancer (PCa) management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy-resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TICs-tailored therapies appears to be a promising approach. Experimental design We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient derived prostate cancer cells and xenograft models to characterize the effects of pharmacological inhibitors of BMI-1. Results We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacological inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor (AR)-directed therapies, without toxic effects on normal tissues. Conclusions Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective PCa treatment. PMID:27307599

  10. In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumor.

    Science.gov (United States)

    Fang, Jun; Sawa, Tomohiro; Akaike, Takaaki; Akuta, Teruo; Sahoo, Sanjeeb K; Khaled, Greish; Hamada, Akinobu; Maeda, Hiroshi

    2003-07-01

    High expression of the inducible isoform of heme oxygenase (HO-1) is now well known in solid tumors in humans and experimental animal models. We reported previously that HO-1 may be involved in tumor growth (Tanaka et al., Br. J. Cancer, 88: 902-909, 2003), in that inhibition of HO activity in tumors by using zinc protoporphyrin (ZnPP) significantly reduced tumor growth in a rat model. We demonstrate here that poly(ethylene glycol)-conjugated ZnPP (PEG-ZnPP), a water-soluble derivative of ZnPP, exhibited potent HO inhibitory activity and had an antitumor effect in vivo. In vitro studies with cultured SW480 cells, which express HO-1, showed that PEG-ZnPP induced oxidative stress, and consequently apoptotic death, of these cells. Pharmacokinetic analysis revealed that PEG-ZnPP-administered i.v. had a circulation time in blood that was 40 times longer than that for nonpegylated ZnPP. More important, PEG-ZnPP preferentially accumulated in solid tumor tissue in a murine model. In vivo treatment with PEG-ZnPP (equivalent to 1.5 or 5 mg of ZnPP/kg, i.v., injected daily for 6 days) remarkably suppressed the growth of Sarcoma 180 tumors implanted in the dorsal skin of ddY mice without any apparent side effects. In addition, this PEG-ZnPP treatment produced tumor-selective suppression of HO activity as well as induction of apoptosis. The major reason for tumor-selective targeting of PEG-ZnPP is attributed to the enhanced permeability and retention effect that is observed commonly in solid tumors for biocompatible macromolecular drugs. These findings suggest that tumor-targeted inhibition of HO activity could be achieved by using PEG-ZnPP, which induces apoptosis in solid tumors, probably through increased oxidative stress.

  11. Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles.

    Science.gov (United States)

    Tivnan, Amanda; Orr, Wayne Shannon; Gubala, Vladimir; Nooney, Robert; Williams, David E; McDonagh, Colette; Prenter, Suzanne; Harvey, Harry; Domingo-Fernández, Raquel; Bray, Isabella M; Piskareva, Olga; Ng, Catherine Y; Lode, Holger N; Davidoff, Andrew M; Stallings, Raymond L

    2012-01-01

    Neuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in paediatric oncology, underlining the need for novel therapeutic approaches. Typically, patients with high risk disease undergo an initial remission in response to treatment, followed by disease recurrence that has become refractory to further treatment. Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model. These tumors express high levels of the cell surface antigen disialoganglioside GD2 (GD(2)), providing a target for tumor-specific delivery. Nanoparticles encapsulating miR-34a and conjugated to a GD(2) antibody facilitated tumor-specific delivery following systemic administration into tumor bearing mice, resulted in significantly decreased tumor growth, increased apoptosis and a reduction in vascularisation. We further demonstrate a novel, multi-step molecular mechanism by which miR-34a leads to increased levels of the tissue inhibitor metallopeptidase 2 precursor (TIMP2) protein, accounting for the highly reduced vascularisation noted in miR-34a-treated tumors. These novel findings highlight the potential of anti-GD(2)-nanoparticle-mediated targeted delivery of miR-34a for both the treatment of GD(2)-expressing tumors, and as a basic discovery tool for elucidating biological effects of novel miRNAs on tumor growth.

  12. Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles.

    Directory of Open Access Journals (Sweden)

    Amanda Tivnan

    Full Text Available Neuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in paediatric oncology, underlining the need for novel therapeutic approaches. Typically, patients with high risk disease undergo an initial remission in response to treatment, followed by disease recurrence that has become refractory to further treatment. Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model. These tumors express high levels of the cell surface antigen disialoganglioside GD2 (GD(2, providing a target for tumor-specific delivery.Nanoparticles encapsulating miR-34a and conjugated to a GD(2 antibody facilitated tumor-specific delivery following systemic administration into tumor bearing mice, resulted in significantly decreased tumor growth, increased apoptosis and a reduction in vascularisation. We further demonstrate a novel, multi-step molecular mechanism by which miR-34a leads to increased levels of the tissue inhibitor metallopeptidase 2 precursor (TIMP2 protein, accounting for the highly reduced vascularisation noted in miR-34a-treated tumors.These novel findings highlight the potential of anti-GD(2-nanoparticle-mediated targeted delivery of miR-34a for both the treatment of GD(2-expressing tumors, and as a basic discovery tool for elucidating biological effects of novel miRNAs on tumor growth.

  13. Strategies to target drugs to gliomas and CNS metastases of solid tumors

    NARCIS (Netherlands)

    Milojkovic Kerklaan, B.; van Tellingen, O.; Huitema, A. D R; Beijnen, J. H.; Boogerd, W.; Schellens, J. H M; Brandsma, D.

    The treatment for central nervous system metastases of solid tumors and gliomas is limited as the blood–brain barrier (BBB) is an obstacle to systemic therapy. Here, we review the physiochemical properties of the BBB and both current and new drug strategies to penetrate brain tumors. We focus on

  14. Kidney–targeted drug delivery systems

    Directory of Open Access Journals (Sweden)

    Peng Zhou

    2014-02-01

    Full Text Available Kidney-targeted drug delivery systems represent a promising technology to improve drug efficacy and safety in the treatment of renal diseases. In this review, we summarize the strategies that have been employed to develop kidney-targeted drug delivery systems. We also describe how macromolecular carriers and prodrugs play crucial roles in targeting drugs to particular target cells in the kidney. New technologies render it possible to create renal targeting conjugates and other delivery systems including nanoparticles and liposomes present promising strategies to achieve the goal of targeting drugs to the kidney.

  15. Targeting gastrointestinal stromal tumors: the role of regorafenib

    Directory of Open Access Journals (Sweden)

    Schroeder B

    2016-05-01

    Full Text Available Brett Schroeder,1 Zula Li,2,3 Lee D Cranmer,2,3 Robin L Jones,4 Seth M Pollack2,3 1College of Human Medicine, Michigan State University, Grand Rapids, MI, 2Division of Medical Oncology, University of Washington, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 4Royal Marsden Hospital, Institute of Cancer Research, London, UK Abstract: Gastrointestinal stromal tumor (GIST is a devastating disease in the metastatic setting, but its natural history has been dramatically altered by the development of small molecule tyrosine kinase inhibitors, most notably imatinib. Although patients with advanced GIST live much longer today than they did in the past, imatinib-refractory disease remains a tremendous problem. For disease that is refractory to imatinib and sunitinib, regorafenib is an excellent option. In this review, we discuss the biology and clinical work establishing regorafenib as the standard of care for advanced GIST refractory to both imatinib and sunitinib. Keywords: regorafenib, GIST, refractory, imatinib

  16. Site-specifically radioiodinated antibody for targeting tumors

    International Nuclear Information System (INIS)

    Rea, D.W.; Ultee, M.E.; Belinka, B.A. Jr.; Coughlin, D.J.; Alvarez, V.L.

    1990-01-01

    Labeling of an antibody site specifically through its carbohydrate regions preserves its antigen-binding activity. Previously site-specific labeling studies have conjugated antibodies with metallic radioisotopes or drugs. We now report site-specific labeling with a new radioiodinated compound, 2-hydroxy-5-iodo-3-methylbenzoyl hydrazide, whose synthesis we described earlier. The compound is reacted with aldehyde groups produced by specific oxidation of the carbohydrate portion of the antibody with sodium m-periodate. Optimized conjugation conditions give good recovery of active antibody containing 10 groups per molecule. The conjugate is stable in solution for at least several weeks at both 4 and -70 degrees C. When injected into nude mice bearing LS174T human cancer xenografts, the conjugate of B72.3 antibody localizes well to tumor tissue, with low uptake by other organs. This biodistribution is similar to that of conjugate prepared by using solid-phase chloramine-T (Iodohead). There are only two significant differences. First, the carbohydrate conjugate is much less susceptible to dehalogenation, and thus shows much less thyroid uptake. Secondly, the biological half-life of the carbohydrate conjugate was about half that of the chloramine-T one. This could be due primarily to lysis of the hydrazine bond through which the antibody is attached to the compound, which would then be excreted rapidly by itself. The new reagent will be especially useful for antibodies which either cannot be labeled by chloramine-T methods, or whose activity is impaired by them

  17. Orbital tumor revealing a systemic sarcoidosis.

    Directory of Open Access Journals (Sweden)

    Samia Hannanachi Sassi

    2015-03-01

    Full Text Available Ocular involvement is seen in approximately 25% of patients with sarcoidosis. Uveitis is the most common ocular manifestation, but sarcoidosis may involve any part of the eye. Orbital manifestations of sarcoidosis are uncommon with few series in the literature. A 65-year-old woman presented with redness of the right eye and painless, unilateral eyelid swelling. Orbital scanning revealed mass infiltrating the soft tissue of the inferior right orbital quadrant. Biopsy results showed nodular, noncaseating granulomas consistent with sarcoidosis. The complete systemic workup revealed systemic manifestations of sarcoidosis at the time of examination with hilar and mediastinal lymphadenopathies noted on CT scan. The orbital surgical treatment was followed by systemic prednisone therapy with good response. Although rare, orbital sarcoidosis must be considered in the evaluation of orbital tumors in elderly patients. A search for systemic findings should be undertaken and appropriate therapy should be instituted.

  18. Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

    Science.gov (United States)

    Woolf, N; Pearson, B E; Bondzie, P A; Meyer, R D; Lavaei, M; Belkina, A C; Chitalia, V; Rahimi, N

    2017-09-18

    Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

  19. Targeting the epidermal growth factor receptor in solid tumors: focus on safety.

    Science.gov (United States)

    Lucchini, Eleonora; Pilotto, Sara; Spada, Elisa; Melisi, Davide; Bria, Emilio; Tortora, Giampaolo

    2014-05-01

    Inhibition of the EGFR has emerged as a promising anticancer strategy, offering improved efficacy and quality of life for patients affected by tumors. The overall level of toxicity associated with EGFR inhibitors is low compared to other chemotherapy drugs, although they are commonly associated with skin and gastrointestinal adverse events. Thus, patients' quality of life may be considerably affected both by a physical and a psychosocial perspective. Adverse events that lead to treatment interruption or cessation may significantly compromise their outcome. This review summarizes the characteristics of the distinctive toxicities of drugs targeting EGFR, addressing their incidence, pathophysiology and clinical presentation with a focus on the management of skin rash and other relevant adverse events, according to the available clinical evidence. Data regarding the correlation between the development of skin rash and clinical outcome are also reported. Drugs targeting EGFR are associated with a lower overall incidence of systemic side effects compared to standard chemotherapeutic agents; nevertheless, an increased risk of distinct toxicities that may affect patient's quality of life and anticancer treatment compliance is observed. Thus, clinical training projects directed toward a more accurate knowledge of such adverse events are essential to maximize the progress of targeted therapies against cancer.

  20. Cryptotanshinone targets tumor-initiating cells through down-regulation of stemness genes expression

    OpenAIRE

    ZHANG, YING; CABARCAS, STEPHANIE M.; ZHENG, JI; SUN, LEI; MATHEWS, LESLEY A.; ZHANG, XIAOHU; LIN, HONGSHENG; FARRAR, WILLIAM L.

    2016-01-01

    Recent evidence indicates that tumor-initiating cells (TICs), also called cancer stem cells (CSCs), are responsible for tumor initiation and progression, therefore representing an important cell population that may be used as a target for the development of future anticancer therapies. In the present study, Cryptotanshinone (CT), a traditional Chinese herbal medicine, was demonstrated to regulate the behaviors of LNCaP prostate cells and prostate LNCaP TICs. The results demonstrate that treat...

  1. Structural features facilitating tumor cell targeting and internalization by bleomycin and its disaccharide.

    Science.gov (United States)

    Yu, Zhiqiang; Paul, Rakesh; Bhattacharya, Chandrabali; Bozeman, Trevor C; Rishel, Michael J; Hecht, Sidney M

    2015-05-19

    We have shown previously that the bleomycin (BLM) carbohydrate moiety can recapitulate the tumor cell targeting effects of the entire BLM molecule, that BLM itself is modular in nature consisting of a DNA-cleaving aglycone which is delivered selectively to the interior of tumor cells by its carbohydrate moiety, and that there are disaccharides structurally related to the BLM disaccharide which are more efficient than the natural disaccharide at tumor cell targeting/uptake. Because BLM sugars can deliver molecular cargoes selectively to tumor cells, and thus potentially form the basis for a novel antitumor strategy, it seemed important to consider additional structural features capable of affecting the efficiency of tumor cell recognition and delivery. These included the effects of sugar polyvalency and net charge (at physiological pH) on tumor cell recognition, internalization, and trafficking. Since these parameters have been shown to affect cell surface recognition, internalization, and distribution in other contexts, this study has sought to define the effects of these structural features on tumor cell recognition by bleomycin and its disaccharide. We demonstrate that both can have a significant effect on tumor cell binding/internalization, and present data which suggests that the metal ions normally bound by bleomycin following clinical administration may significantly contribute to the efficiency of tumor cell uptake, in addition to their characterized function in DNA cleavage. A BLM disaccharide-Cy5** conjugate incorporating the positively charged dipeptide d-Lys-d-Lys was found to associate with both the mitochondria and the nuclear envelope of DU145 cells, suggesting possible cellular targets for BLM disaccharide-cytotoxin conjugates.

  2. Hypoxia targeting therapy with prodrug specifically stabilized and activated in hypoxic tumor cells

    International Nuclear Information System (INIS)

    Kondoh, S.K.; Ueda, T.; Harada, H.; Hiraoka, M.; Akagi, K.

    2003-01-01

    Hypoxia fraction in tumors is associated with increased metastasis and poor survival in patients suffering from malignant tumors such as the head and neck, cervical or breast cancers. Hypoxia can be a direct cause of therapeutic resistance because some drugs and radiation require oxygen to be maximally cytotoxic. Recently we have reported a novel hypoxia targeting prodrug, TOP3, which is a fusion protein, composed of HIV TAT protein transduction domain, a part of HIF1 α ODD domain, and Procaspase-3. TOP3 can be transferred into every cell both in vitro and in vivo but becomes stable only in hypoxic cells, in which TOP3 is activated and induces apoptosis. The application of this fusion protein to a tumor-bearing mouse resulted in significant suppression of the tumor growth and even in reduction of the tumor mass without any obvious side effects. The administrations of TOP3 in combination with a low dose of X-ray showed an additive antitumor effect on pancreatic tumor cells. Furthermore, we show that the rodent model of ascites generated by malignant cells provides an excellent platform of testing hypoxia targeting drugs, since it comprises homogeneous fluid with tumor cells surviving and proliferating under hypoxic condition. TOP3 induced apoptosis of AH130, rat ascites hepatoma cells, in vitro only under hypoxic but not normoxic condition. Intraperitoneal administration of TOP3 prolonged life span of the rats with AH130 derived malignant ascites. Sixty percent of the treated rats were cured of ascites without recurrence for more than six months, in contrast all untreated rats died within 20 days after tumor cell inoculation. These results strongly suggest that TOP3 would provide a new strategy for hypoxia targeting therapy and that the combination of TOP3 with radiotherapy or chemotherapy may provide a new strategy for annihilating malignant tumors

  3. COX-2 – A Novel Target for Reducing Tumor Angiogenesis and Metastasis | Center for Cancer Research

    Science.gov (United States)

    Angiogenesis is essential for tumor growth and metastasis, by supplying a steady stream of nutrients, removing waste, and providing tumor cells access to other sites in the body. The vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a key role in tumor-mediated angiogenesis, and this pathway is the target of monoclonal antibodies and tyrosine kinase inhibitors (TKIs) that have been approved to treat patients with cancer. Unfortunately, tumors can use alternative angiogenesis mechanisms to escape VEGF pathway blockade, but these alternate pathways are not well understood. Brad St. Croix, Ph.D., of CCR’s Mouse Cancer Genetics Program, along with Lihong Xu, Ph.D., a Postdoctoral Fellow in the St. Croix laboratory, and colleagues set out to identify VEGF-independent mediators of tumor angiogenesis.

  4. MHC class II restricted neoantigen: A promising target in tumor immunotherapy.

    Science.gov (United States)

    Sun, Zhichen; Chen, Fangjun; Meng, Fanyan; Wei, Jia; Liu, Baorui

    2017-04-28

    Neoantigen is a patient-specific tumor antigen resulted from mutations during oncogenesis. Emerging data suggested that immune responsiveness against neoantigens correlated with the success of clinical tumor immunotherapies. Nowadays, the majority of studies on neoantigens have focused on MHC class I restricted antigens recognized by CD8+ T cells. With improved understanding of the underlying principles of tumor biology and immunology, increasing emphasis has been put on CD4+ T cells and MHC class II restricted antigens. MHC class II restricted neoantigen has the potential to be a promising target of tumor immunotherapy, although the limited comprehension and technical difficulties need to be overcome before being applied into clinical practice. This review discussed the immunologic mechanism, screening technique, clinical application, limitations and prospectives of MHC class II restricted neoantigens in tumor immunotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Selecting Targets for Tumor Imaging: An Overview of Cancer-Associated Membrane Proteins

    Directory of Open Access Journals (Sweden)

    Martin C. Boonstra

    2016-01-01

    Full Text Available Tumor targeting is a booming business: The global therapeutic monoclonal antibody market accounted for more than $78 billion in 2012 and is expanding exponentially. Tumors can be targeted with an extensive arsenal of monoclonal antibodies, ligand proteins, peptides, RNAs, and small molecules. In addition to therapeutic targeting, some of these compounds can also be applied for tumor visualization before or during surgery, after conjugation with radionuclides and/or near-infrared fluorescent dyes. The majority of these tumor-targeting compounds are directed against cell membrane-bound proteins. Various categories of targetable membrane-bound proteins, such as anchoring proteins, receptors, enzymes, and transporter proteins, exist. The functions and biological characteristics of these proteins determine their location and distribution on the cell membrane, making them more, or less, accessible, and therefore, it is important to understand these features. In this review, we evaluate the characteristics of cancer-associated membrane proteins and discuss their overall usability for cancer targeting, especially focusing on imaging applications.

  6. Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus.

    Directory of Open Access Journals (Sweden)

    Yonatan Y Mahller

    Full Text Available Although disease remission can frequently be achieved for patients with neuroblastoma, relapse is common. The cancer stem cell theory suggests that rare tumorigenic cells, resistant to conventional therapy, are responsible for relapse. If true for neuroblastoma, improved cure rates may only be achieved via identification and therapeutic targeting of the neuroblastoma tumor initiating cell. Based on cues from normal stem cells, evidence for tumor populating progenitor cells has been found in a variety of cancers.Four of eight human neuroblastoma cell lines formed tumorspheres in neural stem cell media, and all contained some cells that expressed neurogenic stem cell markers including CD133, ABCG2, and nestin. Three lines tested could be induced into multi-lineage differentiation. LA-N-5 spheres were further studied and showed a verapamil-sensitive side population, relative resistance to doxorubicin, and CD133+ cells showed increased sphere formation and tumorigenicity. Oncolytic viruses, engineered to be clinically safe by genetic mutation, are emerging as next generation anticancer therapeutics. Because oncolytic viruses circumvent typical drug-resistance mechanisms, they may represent an effective therapy for chemotherapy-resistant tumor initiating cells. A Nestin-targeted oncolytic herpes simplex virus efficiently replicated within and killed neuroblastoma tumor initiating cells preventing their ability to form tumors in athymic nude mice.These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus.

  7. Aldoxorubicin: a tumor-targeted doxorubicin conjugate for relapsed or refractory soft tissue sarcomas

    Directory of Open Access Journals (Sweden)

    Gong J

    2018-04-01

    Full Text Available Jun Gong,1,* Jessica Yan,2,* Charles Forscher,3 Andrew Hendifar4 1Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA; 2Department of Hematology and Oncology, Harbor-UCLA Medical Center, Torrance, CA, USA; 3Sarcoma Program, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 4Gastrointestinal and Neuroendocrine Malignancies, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA *These authors contributed equally to this work Abstract: Despite available therapies after initial systemic therapy, prognosis remains poor in relapsed or refractory soft tissue sarcomas (STS. The rational and clinical development of novel agents to improve outcomes in this area of high unmet need is desperately warranted. Aldoxorubicin is a prodrug of doxorubicin that binds to serum albumin immediately after administration through an acid-sensitive hydrazone linker and is subsequently transported to tumor tissues where the acidic environment cleaves the linker and facilitates delivery of a tumor-targeted drug payload. In clinical studies to date, there has been evidence of efficacy and mitigated cardiac toxicity. In this review, we comprehensively detail the clinical development of aldoxorubicin in STS to date. Specifically, we highlight available data on the pharmacokinetics and efficacy from Phase I, Phase II, and Phase III trials in advanced or metastatic STS. We conclude with considerations for future directions of investigation for this promising antitumor agent.Keywords: aldoxorubicin, albumin conjugate, soft tissue sarcomas, clinical trials, pharmacokinetics, cardiotoxicity 

  8. Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

    Directory of Open Access Journals (Sweden)

    Maria Victoria Maliandi

    2011-01-01

    Full Text Available The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed.

  9. Role of the Autonomic Nervous System in the Tumor Micro-Environment and its Therapeutic Potential.

    Science.gov (United States)

    Xu, Zhifang; Shioda, Seiji; Masahisa, Jinushi; Kawakami, Yutaka; Ohtaki, Hirokazu; Lim, Huimin Calista; Wang, Shenjun; Zhao, Xue; Liu, Yangyang; Zhou, Dan; Guo, Yi

    2017-01-01

    Although evidence over the last 30 years suggests that the autonomic nervous system (ANS) mediates stress-induced allostatic and immune responses, the crucial role that it plays in the tumor micro-environment has only recently been reported. Here, we review the action of ANS signaling in this micro-environment. Emerging data suggest that primary tumors are innervated by the ANS which mediates stress-related effects on tumor progression. The activation of the sympathetic nervous system (SNS) takes advantage of neurotransmitters and neuropeptides from the innervating neural circuitry and/or hypothalamic-pituitary-adrenal axis glucocorticoids via their receptors to modulate the gene expression associated with oncogenesis, the proliferation and apoptosis of tumor cells, angiogenesis, and the tumor-associated immune response. The parasympathetic nervous system has also been implicated in some tumor types, but its contribution in the tumor micro-environment remains unclear. In addition to identifying the ANS signaling pathways involved in tumor progression, recent reports suggest that the ANS could be a potential biomarker to predict tumor progression, and have identified new pharmacological strategies, such as the use of β-adrenergic blockers, to inhibit tumor progression and metastasis by targeting this system. These findings are reviewed here. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Evaluation of tumor targeting with radiolabeled F(ab2 fragment of a humanized monoclonal antibody

    Directory of Open Access Journals (Sweden)

    "Babaei MH

    2002-08-01

    Full Text Available Humanized monoclonal antibody U36 and its F(ab'2 fragment, radio labeled with 125I, were tested for tumor localization in nude mice bearing a squamous cell carcinoma xenograft line derived from a head and neck carcinoma. Monoclonal antibody IgG or F(ab'2 fragment were injected in parallel and at days 1, 2 and 3, mice were dissected for determination of isotope biodistribution. IgG as well as F(ab'2 showed highly specific localization in tumor tissue. The mean tumor uptake (n=3 is expressed as the percentage of the injected dose per gram of tumor tissue (%ID/g. %ID/g of IgG was 11.7% at day 1 and decreased to 10.9% at day 3 whereas %ID/g of F(ab'2 was 2.9% at day 1 and decreased on following days. Tumor to blood ratios (T/B at day 1 were 0.86 for IgG and 1.32 for F(ab'2 and reached a maximum at day 3 with values of 4.41 and 1.84 respectively. These findings suggest that the superior tumor to non-tumor ratios in the day of 1 render the F(ab'2 fragment more qualified for specific targeting radioisotopes to tumor xenografts in this exprimental setting.

  11. Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

    Directory of Open Access Journals (Sweden)

    Grant Sugiura

    2014-02-01

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

  12. PET imaging of 64Cu-DOTA-scFv-anti-PSMA lipid nanoparticles (LNPs): Enhanced tumor targeting over anti-PSMA scFv or untargeted LNPs

    International Nuclear Information System (INIS)

    Wong, Patty; Li, Lin; Chea, Junie; Delgado, Melissa K.; Crow, Desiree; Poku, Erasmus; Szpikowska, Barbara; Bowles, Nicole; Channappa, Divya; Colcher, David; Wong, Jeffrey Y.C.; Shively, John E.; Yazaki, Paul J.

    2017-01-01

    Introduction: Single chain (scFv) antibodies are ideal targeting ligands due to their modular structure, high antigen specificity and affinity. These monovalent ligands display rapid tumor targeting but have limitations due to their fast urinary clearance. Methods: An anti-prostate membrane antigen (PSMA) scFv with a site-specific cysteine was expressed and evaluated in a prostate cancer xenograft model by Cu-64 PET imaging. To enhance tumor accumulation, the scFv-cys was conjugated to the co-polymer DSPE-PEG-maleimide that spontaneously assembled into a homogeneous multivalent lipid nanoparticle (LNP). Results: The targeted LNP exhibited a 2-fold increase in tumor uptake compared to the scFv alone using two different thiol ester chemistries. The anti-PSMA scFv-LNP exhibited a 1.6 fold increase in tumor targeting over the untargeted LNP. Conclusions: The targeted anti-PSMA scFv-LNP showed enhanced tumor accumulation over the scFv alone or the untargeted DOTA-micelle providing evidence for the development of this system for drug delivery. Advances in knowledge and implications for patient care: Anti-tumor scFv antibody fragments have not achieved their therapeutic potential due to their fast blood clearance. Conjugation to an LNP enables multivalency to the tumor antigen as well as increased molecular size for chemotherapy drug delivery.

  13. Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth.

    Science.gov (United States)

    Enderling, Heiko; Hlatky, Lynn; Hahnfeldt, Philip

    2012-07-28

    The role of the immune system in tumor progression has been a subject for discussion for many decades. Numerous studies suggest that a low immune response might be beneficial, if not necessary, for tumor growth, and only a strong immune response can counter tumor growth and thus inhibit progression. We implement a cellular automaton model previously described that captures the dynamical interactions between the cancer stem and non-stem cell populations of a tumor through a process of self-metastasis. By overlaying on this model the diffusion of immune reactants into the tumor from a peripheral source to target cells, we simulate the process of immune-system-induced cell kill on tumor progression. A low cytotoxic immune reaction continuously kills cancer cells and, although at a low rate, thereby causes the liberation of space-constrained cancer stem cells to drive self-metastatic progression and continued tumor growth. With increasing immune system strength, however, tumor growth peaks, and then eventually falls below the intrinsic tumor sizes observed without an immune response. With this increasing immune response the number and proportion of cancer stem cells monotonically increases, implicating an additional unexpected consequence, that of cancer stem cell selection, to the immune response. Cancer stem cells and immune cytotoxicity alone are sufficient to explain the three-step "immunoediting" concept - the modulation of tumor growth through inhibition, selection and promotion.

  14. Preclinical evaluation of a novel CEA-targeting near-infrared fluorescent tracer delineating colorectal and pancreatic tumors.

    Science.gov (United States)

    Boonstra, Martin C; Tolner, Berend; Schaafsma, Boudewijn E; Boogerd, Leonora S F; Prevoo, Hendrica A J M; Bhavsar, Guarav; Kuppen, Peter J K; Sier, Cornelis F M; Bonsing, Bert A; Frangioni, John V; van de Velde, Cornelis J H; Chester, Kerry A; Vahrmeijer, Alexander L

    2015-10-15

    Surgery is the cornerstone of oncologic therapy with curative intent. However, identification of tumor cells in the resection margins is difficult, resulting in nonradical resections, increased cancer recurrence and subsequent decreased patient survival. Novel imaging techniques that aid in demarcating tumor margins during surgery are needed. Overexpression of carcinoembryonic antigen (CEA) is found in the majority of gastrointestinal carcinomas, including colorectal and pancreas. We developed ssSM3E/800CW, a novel CEA-targeted near-infrared fluorescent (NIRF) tracer, based on a disulfide-stabilized single-chain antibody fragment (ssScFv), to visualize colorectal and pancreatic tumors in a clinically translatable setting. The applicability of the tracer was tested for cell and tissue binding characteristics and dosing using immunohistochemistry, flow cytometry, cell-based plate assays and orthotopic colorectal (HT-29, well differentiated) and pancreatic (BXPC-3, poorly differentiated) xenogeneic human-mouse models. NIRF signals were visualized using the clinically compatible FLARE™ imaging system. Calculated clinically relevant doses of ssSM3E/800CW selectively accumulated in colorectal and pancreatic tumors/cells, with highest tumor-to-background ratios of 5.1 ± 0.6 at 72 hr postinjection, which proved suitable for intraoperative detection and delineation of tumor boarders and small (residual) tumor nodules in mice, between 8 and 96 hr postinjection. Ex vivo fluorescence imaging and pathologic examination confirmed tumor specificity and the distribution of the tracer. Our results indicate that ssSM3E/800CW shows promise as a diagnostic tool to recognize colorectal and pancreatic cancers for fluorescent-guided surgery applications. If successfully translated clinically, this tracer could help improve the completeness of surgery and thus survival. © 2015 UICC.

  15. Oncolytic adenovirus targeting cyclin E overexpression repressed tumor growth in syngeneic immunocompetent mice

    International Nuclear Information System (INIS)

    Cheng, Pei-Hsin; Rao, Xiao-Mei; Wechman, Stephen L.; Li, Xiao-Feng; McMasters, Kelly M.; Zhou, Heshan Sam

    2015-01-01

    Clinical trials have indicated that preclinical results obtained with human tumor xenografts in mouse models may overstate the potential of adenovirus (Ad)-mediated oncolytic therapies. We have previously demonstrated that the replication of human Ads depends on cyclin E dysregulation or overexpression in cancer cells. ED-1 cell derived from mouse lung adenocarcinomas triggered by transgenic overexpression of human cyclin E may be applied to investigate the antitumor efficacy of oncolytic Ads. Ad-cycE was used to target cyclin E overexpression in ED-1 cells and repress tumor growth in a syngeneic mouse model for investigation of oncolytic virotherapies. Murine ED-1 cells were permissive for human Ad replication and Ad-cycE repressed ED-1 tumor growth in immunocompetent FVB mice. ED-1 cells destroyed by oncolytic Ads in tumors were encircled in capsule-like structures, while cells outside the capsules were not infected and survived the treatment. Ad-cycE can target cyclin E overexpression in cancer cells and repress tumor growth in syngeneic mouse models. The capsule structures formed after Ad intratumoral injection may prevent viral particles from spreading to the entire tumor. The online version of this article (doi:10.1186/s12885-015-1731-x) contains supplementary material, which is available to authorized users

  16. miR-203 Suppresses Tumor Growth and Angiogenesis by Targeting VEGFA in Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Xiangyu Zhu

    2013-07-01

    Full Text Available Background/Aims: MicroRNA (miRNA plays important roles in the development of different cancers. In this study, we investigated the roles and mechanisms of miR-203 in human cervical cancer. Methods: miR-203 expression was detected in cervical cancer tumors and cell lines by qRT-PCR. The methylation status in the promoter region of miR-203 was examined by methylation-specific PCR. The functional effect of miR-203 was determined by both in vitro and in vivo assays. Results: miR-203 was frequently down-regulated in cervical cancer tumors and cell lines. This down-regulation of miR-203 was associated with methylation of the miR-203 promoter. Furthermore, miR-203 down-regulated vascular endothelial growth factor alpha (VEGFA expression by directly targeting its 3'-untranslated region. Functional assays revealed that miR-203 suppressed cervical cancer cell proliferation, tumor growth, and angiogenesis in nude mice, whereas forced expression of VEGFA rescued this inhibitory effect. Conclusion: Our collective findings indicate that miR-203 functions as a tumor suppressor by targeting VEGFA, resulting in the inhibition of tumor growth and angiogenesis. Thus, miR-203 may be a potential therapeutic target and prognostic marker in cervical cancer.

  17. Gold markers for tumor localization and target volume delineation in radiotherapy for rectal cancer

    International Nuclear Information System (INIS)

    Vorwerk, Hilke; Christiansen, Hans; Hess, Clemens Friedrich; Hermann, Robert Michael; Liersch, Thorsten; Ghadimi, Michael; Rothe, Hilka

    2009-01-01

    In locally advanced rectal cancer, neoadjuvant radiochemotherapy is indicated. To improve target volume definition for radiotherapy planning, the potential of implanted gold markers in the tumor region was evaluated. In nine consecutive patients, two to three gold markers were implanted in the tumor region during rigid rectoscopy. Computed tomography scans were performed during treatment planning. All electronic portal imaging devices (EPIDs) recorded during treatment series were analyzed. All patients underwent complete tumor resection with meticulous histopathologic examination. The gold markers could easily be implanted into the mesorectal tissue at the caudal tumor border without any complications. They were helpful in identifying the inferior border of the planning target volume in order to spare normal tissue (in particular anal structures). No significant shift of the markers was found during the course of therapy. Marker matching of the EPIDs did not improve patient positioning in comparison to bone structure matching. The former position of at least one marker could be identified in all patients during histopathologic examination. The use of gold marker enables a more precise definition of the target volume for radiotherapy in patients with rectal cancer. This could eventually allow a better protection of anal structures of patients with a tumor localization = 5 cm cranial of the anal sphincter. The implantation of the gold markers improved communication between the surgeon, the radiooncologist and the pathologist resulting in intensified exchange of relevant informations. (orig.)

  18. Fatty acid synthase - Modern tumor cell biology insights into a classical oncology target.

    Science.gov (United States)

    Buckley, Douglas; Duke, Gregory; Heuer, Timothy S; O'Farrell, Marie; Wagman, Allan S; McCulloch, William; Kemble, George

    2017-09-01

    Decades of preclinical and natural history studies have highlighted the potential of fatty acid synthase (FASN) as a bona fide drug target for oncology. This review will highlight the foundational concepts upon which this perspective is built. Published studies have shown that high levels of FASN in patient tumor tissues are present at later stages of disease and this overexpression predicts poor prognosis. Preclinical studies have shown that experimental overexpression of FASN in previously normal cells leads to changes that are critical for establishing a tumor phenotype. Once the tumor phenotype is established, FASN elicits several changes to the tumor cell and becomes intertwined with its survival. The product of FASN, palmitate, changes the biophysical nature of the tumor cell membrane; membrane microdomains enable the efficient assembly of signaling complexes required for continued tumor cell proliferation and survival. Membranes densely packed with phospholipids containing saturated fatty acids become resistant to the action of other chemotherapeutic agents. Inhibiting FASN leads to tumor cell death while sparing normal cells, which do not have the dependence of this enzyme for normal functions, and restores membrane architecture to more normal properties thereby resensitizing tumors to killing by chemotherapies. One compound has recently reached clinical studies in solid tumor patients and highlights the need for continued evaluation of the role of FASN in tumor cell biology. Significant advances have been made and much remains to be done to optimally apply this class of pharmacological agents for the treatment of specific cancers. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics

    Directory of Open Access Journals (Sweden)

    Marianela Candolfi

    2012-08-01

    Full Text Available Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM] models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α, their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM.

  20. Mathematical Modeling of Tumor-Tumor Distant Interactions Supports a Systemic Control of Tumor Growth.

    Science.gov (United States)

    Benzekry, Sebastien; Lamont, Clare; Barbolosi, Dominique; Hlatky, Lynn; Hahnfeldt, Philip

    2017-09-15

    Interactions between different tumors within the same organism have major clinical implications, especially in the context of surgery and metastatic disease. Three main explanatory theories (competition, angiogenesis inhibition, and proliferation inhibition) have been proposed, but precise determinants of the phenomenon remain poorly understood. Here, we formalized these theories into mathematical models and performed biological experiments to test them with empirical data. In syngeneic mice bearing two simultaneously implanted tumors, growth of only one of the tumors was significantly suppressed (61% size reduction at day 15, P < 0.05). The competition model had to be rejected, whereas the angiogenesis inhibition and proliferation inhibition models were able to describe the data. Additional models including a theory based on distant cytotoxic log-kill effects were unable to fit the data. The proliferation inhibition model was identifiable and minimal (four parameters), and its descriptive power was validated against the data, including consistency in predictions of single tumor growth when no secondary tumor was present. This theory may also shed new light on single cancer growth insofar as it offers a biologically translatable picture of how local and global action may combine to control local tumor growth and, in particular, the role of tumor-tumor inhibition. This model offers a depiction of concomitant resistance that provides an improved theoretical basis for tumor growth control and may also find utility in therapeutic planning to avoid postsurgery metastatic acceleration. Cancer Res; 77(18); 5183-93. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor

    KAUST Repository

    Gadd, Samantha

    2017-08-21

    We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

  2. Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFN gamma Signaling

    DEFF Research Database (Denmark)

    Donia, Marco; Harbst, Katja; van Buuren, Marit

    2017-01-01

    disease recurrence following an initial, unequivocal radiologic complete regression after T-cell-based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune...... responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFN gamma signaling, led to impaired recognition by tumor......-specific CD8(+) T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I-related APM. Loss of target antigens or impaired IFN gamma signaling does not appear to be mandatory for tumor relapse after a complete...

  3. Noninvasive detection of passively targeted poly(ethylene glycol) nanocarriers in tumors.

    Science.gov (United States)

    Singh, Yashveer; Gao, Dayuan; Gu, Zichao; Li, Shike; Stein, Stanley; Sinko, Patrick J

    2012-01-01

    The present studies noninvasively investigate the passive tumor distribution potential of a series of poly(ethylene glycol) (PEG) nanocarriers using a SkinSkan spectrofluorometer and an In Vivo Imaging System (IVIS) 100. Fluorescein conjugated PEG nanocarriers of varying molecular weights (10, 20, 30, 40, and 60 kDa) were prepared and characterized. The nanocarriers were administered intravenously to female balb/c mice bearing subcutaneous 4T1 tumors. Passive distribution was measured in vivo (λ(exc), 480 nm; λ(em), 515-520 nm) from the tumor and a contralateral skin site (i.e., control site). The signal intensity from the tumor was always significantly higher than that from the contralateral site. Trends in results between the two methods were consistent with tumor distribution increasing in a molecular weight-dependent manner (10 hydrodynamic radii of PEG polymers, measured using dynamic light scattering (DLS), showed that nanocarriers obtained from polymers with hydrodynamic radii ≥8 nm exhibited higher tumor distribution. Ex vivo mass balance studies revealed that nanocarrier tissue distribution followed the rank order tumor > lung > spleen > liver > kidney > muscle > heart, thus validating the in vivo studies. The results of the current studies suggest that noninvasive dermal imaging of tumors provides a reliable and rapid method for the initial screening of nanocarrier tumor distribution pharmacokinetics.

  4. M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis.

    Directory of Open Access Journals (Sweden)

    He Zhou

    Full Text Available Heparan sulfate proteoglycans (HSPGs play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.

  5. Targeted tumor imaging of anti-CD20-polymeric nanoparticles developed for the diagnosis of B-cell malignancies

    Directory of Open Access Journals (Sweden)

    Capolla S

    2015-06-01

    Full Text Available Sara Capolla,1 Chiara Garrovo,2 Sonia Zorzet,1 Andrea Lorenzon,3 Enrico Rampazzo,4 Ruben Spretz,5 Gabriele Pozzato,6 Luis Núñez,7 Claudio Tripodo,8 Paolo Macor,1,9 Stefania Biffi2 1Department of Life Sciences, University of Trieste, 2Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”, Trieste, 3Animal Care Unit, Cluster in Biomedicine (CBM scrl, Trieste, Italy; 4Department of Chemistry “G. Ciamician”, University of Bologna, Bologna, Italy; 5LNK Chemsolutions LLC, Lincoln, NE, USA; 6Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy; 7Bio-Target, Inc., University of Chicago, Chicago, IL, USA; 8Department of Human Pathology, University of Palermo, Palermo, Italy; 9Callerio Foundation Onlus, Institutes of Biological Researches, Trieste, Italy Abstract: The expectations of nanoparticle (NP-based targeted drug delivery systems in cancer, when compared with convectional therapeutic methods, are greater efficacy and reduced drug side effects due to specific cellular-level interactions. However, there are conflicting literature reports on enhanced tumor accumulation of targeted NPs, which is essential for translating their applications as improved drug-delivery systems and contrast agents in cancer imaging. In this study, we characterized biodegradable NPs conjugated with an anti-CD20 antibody for in vivo imaging and drug delivery onto tumor cells. NPs’ binding specificity mediated by anti-CD20 antibody was evaluated on MEC1 cells and chronic lymphocytic leukemia patients’ cells. The whole-body distribution of untargeted NPs and anti-CD20 NPs were compared by time-domain optical imaging in a localized human/mouse model of B-cell malignancy. These studies provided evidence that NPs’ functionalization by an anti-CD20 antibody improves tumor pharmacokinetic profiles in vivo after systemic administration and increases in vivo imaging of tumor mass compared to non-targeted NPs. Together

  6. Targeting Angiogenesis and Tumor Microenvironment in Metastatic Colorectal Cancer: Role of Aflibercept

    Directory of Open Access Journals (Sweden)

    Guido Giordano

    2014-01-01

    Full Text Available In the last decades, we have progressively observed an improvement in therapeutic options for metastatic colorectal cancer (mCRC treatment with a progressive prolongation of survival. mCRC prognosis still remains poor with low percentage of 5-year survival. Targeted agents have improved results obtained with standard chemotherapy. Angiogenesis plays a crucial role in colorectal cancer growth, proliferation, and metastasization and it has been investigated as a potential target for mCRC treatment. Accordingly, novel antiangiogenic targeted agents bevacizumab, regorafenib, and aflibercept have been approved for mCRC treatment as the result of several phase III randomized trials. The development of a tumor permissive microenvironment via the aberrant expression by tumor cells of paracrine factors alters the tumor-stroma interactions inducing an expansion of proangiogenic signals. Recently, the VELOUR study showed that addition of aflibercept to FOLFIRI regimen as a second-line therapy for mCRC improved significantly OS, PFS, and RR. This molecule represents a valid second-line therapeutic option and its peculiar ability to interfere with placental growth factor (PlGF/vascular endothelial growth factor receptor 1 (VEGFR1 axis makes it effective in targeting angiogenesis, inflammatory cells and in overcoming resistances to anti-angiogenic first-line treatment. Here, we discuss about Aflibercept peculiar ability to interfere with tumor microenvironment and angiogenic pathway.

  7. Molecular machineries of pH dysregulation in tumor microenvironment: potential targets for cancer therapy

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Asgharzadeh

    2017-06-01

    Conclusion: Taken all, along with other treatment strategies, targeting the key molecular machineries related to intra- and extracellular metabolisms within the TME is proposed as a novel strategy to inhibit or block PETs that are involved in the pH dysregulation of solid tumors.

  8. Phenotype switching : tumor cell plasticity as a resistance mechanism and target for therapy

    NARCIS (Netherlands)

    Kemper, K.; de Goeje, P.L.; Peeper, D.S.; van Amerongen, R.

    2014-01-01

    Mutations in BRAF are present in the majority of patients with melanoma, rendering these tumors sensitive to targeted therapy with BRAF and MEK inhibitors. Unfortunately, resistance almost invariably develops. Recently, a phenomenon called "phenotype switching" has been identified as an escape

  9. Targeting brain tumor cAMP: the case for sex-specific therapeutics

    Directory of Open Access Journals (Sweden)

    Nicole M Warrington

    2015-07-01

    Full Text Available A relationship between cyclic adenosine 3’, 5’-monophosphate (cAMP levels and brain tumor biology has been evident for nearly as long as cAMP and its synthetase, adenylate cyclase (ADCY have been known. The importance of the pathway in brain tumorigenesis has been demonstrated in vitro and in multiple animal models. Recently, we provided human validation for a cooperating oncogenic role for cAMP in brain tumorigenesis when we found that SNPs in ADCY8 were correlated with glioma (brain tumor risk in individuals with Neurofibromatosis type 1 (NF1. Together, these studies provide a strong rationale for targeting cAMP in brain tumor therapy. However, the cAMP pathway is well known to be sexually dimorphic, and SNPs in ADCY8 affected glioma risk in a sex-specific fashion, elevating the risk for females while protecting males. The cAMP pathway can be targeted at multiple levels in the regulation of its synthesis and degradation. Sex differences in response to drugs that target cAMP regulators indicate that successful targeting of the cAMP pathway for brain tumor patients is likely to require matching specific mechanisms of drug action with patient sex.

  10. In vivo imaging of passively tumor targeted polymer carrier and the enzymatically cleavable drug model

    Czech Academy of Sciences Publication Activity Database

    Pola, Robert; Heinrich, A. K.; Mueller, T.; Kostka, Libor; Mäder, K.; Pechar, Michal; Etrych, Tomáš

    2017-01-01

    Roč. 6, 4 (Suppl) (2017), s. 90 ISSN 2325-9604. [International Conference and Exhibition on Nanomedicine and Drug Delivery. 29.05.2017-31.05.2017, Osaka] R&D Projects: GA MZd(CZ) NV16-28594A Institutional support: RVO:61389013 Keywords : polymer drug carrier * tumor targeting * enzymatic release Subject RIV: FD - Oncology ; Hematology

  11. IDENTIFYING AND TARGETING TUMOR-INITIATING CELLS IN THE TREATMENT OF BREAST CANCER

    Science.gov (United States)

    Wei, Wei; Lewis, Michael T.

    2015-01-01

    Breast cancer is the most common cancer in women (exclusive of skin cancer), and is the second leading cause of cancer-related deaths. Although conventional and targeted therapies have improved survival rates, there are still considerable challenges in treating breast cancer, including treatment resistance, disease recurrence, and metastasis. Treatment resistance can be either de novo - due to traits that tumor cells possess prior to treatment, or acquired, - due to traits that tumor cells gain in response to treatment. A recently proposed mechanism of de novo resistance invokes existence of a specialized subset of cancer cells defined as tumor-initiating cells (TICs), or cancer stem cells (CSC). TICs have the capacity to self-renew and regenerate new tumors that consist of all clonally-derived cell types present in the parental tumor. There are data to suggest that TICs are resistant to many conventional cancer therapies, and survive treatment in spite of dramatic shrinkage of the tumor. Residual TICs can then eventually regrow resulting in disease relapse. It is also hypothesized that TIC may be responsible for metastatic disease. If these hypotheses are correct, targeting TICs may be imperative to achieve cure. In this review, we discuss evidence for breast TICs and their apparent resistance to conventional chemotherapy and radiotherapy, as well as to various targeted therapies. We also address the potential impact of breast TIC plasticity and metastatic potential on therapeutic strategies. Finally, we describe several genes and signaling pathways that appear important for TIC function that may represent promising therapeutic targets. PMID:25876646

  12. Highly Specific and Effective Targeting of EGFRvIII-Positive Tumors with TandAb Antibodies.

    Science.gov (United States)

    Ellwanger, Kristina; Reusch, Uwe; Fucek, Ivica; Knackmuss, Stefan; Weichel, Michael; Gantke, Thorsten; Molkenthin, Vera; Zhukovsky, Eugene A; Tesar, Michael; Treder, Martin

    2017-01-01

    To harness the cytotoxic capacity of immune cells for the treatment of solid tumors, we developed tetravalent, bispecific tandem diabody (TandAb) antibodies that recognize EGFRvIII, the deletion variant III of the epidermal growth factor receptor (EGFR), and CD3 on T-cells, thereby directing immune cells to eliminate EGFRvIII-positive tumor cells. Using phage display, we identified scFv antibodies selectively binding to EGFRvIII. These highly EGFRvIII-specific, fully human scFv were substantially improved by affinity maturation, achieving K D s in the picomolar range, and were used to construct a set of bispecific EGFRvIII-targeting TandAbs with a broad range of binding and cytotoxic properties. These antibodies exhibited an exquisite specificity for a distinguished epitope in the N-terminal portion of EGFRvIII, as shown on recombinant antigen in Western Blot, SPR, and ELISA, as well as on antigen-expressing cells in FACS assays, and did not bind to the wild-type EGFR. High-affinity EGFRvIII/CD3 TandAbs were most potent in killing assays, displaying cytotoxicity toward EGFRvIII-expressing CHO, F98 glioma, or human DK-MG cells with EC 50 values in the range of 1-10 pM in vitro . They also demonstrated dose-dependent growth control in vivo in an EGFRvIII-positive subcutaneous xenograft tumor model. Together with the tumor-exclusive expression of EGFRvIII, the EGFRvIII/CD3 TandAbs' high specificity and strictly target-dependent activation with no off-target activity provide an opportunity to target tumor cells and spare normal tissues, thereby reducing the side effects associated with other anti-EGFR therapies. In summary, EGFRvIII/CD3 TandAbs are highly attractive therapeutic antibody candidates for selective immunotherapy of EGFRvIII-positive tumors.

  13. Highly Specific and Effective Targeting of EGFRvIII-Positive Tumors with TandAb Antibodies

    Directory of Open Access Journals (Sweden)

    Kristina Ellwanger

    2017-05-01

    Full Text Available To harness the cytotoxic capacity of immune cells for the treatment of solid tumors, we developed tetravalent, bispecific tandem diabody (TandAb antibodies that recognize EGFRvIII, the deletion variant III of the epidermal growth factor receptor (EGFR, and CD3 on T-cells, thereby directing immune cells to eliminate EGFRvIII-positive tumor cells. Using phage display, we identified scFv antibodies selectively binding to EGFRvIII. These highly EGFRvIII-specific, fully human scFv were substantially improved by affinity maturation, achieving KDs in the picomolar range, and were used to construct a set of bispecific EGFRvIII-targeting TandAbs with a broad range of binding and cytotoxic properties. These antibodies exhibited an exquisite specificity for a distinguished epitope in the N-terminal portion of EGFRvIII, as shown on recombinant antigen in Western Blot, SPR, and ELISA, as well as on antigen-expressing cells in FACS assays, and did not bind to the wild-type EGFR. High-affinity EGFRvIII/CD3 TandAbs were most potent in killing assays, displaying cytotoxicity toward EGFRvIII-expressing CHO, F98 glioma, or human DK-MG cells with EC50 values in the range of 1–10 pM in vitro. They also demonstrated dose-dependent growth control in vivo in an EGFRvIII-positive subcutaneous xenograft tumor model. Together with the tumor-exclusive expression of EGFRvIII, the EGFRvIII/CD3 TandAbs’ high specificity and strictly target-dependent activation with no off-target activity provide an opportunity to target tumor cells and spare normal tissues, thereby reducing the side effects associated with other anti-EGFR therapies. In summary, EGFRvIII/CD3 TandAbs are highly attractive therapeutic antibody candidates for selective immunotherapy of EGFRvIII-positive tumors.

  14. Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement

    Directory of Open Access Journals (Sweden)

    Scott D Swanson

    2008-06-01

    Full Text Available Scott D Swanson1, Jolanta F Kukowska-Latallo2, Anil K Patri5, Chunyan Chen6, Song Ge4, Zhengyi Cao3, Alina Kotlyar3, Andrea T East7, James R Baker31Department of Radiology, The University of Michigan Medical School, 2Department of Internal Medicine, The University of Michigan Medical School, 3Michigan Nanotechnology Institute for Medicine and Biological Sciences, The University of Michigan, 4Applied Physics, The University of Michigan, MD, USA; 5Present address: National Cancer Institute at Frederick (Contractor, MD, USA; 6Present address: Intel Corporation, Chandler, AZ, USA; 7Present address: Stritch School of Medicine, Chicago, ILL, USAAbstract: A target-specific MRI contrast agent for tumor cells expressing high affinity folate receptor was synthesized using generation five (G5 of polyamidoamine (PAMAM dendrimer. Surface modified dendrimer was functionalized for targeting with folic acid (FA and the remaining terminal primary amines of the dendrimer were conjugated with the bifunctional NCS-DOTA chelator that forms stable complexes with gadolinium (Gd III. Dendrimer-DOTA conjugates were then complexed with GdCl3, followed by ICP-OES as well as MRI measurement of their longitudinal relaxivity (T1 s−1 mM−1 of water. In xenograft tumors established in immunodeficient (SCID mice with KB human epithelial cancer cells expressing folate receptor (FAR, the 3D MRI results showed specific and statistically significant signal enhancement in tumors generated with targeted Gd(III-DOTA-G5-FA compared with signal generated by non-targeted Gd(III-DOTA-G5 contrast nanoparticle. The targeted dendrimer contrast nanoparticles infiltrated tumor and were retained in tumor cells up to 48 hours post-injection of targeted contrast nanoparticle. The presence of folic acid on the dendrimer resulted in specific delivery of the nanoparticle to tissues and xenograft tumor cells expressing folate receptor in vivo. We present the specificity of the dendrimer

  15. Central nervous system tumors: Radiologic pathologic correlation and diagnostic approach

    Directory of Open Access Journals (Sweden)

    Ishita Pant

    2015-01-01

    Full Text Available Objective: This study was conducted to formulate location-wise radiologic diagnostic algorithms and assess their concordance with the final histopathological diagnosis so as to evaluate their utility in a rural setting where only basic facilities are available. Materials and Methods: A retrospective analysis to assess the concordance of radiology (primarily MRI with final histopathology report was done. Based on the most common incidence of tumor location and basic radiology findings, diagnostic algorithms were prepared. Results: For supratentorial intraaxial parenchymal location concordance was seen in all high-grade astrocytomas, low- and high-grade oligodendrogliomas, metastatic tumors, primitive neuroectodermal tumors, high-grade ependymomas, neuronal and mixed neuro-glial tumors and tumors of hematopoietic system. Lowest concordance was seen in low-grade astrocytomas. In the supratentorial intraaxial ventricular location, agreement was observed in choroid plexus tumors, ependymomas, low-grade astrocytomas and meningiomas; in the supratentorial extraaxial location, except for the lack of concordance in the only case of metastatic tumor, concordance was observed in meningeal tumors, tumors of the sellar region, tumors of cranial and paraspinal nerves; the infratentorial intraaxial parenchymal location showed agreement in low- as well as high-grade astrocytomas, metastatic tumors, high-grade ependymoma, embryonal tumors and hematopoietic tumors; in the infratentorial intraaxial ventricular location, except for the lack of concordance in one case of low-grade astrocytoma and two cases of medulloblastomas, agreement was observed in low- and high-grade ependymoma; infratentorial extraaxial tumors showed complete agreement in all tumors of cranial and paraspinal nerves, meningiomas, and hematopoietic tumors. Conclusion: A location-based approach to central nervous system (CNS tumors is helpful in establishing an appropriate differential diagnosis.

  16. A new transfer system for solid targets

    Science.gov (United States)

    Klug, J.; Buckley, K. R.; Zeisler, S. K.; Dodd, M.; Tsao, P.; Hoehr, C.; Economou, C.; Corsaut, J.; Appiah, J. P.; Kovacs, M. S.; Valliant, J. F.; Benard, F.; Ruth, T. J.; Schaffer, P.

    2012-12-01

    As part of a collaborative research project funded by Natural Resources Canada, TRIUMF has designed and manufactured solid target and solid target processing systems for the production of technetium-99m using small medical cyclotrons. The system described herein is capable of transporting the target from a hotcell, where the target is loaded and processed, to the cyclotron and back again. The versatility of the transfer system was demonstrated through the successful installation and operation on the ACSI TR 19 at the BC Cancer Agency, the GE PETtrace cyclotrons at Lawson Health Research (LHRI) and the Centre for Probe Development and Commercialization (CDPC).

  17. The targeted transduction of MMP-overexpressing tumor cells by ACPP-HPMA copolymer-coated adenovirus conjugates.

    Directory of Open Access Journals (Sweden)

    Shuhua Li

    Full Text Available We have designed and tested a new way to selectively deliver HPMA polymer-coated adenovirus type 5 (Ad5 particles into matrix metalloproteinase (MMP-overexpressing tumor cells. An activatable cell penetrating peptide (ACPP was designed and attached to the reactive 4-nitrophenoxy groups of HPMA polymers by the C-terminal amino acid (asparagine, N. ACPPs are activatable cell penetrating peptides (CPPs with a linker between polycationic and polyanionic domains, and MMP-mediated cleavage releases the CPP portion and its attached cargo to enable cell entry. Our data indicate that the transport of these HPMA polymer conjugates by a single ACPP molecule to the cytoplasm occurs via a nonendocytotic and concentration-independent process. The uptake was observed to finish within 20 minutes by inverted fluorescence microscopy. In contrast, HPMA polymer-coated Ad5 without ACPPs was internalized solely by endocytosis. The optimal formulation was not affected by the presence of Ad5 neutralizing antibodies during transduction, and ACPP/polymer-coated Ad5 also retained high targeting capability to several MMP-overexpressing tumor cell types. For the first time, ACPP-mediated cytoplasmic delivery of polymer-bound Ad5 to MMP-overexpressing tumor cells was demonstrated. These findings are significant, as they demonstrate the use of a polymer-based system for the targeted delivery into MMP-overexpressing solid tumors and highlight how to overcome major cellular obstacles to achieve intracellular macromolecular delivery.

  18. Mathematical Modeling of Cellular Cross-Talk Between Endothelial and Tumor Cells Highlights Counterintuitive Effects of VEGF-Targeted Therapies.

    Science.gov (United States)

    Jain, Harsh; Jackson, Trachette

    2017-04-24

    Tumor growth and progression are critically dependent on the establishment of a vascular support system. This is often accomplished via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. VEGF ligands are overexpressed in a wide variety of solid tumors and therefore have inspired optimism that inhibition of the different axes of the VEGF pathway-alone or in combination-would represent powerful anti-angiogenic therapies for most cancer types. When considering treatments that target VEGF and its receptors, it is difficult to tease out the differential anti-angiogenic and anti-tumor effects of all combinations experimentally because tumor cells and vascular endothelial cells are engaged in a dynamic cross-talk that impacts key aspects of tumorigenesis, independent of angiogenesis. Here we develop a mathematical model that connects intracellular signaling responsible for both endothelial and tumor cell proliferation and death to population-level cancer growth and angiogenesis. We use this model to investigate the effect of bidirectional communication between endothelial cells and tumor cells on treatments targeting VEGF and its receptors both in vitro and in vivo. Our results underscore the fact that in vitro therapeutic outcomes do not always translate to the in vivo situation. For example, our model predicts that certain therapeutic combinations result in antagonism in vivo that is not observed in vitro. Mathematical modeling in this direction can shed light on the mechanisms behind experimental observations that manipulating VEGF and its receptors is successful in some cases but disappointing in others.

  19. Kansas Water Quality Action Targeting System (KATS)

    Data.gov (United States)

    Kansas Data Access and Support Center — This system is a revision of the original KATS system developed in 1990 as a tool to aid resource managers target Kansas valuable and vulnerable water resources for...

  20. I sup(123) target transfer system

    International Nuclear Information System (INIS)

    Almeida, G.L. de; Rautenberg, F.A.

    1986-01-01

    The construction of target transfer system using a robot into hot cell of IEN cyclotron (Brazilian-CNEN) for sup(123)I production is presented. The system operation is described, and the advantages are shown. (M.C.K.)

  1. Targeting the endocannabinoid system : future therapeutic strategies

    NARCIS (Netherlands)

    Aizpurua-Olaizola, Oier; Elezgarai, Izaskun; Rico-Barrio, Irantzu; Zarandona, Iratxe; Etxebarria, Nestor; Usobiaga, Aresatz

    2017-01-01

    The endocannabinoid system (ECS) is involved in many physiological regulation pathways in the human body, which makes this system the target of many drugs and therapies. In this review, we highlight the latest studies regarding the role of the ECS and the drugs that target it, with a particular

  2. Growing tumor vessels: more than one way to skin a cat - implications for angiogenesis targeted cancer therapies.

    Science.gov (United States)

    Leite de Oliveira, Rodrigo; Hamm, Alexander; Mazzone, Massimiliano

    2011-04-01

    The establishment of a functional, integrated vascular system is instrumental for tissue growth and homeostasis. Without blood vessels no adequate nutrition and oxygen would be provided to cells, nor could the undesired waste products be efficiently removed. Blood vessels constitute therefore one of the largest and most complex body network whose assembly depends on the precise balance of growth factors acting in a complementary and coordinated manner with cells of several identities. However, the vessels that are crucial for life can also foster death, given their involvement in cancer progression towards malignancy and metastasis. Targeting tumor vasculature has thus arisen as an appealing anti-cancer therapeutic approach. Since the milestone achievements that vascular endothelial growth factor (VEGF) blockade suppressed angiogenesis and tumor growth in mice and prolonged the survival of cancer patients when administered in combination with chemotherapy, the clinical development of anti-VEGF(R) drugs has accelerated remarkably. FDA has approved the use of bevacizumab - a humanized monoclonal antibody against VEGF - in colorectal, lung and metastatic breast cancers in combination with standard chemotherapy. Additional broad-spectrum VEGF receptor tyrosine kinase inhibitors, such as sunitinib and sorafenib, are used in monotherapy for metastatic renal carcinoma, while sunitinib is also approved for imatinib resistant gastrointestinal stromal tumors and sorafenib for advanced stage hepatocellular carcinoma. Nevertheless, the survival benefit offered by VEGF(R) blockers, either as single agents or in combination with chemotherapy, is calculated merely in the order of months. Posterior studies in preclinical models have reported that despite reducing primary tumor growth, the inhibition of VEGF increased tumor invasiveness and metastasis. The clinical implications of these findings urge the need to reconcile these conflicting results. Anti-angiogenic therapy

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

    Science.gov (United States)

    Liu, Hao; Li, Ke; Xu, Liang; Wu, Daocheng

    2014-12-01

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-12-15

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

  5. Modulation of Tumor Tolerance in Primary Central Nervous System Malignancies

    Directory of Open Access Journals (Sweden)

    Theodore S. Johnson

    2012-01-01

    Full Text Available Central nervous system tumors take advantage of the unique immunology of the CNS and develop exquisitely complex stromal networks that promote growth despite the presence of antigen-presenting cells and tumor-infiltrating lymphocytes. It is precisely this immunological paradox that is essential to the survival of the tumor. We review the evidence for functional CNS immune privilege and the impact it has on tumor tolerance. In this paper, we place an emphasis on the role of tumor-infiltrating myeloid cells in maintaining stromal and vascular quiescence, and we underscore the importance of indoleamine 2,3-dioxygenase activity as a myeloid-driven tumor tolerance mechanism. Much remains to be discovered regarding the tolerogenic mechanisms by which CNS tumors avoid immune clearance. Thus, it is an open question whether tumor tolerance in the brain is fundamentally different from that of peripheral sites of tumorigenesis or whether it simply stands as a particularly strong example of such tolerance.

  6. Photosensitizer enhanced disassembly of amphiphilic micelle for ROS-response targeted tumor therapy in vivo.

    Science.gov (United States)

    Dai, Liangliang; Yu, Yonglin; Luo, Zhong; Li, Menghuan; Chen, Weizhen; Shen, Xinkun; Chen, Feng; Sun, Qiang; Zhang, Qingfeng; Gu, Hao; Cai, Kaiyong

    2016-10-01

    This study reports a reactive oxygen species (ROS) sensitive drug delivery system based on amphiphilic polymer of poly(propylene sulfide)-polyethylene glycol-serine-folic acid (PPS-mPEG-Ser-FA). The polymer could form homogeneous micelles with an average diameter of around 80 nm through self-assembly, which would then be loaded with the singlet oxygen-generating photosensitizer of zinc phthalocyanine (ZNPC) and anti-cancer drug of DOX. The disassembly of micelles could be triggered by the hydrophobic to hydrophilic transition of the PPS core in response to ROS-induced oxidation in vitro. ZNPC molecules are capable of producing ROS under laser irradiation, which results in the rapid disassembly of micelles and releasing of the anti-tumor drug for tumor therapy under physiological condition otherwise. Moreover, the excessive ROS production deriving from ZNPC synergically induces cells apoptosis. Furthermore, the DOX loaded amphiphilic micelles could be internalized by tumor cells via FA receptor-mediated endocytosis to effectively inhibit the tumor growth in vivo, while with only minimal toxic side effects. The results in vitro and in vivo consistently demonstrate that the light-responsive micelle is a promising biodegradable nanocarrier for on-command drug release and targeted tumor therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine.

    Science.gov (United States)

    Tsume, Yasuhiro; Drelich, Adam J; Smith, David E; Amidon, Gordon L

    2017-08-10

    One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs.

  8. Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models

    Directory of Open Access Journals (Sweden)

    Celina Yang

    2018-03-01

    Full Text Available Optimizing the interface between nanoparticles (NPs and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG functionalized gold nanoparticles (GNPs was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid, to improve internalization at the cellular level. A 10–12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.

  9. Targeting cytokine signaling checkpoint CIS activates NK cells to protect from tumor initiation and metastasis

    Science.gov (United States)

    Putz, Eva M.; Guillerey, Camille; Kos, Kevin; Stannard, Kimberley; Miles, Kim; Delconte, Rebecca B.; Nicholson, Sandra E.; Huntington, Nicholas D.; Smyth, Mark J.

    2017-01-01

    ABSTRACT The cytokine-induced SH2-containing protein CIS belongs to the suppressor of cytokine signaling (SOCS) protein family. Here, we show the critical role of CIS in suppressing natural killer (NK) cell control of tumor initiation and metastasis. Cish-deficient mice were highly resistant to methylcholanthrene-induced sarcoma formation and protected from lung metastasis of B16F10 melanoma and RM-1 prostate carcinoma cells. In contrast, the growth of primary subcutaneous tumors, including those expressing the foreign antigen OVA, was unchanged in Cish-deficient mice. The combination of Cish deficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis. The data clearly indicate that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy. PMID:28344878

  10. Microenvironment around tumors and their radiation sensitivity. The possibility of molecular target for radiation sensitization

    Energy Technology Data Exchange (ETDEWEB)

    Akimoto, Tetsuo; Ishikawa, Hitoshi [Gunma Univ., Maebashi (Japan). School of Medicine; Mitsuhashi, Norio [Tokyo Women' s Medical Coll. (Japan)

    2001-12-01

    There have been scarce studies concerning the effect of microenvironment around tumors on their radiation sensitivity and this review describes the influence of environmental factors of cell adhesion, growth factors, cytokines, hypoxia and angiogenesis on the sensitivity and response to radiation and on the signal transduction to consider the possibility of molecular target for radiation sensitization. Cell-cell adhesion and cell-matrix interaction in response to radiation may have a role in inducing apoptotic process like anti-apoptotic or pro-apoptotic one. Growth factors and cytokines can affect the tumor response to radiation in more extent than p53 gene status since apoptosis induction is not always an indication of radiation sensitivity in many tumors clinically encountered. Radiation sensitivity is low in tumor cells under hypoxic conditions and it is important to know the relationship between those hypoxic cell response and angiogenesis by factors like HIF (hypoxia-inducible factor)-1. Molecular targets for radiation sensitization are now under development and both basic and clinical studies are important for future application of those sensitizing agents for the radiotherapy of tumors. (K.H.)

  11. Microenvironment around tumors and their radiation sensitivity. The possibility of molecular target for radiation sensitization

    International Nuclear Information System (INIS)

    Akimoto, Tetsuo; Ishikawa, Hitoshi

    2001-01-01

    There have been scarce studies concerning the effect of microenvironment around tumors on their radiation sensitivity and this review describes the influence of environmental factors of cell adhesion, growth factors, cytokines, hypoxia and angiogenesis on the sensitivity and response to radiation and on the signal transduction to consider the possibility of molecular target for radiation sensitization. Cell-cell adhesion and cell-matrix interaction in response to radiation may have a role in inducing apoptotic process like anti-apoptotic or pro-apoptotic one. Growth factors and cytokines can affect the tumor response to radiation in more extent than p53 gene status since apoptosis induction is not always an indication of radiation sensitivity in many tumors clinically encountered. Radiation sensitivity is low in tumor cells under hypoxic conditions and it is important to know the relationship between those hypoxic cell response and angiogenesis by factors like HIF (hypoxia-inducible factor)-1. Molecular targets for radiation sensitization are now under development and both basic and clinical studies are important for future application of those sensitizing agents for the radiotherapy of tumors. (K.H.)

  12. Nanomedicine targeting the tumor microenvironment: Therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses

    Directory of Open Access Journals (Sweden)

    Elizabeth L. Siegler

    2016-11-01

    Full Text Available Increasing attention has been given to the tumor microenvironment (TME, which includes cellular and structural components such as fibroblasts, immune cells, vasculature, and extracellular matrix (ECM that surround tumor sites. These components contribute to tumor growth and metastasis and are one reason why traditional chemotherapy often is insufficient to eradicate the tumor completely. Newer treatments that target aspects of the TME, such as antiangiogenic and immunostimulatory therapies, have seen limited clinical success despite promising preclinical results. This can be attributed to a number of reasons, including a lack of drug penetration deeper into the necrotic tumor core, nonspecific delivery, rapid clearance from serum, or toxic side effects at high doses. Nanoparticles offer a potential solution to all of these obstacles, and many recent studies have shown encouraging results using nanomedicine to target TME vasculature, ECM, and immune response. While few of these platforms have made it to clinical trials to date, these strategies are relatively new and may offer a way to improve the effects of anticancer therapies.

  13. Targeted Tumor Therapy Based on Nanodiamonds Decorated with Doxorubicin and Folic Acid.

    Science.gov (United States)

    Ryu, Tae-Kyung; Baek, Seung Woon; Lee, Gyoung-Ja; Rhee, Chang-Kyu; Choi, Sung-Wook

    2017-02-01

    The fabrication of nanodiamond (ND)-based drug carriers for tumor-targeted drug delivery is described. The ND clusters with an average size of 52.84 nm are fabricated using a simple fluidic device combined with a precipitation method and then conjugated with folic acid (FA) and doxorubicin (Dox) via carbodiimide chemistry to obtain FA/Dox-modified ND (FA/Dox-ND) clusters. Cell culture experiments revealed that KB (folate receptor-positive) cells are preferentially ablated by FA/Dox-ND clusters compared to A549 (folate receptor-negative) cells. In vivo results revealed that FA/Dox-ND clusters are specifically accumulated in tumor tissues after intravenous injection into tumor-bearing mice, effectively reducing the volume of tumor. Based on these results, this study suggests that FA/Dox-ND clusters can be a good candidate as tumor-targeted nanovehicles for delivery of antitumor drug. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma

    Directory of Open Access Journals (Sweden)

    Schafer Peter H

    2007-07-01

    Full Text Available Abstract Background Ocular melanoma is the leading intraocular malignancy. There is no effective treatment for metastatic ocular melanoma. We sought a treatment targeting the tumor microenvironment as well as the tumor cells. Methods Migration of HUVEC cells, the ability of HUVEC cells to form tubes, and proliferative capacity of a human ocular melanoma cell line were tested in the presence of lenalidomide and sorafenib alone and in combination. The compounds were also tested in a rat aortic ring assay and were tested in a highly aggressive human ocular melanoma xenograft model. Results Lenalidomide and Sorafenib inhibit HUVEC ability to migrate and form tubes and when used in combination the inhibition is increased. The agents alone and in combination inhibit outgrowth in the rat aortic ring model. The combination of the agents improved the inhibition over either single agent. In a xenograft model, combination therapy inhibited tumor growth over inhibition by single agent alone in a significant fashion (p Conclusion Lenalidomide and sorafenib are effective at targeting endothelial cells, inhibiting growth of ocular melanoma cells and can inhibit growth of tumors in a xenograft model as well as inhibit development of metastases. Combining these agents works in an additive to synergistic way to inhibit the growth of tumors and development of metastases.

  15. The sweet trap in tumors: aerobic glycolysis and potential targets for therapy.

    Science.gov (United States)

    Yu, Li; Chen, Xun; Wang, Liantang; Chen, Shangwu

    2016-06-21

    Metabolic change is one of the hallmarks of tumor, which has recently attracted a great of attention. One of main metabolic characteristics of tumor cells is the high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in glycolysis pathway than that in tricarboxylic acid cycle. The molecular mechanism of a high glycolytic flux in tumor cells remains unclear. A large amount of intermediates derived from glycolytic pathway could meet the biosynthetic requirements of the proliferating cells. Hypoxia-induced HIF-1α, PI3K-Akt-mTOR signaling pathway, and many other factors, such as oncogene activation and tumor suppressor inactivation, drive cancer cells to favor glycolysis over mitochondrial oxidation. Several small molecules targeting glycolytic pathway exhibit promising anticancer activity both in vitro and in vivo. In this review, we will focus on the latest progress in the regulation of aerobic glycolysis and discuss the potential targets for the tumor therapy.

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

    Directory of Open Access Journals (Sweden)

    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

  17. The SSX Family of Cancer-Testis Antigens as Target Proteins for Tumor Therapy

    Directory of Open Access Journals (Sweden)

    Heath A. Smith

    2010-01-01

    Full Text Available Cancer-testis antigens (CTAs represent an expanding class of tumor-associated proteins defined on the basis of their tissue-restricted expression to testis or ovary germline cells and frequent ectopic expression in tumor tissue. The expression of CTA in MHC class I-deficient germline cells makes these proteins particularly attractive as immunotherapeutic targets because they serve as essentially tumor-specific antigens for MHC class I-restricted CD8+ T cells. Moreover, because CTAs are expressed in many types of cancer, any therapeutic developed to target these antigens might have efficacy for multiple cancer types. Of particular interest among CTAs is the synovial sarcoma X chromosome breakpoint (SSX family of proteins, which includes ten highly homologous family members. Expression of SSX proteins in tumor tissues has been associated with advanced stages of disease and worse patient prognosis. Additionally, both humoral and cell-mediated immune responses to SSX proteins have been demonstrated in patients with tumors of varying histological origin, which indicates that natural immune responses can be spontaneously generated to these antigens in cancer patients. The current review will describe the history and identification of this family of proteins, as well as what is known of their function, expression in normal and malignant tissues, and immunogenicity.

  18. Cornering metastases: therapeutic targeting of circulating tumor cells and stem cells.

    Directory of Open Access Journals (Sweden)

    Bishoy eFaltas

    2012-07-01

    Full Text Available The last decade has witnessed an evolution of our understanding of the biology of the metastatic cascade. Recent insights into the metastatic process show that it is complex, dynamic and multi-directional. This process starts at a very early stage in the natural history of solid tumor growth leading to early development of metastases that grow in parallel with the primary tumor. The role of stem cells in perpetuating cancer metastases is increasingly becoming more evident. At the same time, there is a growing recognition of the crucial role circulating tumor cells (CTCs play in the development of metastases. These insights have laid the biological foundations for therapeutic targeting of CTCs, a promising area of research that aims to reduce cancer morbidity and mortality by preventing the development of metastases at a very early stage. The hematogenous transport phase of the metastatic cascade provides critical access to CTCs for therapeutic targeting aiming to interrupt the metastatic process. Recent advances in the fields of nanotechnology and micro-fluidics have led to the development of several devices for in-vivo targeting of CTC during transit in the circulation. Selectin-coated tubes that target cell adhesion molecules, immuno-magnetic separators and in-vivo photoacoustic flow cytometers are currently being developed for this purpose. On the pharmacological front, several pharmacological and immunological agents targeting cancer stem cells are currently being developed. Such agents may ultimately prove to be effective against circulating tumor stem cells (CTSCs. Although still in its infancy, therapeutic targeting of CTCs and CTSCs offers an unprecedented opportunity to prevent the development of metastasis and potentially alter the natural history of cancer. By rendering cancer a local disease, these approaches could lead to major reductions in metastasis-related morbidity and mortality.

  19. The tumor-targeting core-shell structured DTX-loaded PLGA@Au nanoparticles for chemo-photothermal therapy and X-ray imaging.

    Science.gov (United States)

    Hao, Yongwei; Zhang, Bingxiang; Zheng, Cuixia; Ji, Rui; Ren, Xiangyi; Guo, Fangfang; Sun, Shili; Shi, Jinjin; Zhang, Hongling; Zhang, Zhenzhong; Wang, Lei; Zhang, Yun

    2015-12-28

    In this study, an organic-inorganic hybrid nanocomposite was synthesized by deposition of Au onto the surface of docetaxel (DTX)-loaded poly (lactide-co-glycolide) (PLGA) nanoparticle cores to form the core-shell structured DTX-loaded PLGA@Au nanoparticles. The tumor targeting peptide, angiopep-2, was then introduced onto the gold nanoshell through Au-S bond, achieving drug delivery with active targeting capability. This novel system allowed combined chemotherapy and thermal therapy for cancer, resulting from DTX and gold nanoshell. The formation of tumor-targeting gold nanoshell surrounding PLGA nanocore, designated as ANG/GS/PLGA/DTX NPs, was confirmed by its surface plasmon resonance (SPR) band in the UV-Vis spectrum and by a transmission electron microscope (TEM). The release profiles of DTX from this system showed strong dependence on near-infrared (NIR) laser. Compared with DTX alone, the ANG/GS/PLGA/DTX NPs afforded much higher anti-tumor efficiency without obvious toxic effects. Besides, it also showed potential X-ray imaging ability. These results demonstrated that the tumor-targeting core-shell structured DTX-loaded PLGA@Au nanoparticles could be used as a multifunctional nanomaterial system with NIR-triggered drug-releasing properties for tumor-targeted chemo-photothermal therapy and theranostics. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19+tumors.

    Science.gov (United States)

    Zheng, Qian; Wang, Zhaohui; Zhang, Huiping; Huang, Qi; Madsen, Joren C; Sachs, David H; Huang, Christene A; Wang, Zhirui

    2017-05-01

    CD19 is expressed on normal and neoplastic B cells and is a promising target for immunotherapy. However, there is still an unmet need to further develop novel therapeutic drugs for the treatment of the refractory/relapsing human CD19 + tumors. We have developed a diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19 + tumors. We have constructed three isoforms of the CD19 immunotoxin: monovalent, bivalent, and foldback diabody. In vitro binding affinity and efficacy analysis demonstrated that the bivalent isoform had the highest binding affinity and in vitro efficacy. The in vivo efficacy of the CD19 immunotoxins was assessed using human CD19 + JeKo-1 tumor-bearing NOD/SCID IL-2 receptor γ -/- (NSG) mouse model. In these animals, CD19 immunotoxins significantly prolonged the median survival from 31 days in controls to 34, 36, and 40 days in animals receiving the monovalent isoform, foldback diabody isoform, and bivalent isoform, respectively. The bivalent CD19 immunotoxin is a promising therapeutic drug candidate for targeting relapsing/refractory human CD19 + tumors. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  1. Thermosensitive PLA based nanodispersion for targeting brain tumor via intranasal route

    International Nuclear Information System (INIS)

    Jain, Darshana S.; Bajaj, Amrita N.; Athawale, Rajani B.; Shikhande, Shruti S.; Pandey, Abhijeet; Goel, Peeyush N.; Gude, Rajiv P.; Patil, Satish; Raut, Preeti

    2016-01-01

    Delivery of drugs to the brain via nasal route has been studied by many researchers. However, low residence time, mucociliary clearance and enzymatically active environment of nasal cavity pose many challenges to successful nasal delivery of drugs. We aim to deliver methotrexate by designing thermosensitive nanodispersion exhibiting enhanced residence time in nasal cavity and bypassing the blood brain barrier (BBB). PLA nanoparticles were developed using solvent evaporation technique. The developed nanoparticles were further dispersed in prepared thermosensitive vehicle of poloxamer 188 and Carbopol 934 to impart the property of increased residence time. The formulated nanoparticles demonstrated no interaction with the simulated nasal fluids (SNF), mucin, serum proteins and erythrocytes which demonstrate the safety of developed formulation for nasal administration. The penetration property of nanoparticles though the nasal mucosa was higher than the pure drug due to low mucociliary clearance. The developed nanoparticles diffused though the membrane pores and rapidly distributed into the brain portions compared to the pure drug. There was detectable and quantifiable amount of drug seen in the brain as demonstrated by in vivo brain distribution studies with considerably low amount of drug deposition in the lungs. The pharmacokinetic parameters demonstrated the enhancement in circulation half life, area under curve (AUC) and Cmax of the drug when administered intranasal in encapsulated form. Thus, the thermosensitive nanodispersions are surely promising delivery systems for delivering anticancer agents though the nasal route for potential treatment of brain tumors. - Highlights: • The present investigation explores intra-nasal route as potential route for targeting brain tumor. • Thermosensitive nanodispersion has been formulated for enhancing nasal residence time. • PLA nanoparticles enhance penetration into the brain owing to hydrophobic nature and small size

  2. Thermosensitive PLA based nanodispersion for targeting brain tumor via intranasal route

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Darshana S., E-mail: darshanaj_cup@yahoo.com [C.U. Shah College of Pharmacy, S.N.D.T Women' s University, Juhu Tara Road, Santacruz (West), Mumbai 400 049 (India); Bajaj, Amrita N. [C.U. Shah College of Pharmacy, S.N.D.T Women' s University, Juhu Tara Road, Santacruz (West), Mumbai 400 049 (India); Athawale, Rajani B., E-mail: rajani.athawale@gmail.com [C.U. Shah College of Pharmacy, S.N.D.T Women' s University, Juhu Tara Road, Santacruz (West), Mumbai 400 049 (India); Shikhande, Shruti S. [C.U. Shah College of Pharmacy, S.N.D.T Women' s University, Juhu Tara Road, Santacruz (West), Mumbai 400 049 (India); Pandey, Abhijeet [H. R Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra (India); Goel, Peeyush N.; Gude, Rajiv P. [Gude Lab, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410 210 (India); Patil, Satish; Raut, Preeti [Cipla Pvt. Ltd., Vikhroli (West), Mumbai (India)

    2016-06-01

    Delivery of drugs to the brain via nasal route has been studied by many researchers. However, low residence time, mucociliary clearance and enzymatically active environment of nasal cavity pose many challenges to successful nasal delivery of drugs. We aim to deliver methotrexate by designing thermosensitive nanodispersion exhibiting enhanced residence time in nasal cavity and bypassing the blood brain barrier (BBB). PLA nanoparticles were developed using solvent evaporation technique. The developed nanoparticles were further dispersed in prepared thermosensitive vehicle of poloxamer 188 and Carbopol 934 to impart the property of increased residence time. The formulated nanoparticles demonstrated no interaction with the simulated nasal fluids (SNF), mucin, serum proteins and erythrocytes which demonstrate the safety of developed formulation for nasal administration. The penetration property of nanoparticles though the nasal mucosa was higher than the pure drug due to low mucociliary clearance. The developed nanoparticles diffused though the membrane pores and rapidly distributed into the brain portions compared to the pure drug. There was detectable and quantifiable amount of drug seen in the brain as demonstrated by in vivo brain distribution studies with considerably low amount of drug deposition in the lungs. The pharmacokinetic parameters demonstrated the enhancement in circulation half life, area under curve (AUC) and Cmax of the drug when administered intranasal in encapsulated form. Thus, the thermosensitive nanodispersions are surely promising delivery systems for delivering anticancer agents though the nasal route for potential treatment of brain tumors. - Highlights: • The present investigation explores intra-nasal route as potential route for targeting brain tumor. • Thermosensitive nanodispersion has been formulated for enhancing nasal residence time. • PLA nanoparticles enhance penetration into the brain owing to hydrophobic nature and small size

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-01-04

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

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

    International Nuclear Information System (INIS)

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

    2013-01-01

    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.

  5. TU-F-CAMPUS-T-03: Enhancing the Tumor Specific Radiosensitization Using Molecular Targeted Gold Nanorods

    Energy Technology Data Exchange (ETDEWEB)

    Diagaradjane, P [M.D. Anderson Cancer Center, Houston, TX (United States); Deorukhkar, A; Sankaranarayanapillai, M; Singh, P [The UT MD Anderson Cancer Center, Houston, TX (United States); Manohar, N; Tailor, R; Cho, S [UT MD Anderson Cancer Center, Houston, TX (United States); Goodrich, G [Nanospectra Biosciences Inc, Houston, TX (United States); Krishnan, S [The University of Texas MD Anderson Cancer Center, Houston, TX (United States)

    2015-06-15

    Purpose: Gold nanoparticle (GNP) mediated radiosensitization has gained significant attention in recent years. However, the widely used passive targeting strategy requires high concentration of GNPs to induce the desired therapeutic effect, thus dampening the enthusiasm for clinical translation. The purpose of this study is to utilize a molecular targeting strategy to minimize the concentration of GNPs injected while simultaneously enhancing the tumor specific radiosensitization for an improved therapeutic outcome. Methods: Cetuximab (antibody specific to the epidermal growth factor receptor that is over-expressed in tumors) conjugated gold nanorods (cGNRs) was used for the tumor targeting. The binding affinity, internalization, and in vitro radiosensitization were evaluated using dark field microscopy, transmission electron microscopy, and clonogenic cell survival assay, respectively. In vivo biodistribution in tumor (HCT116-colorectal cancer cells) bearing mice were quantified using inductively coupled plasma mass spectrometry. In vivo radiosensitization potential was tested using 250-kVp x-rays and clinically relevant 6-MV radiation beams. Results: cGNRs displayed excellent cell-surface binding and internalization (∼31,000 vs 12,000/cell) when compared to unconjugated GNRs (pGNRs). In vitro, the dose enhancement factor at 10% survival (DEF10) was estimated as 1.06 and 1.17, respectively for both 250-kVp and 6-MV beams. In vivo biodistribution analysis revealed enhanced uptake of cGNRs in tumor (1.3 µg/g of tumor tissue), which is ∼1000-fold less than the reported values using passive targeting strategy. Nonetheless, significant radiosensitization was observed in vivo with cGNRs when compared to pGNRs, when irradiated with 250-kVp (tumor volume doubling time 35 days vs 25 days; p=0.002) and 6 MV (17 days vs 13 days; p=0.0052) beams. Conclusion: The enhanced radiosensitization effect observed with very low intratumoral concentrations of gold and megavoltage x

  6. LED Systems Target Plant Growth

    Science.gov (United States)

    2010-01-01

    To help develop technologies for growing edible biomass (food crops) in space, Kennedy Space Center partnered with Orbital Technologies Corporation (ORBITEC), of Madison, Wisconsin, through the Small Business Innovation Research (SBIR) program. One result of this research was the High Efficiency Lighting with Integrated Adaptive Control (HELIAC) system, components of which have been incorporated into a variety of agricultural greenhouse and consumer aquarium lighting features. The new lighting systems can be adapted to a specific plant species during a specific growth stage, allowing maximum efficiency in light absorption by all available photosynthetic tissues.

  7. Comparison of active, passive and magnetic targeting to tumors of multifunctional paclitaxel/SPIO-loaded nanoparticles for tumor imaging and therapy.

    Science.gov (United States)

    Schleich, Nathalie; Po, Chrystelle; Jacobs, Damien; Ucakar, Bernard; Gallez, Bernard; Danhier, Fabienne; Préat, Véronique

    2014-11-28

    Multifunctional nanoparticles combining therapy and imaging have the potential to improve cancer treatment by allowing personalized therapy. Herein, we aimed to compare in vivo different strategies in terms of targeting capabilities: (1) passive targeting via the EPR effect, (2) active targeting of αvβ3 integrin via RGD grafting, (3) magnetic targeting via a magnet placed on the tumor and (4) the combination of magnetic targeting and active targeting of αvβ3 integrin. For a translational approach, PLGA-based nanoparticles loaded with paclitaxel and superparamagnetic iron oxides were used. Electron Spin Resonance spectroscopy and Magnetic Resonance Imaging (MRI) were used to both quantify and visualize the accumulation of multifunctional nanoparticles into the tumors. We demonstrate that compared to untargeted or single targeted nanoparticles, the combination of both active strategy and magnetic targeting drastically enhanced (i) nanoparticle accumulation into the tumor tissue with an 8-fold increase compared to passive targeting (1.12% and 0.135% of the injected dose, respectively), (ii) contrast in MRI (imaging purpose) and (iii) anti-cancer efficacy with a median survival time of 22 days compared to 13 for the passive targeting (therapeutic purpose). Double targeting of nanoparticles to tumors by different mechanisms could be a promising translational approach for the management of therapeutic treatment and personalized therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Jae Youn Hwang

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

  9. A CD276 Antibody Guided Missile with One Warhead and Two Targets: The Tumor and Its Vasculature.

    Science.gov (United States)

    Khan, Kabir A; Kerbel, Robert S

    2017-04-10

    In this issue of Cancer Cell, Seaman et al. demonstrate that antibody drug conjugates (ADCs) against CD276 expressed by tumor cells and tumor vasculature have promising anti-tumor activity while showing little toxicity. Importantly, these agents have the potential to target both angiogenic vessels and non-angiogenic vessels co-opted by tumor cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Causation of nervous system tumors in children: insights from traditional and genetically engineered animal models

    International Nuclear Information System (INIS)

    Rice, Jerry M.

    2004-01-01

    Pediatric neurogenic tumors include primitive neuroectodermal tumors (PNETs), especially medulloblastoma; ependymomas and choroid plexus papillomas; astrocytomas; retinoblastoma; and sympathetic neuroblastoma. Meningiomas and nerve sheath tumors, although uncommon in childhood, are also significant because they can result from exposures of children to ionizing radiation. Specific chromosomal loci and specific genes are related to each of these tumor types. Virtually all these genes appear to act as tumor suppressor genes, which are inactivated in tumor cells by mutations or by chromosomal loss. In genetically engineered mice, some genes that are clearly associated with specific human tumors (e.g., RB1 in retinoblastoma and NF2 in meningiomas and schwannomas) have no such effect. Other genetic constructs in mice involving the genes p53, ptc1, and Nf1 have produced tumors remarkably similar to some of the human pediatric neoplasms. Some of these tumors become clinically apparent after only a few weeks, while the mice are still juveniles, especially when two or more tumor suppressor genes are inactivated in the same genetic construct. Conversely, at least one genetic pathway in rodents involving point mutation in the coding region of a transforming gene (neu in malignant schwannomas) does not appear to operate in any human tumors. The nervous system is markedly susceptible to experimental carcinogenesis during early life in rodents, dogs, primates, and other nonhuman species, and there is no obvious reason why this generalization should not also apply to humans. However, except for therapeutic ionizing radiation, no physical, chemical, or biological cause of human pediatric nervous system tumors is known. The failure of experimental transplacental carcinogenesis to mirror human pediatric experience more closely may reflect the need for multiple mutational events in target cells, and for experimental carcinogens that are capable of causing the full spectrum of

  11. Preparation, characterization, in vivo pharmacokinetics, and biodistribution of polymeric micellar dimethoxycurcumin for tumor targeting

    Directory of Open Access Journals (Sweden)

    Liu H

    2015-10-01

    Full Text Available Hui Liu,1 Hui Xu,1 Yunxia Jiang,1 Shengyuan Hao,1 Feirong Gong,2 Hongjie Mu,1 Ke Liu3 1School of Pharmacy, Yantai University, Yantai, People’s Republic of China; 2Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, People’s Republic of China; 3Suzhou Nanomedicine R&D Co, Ltd, Suzhou, People’s Republic of China Abstract: Dimethoxycurcumin (DMC is an analog of curcumin with superior efficacy in various disease models. Currently, drug delivery system research on DMC is very limited, and it has become a huge challenge to realize further developments and clinical applications. In the present study, a kind of amphiphilic block copolymer, N-t-butoxycarbonyl-phenylalanine terminated monomethoxyl poly (ethylene glycol-b-poly (ε-caprolactone, or mPEG-PCL-Phe(Boc, was prepared from monomethoxyl poly (ethylene glycol-b-poly (ε-caprolactone (mPEG-PCL with its hydroxyl terminal chemically converted into N-t-butoxycarbonyl-phenylalanine (Boc-Phe. This copolymer was determined to have a fairly low critical micelle concentration (2.56×10-3 mg/mL and passive targeting potential to tumor tissue, and thus was applied to develop a polymeric micellar formulation of DMC for the first time. The DMC-loaded micelles prepared by thin-film hydration method had typical shell–core structure, with an average particle size of 17.9±0.4 nm and a polydispersity index of 0.045±0.011. The drug loading capacity and entrapment efficiency were 9.94%±0.15% and 97.22%±0.18%, respectively, indicating a high-affinity interaction between DMC and the copolymer. At a concentration of 2 mg/mL, the reconstituted micelle solution could be maintained for at least 10 days at room temperature, and displayed a low initial burst release followed by a sustained release in vitro. Pharmacokinetic study in rats revealed that in vivo drug exposure of DMC was significantly

  12. Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth

    International Nuclear Information System (INIS)

    Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing; Bosland, Maarten C.; Kajdacsy-Balla, André; Gnanasekar, Munirathinam

    2012-01-01

    Highlights: ► Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. ► Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. ► Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. ► Knock down of RAGE abrogates prostate tumor growth in vivo. ► Disruption of RAGE expression in prostate tumor activates death receptors. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.

  13. Targeting B16 tumors in vivo with peptide-conjugated gold nanoparticles

    Science.gov (United States)

    Poon, Wilson; Zhang, Xuan; Bekah, Devesh; Teodoro, Jose G.; Nadeau, Jay L.

    2015-07-01

    This study examines the effects of polyethylene glycol (PEG) and peptide conjugation on the biodistribution of ultrasmall (2.7 nm) gold nanoparticles in mice bearing B16 melanoma allografts. Nanoparticles were delivered intravenously, and biodistribution was measured at specific timepoints by organ digestion and inductively coupled plasma mass spectrometry. All major organs were examined. Two peptides were tested: the cyclic RGD peptide (cRGD, which targets integrins); and a recently described peptide derived from the myxoma virus. We found the greatest specific tumor delivery using the myxoma peptide, with or without PEGylation. Un-PEGylated cRGD performed poorly, but PEGylated RGD showed a significant transient collection in the tumor. Liver and kidney were the primary targets of all constructs. None of the particles were able to cross the blood-brain barrier. Although it was able to deliver Au to B16 cells, the myxoma peptide did not show any cytotoxic activity against these cells, in contrast to previous reports. These results indicate that the effect of passive targeting by PEGylation and active targeting by peptides can be independent or combined, and that they should be evaluated on a case-by-case basis when designing new nanosystems for targeted therapies. Both myxoma peptide and cRGD should be considered for specific targeting to melanoma, but a thorough investigation of the cytotoxicity of the myxoma peptide to different cell lines remains to be performed.

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

    Science.gov (United States)

    Zhao, Ziming; Wang, Yu; Han, Jin; Wang, Keli; Yang, Dan; Yang, Yihua; Du, Qian; Song, Yuanjian; Yin, Xiaoxing

    2014-01-01

    micelles reported in this work were a promising drug delivery system for tumor targeting therapy.

  15. Childhood Central Nervous System Embryonal Tumors Treatment

    Science.gov (United States)

    ... Reporting & Auditing Grant Transfer Grant Closeout Contracts & Small Business Training Cancer Training at NCI (Intramural) Funding for ... are open only to patients who have not started treatment. Children who have CNS embryonal tumors should ...

  16. Metallodrugs in targeted cancer therapeutics. Aiming at chemoresistance-related patterns and immunosuppressive tumor networks

    Science.gov (United States)

    Salifoglou, Athanasios; Petanidis, Savvas; Kioseoglou, Efrosini

    2017-11-16

    Tumor cell chemoresistance is a major challenge in cancer therapeutics. Major select metal-based drugs are potent anticancer agents yet they exhibit undesirable side-effects and are effective against only a few types of cancers. A need, therefore, arises for new metallodrugs with an improved spectrum of efficacy and lower toxicity. Development of anticancer drugs based on antitumor metals is currently a very active field, with considerable efforts having been made toward elucidating the mechanisms of immune action of complex metalloforms and optimizing their immunoregulatory bioactivity through appropriate structural modification. In that respect, comprehending the molecular factors involved in drug resistance and immune response may help us develop new strategies toward more promising chemotherapies, reducing the rate of relapse and overcoming chemoresistance. In this review, a) molecular immune-related mechanisms in the tumor microenvironment, leading to decreased drug sensitivity, along with b) strategies for reversing drug resistance and targeting immunosuppressive tumor networks, while concurrently optimizing the design of complex metalloforms bearing anti-tumor activity, are discussed in an effort to identify and overcome underlying mechanisms of chemoresistance to both standard chemotherapeutic agents and targeted molecular therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Development of oligoclonal nanobodies for targeting the tumor-associated glycoprotein 72 antigen

    DEFF Research Database (Denmark)

    Sharifzadeh, Zahra; Rahbarizadeh, Fatemeh; Shokrgozar, Mohammad Ali

    2013-01-01

    The tumor-associated glycoprotein 72 (TAG-72) is a membrane mucin whose over-expression is correlated with advanced tumor stage and increased invasion and metastasis. In this study, we identified a panel of four nanobodies, single variable domains of dromedary heavy-chain antibodies that specific......The tumor-associated glycoprotein 72 (TAG-72) is a membrane mucin whose over-expression is correlated with advanced tumor stage and increased invasion and metastasis. In this study, we identified a panel of four nanobodies, single variable domains of dromedary heavy-chain antibodies...... that specifically recognize the TAG-72 antigen. All selected nanobodies were shown to selectively bind to this cancer-related molecule with low-nanomolar affinities and do not cross-react with other antigens, such as MUC1 or HER2. Furthermore, they can detect TAG-72 in concentrations as low as 5 U/ml which...... nanobody recognizes a distinct epitope on the TAG-72 antigen that is different from the one recognized by the mouse anti-TAG-72 antibody, CC49. Considering their high specificity, reduced immunogenicity and multi-targeting behavior, these oligoclonal nanobodies represent a promising tool to target TAG-72...

  18. Tumor responsive targeted multifunctional nanosystems for cancer imaging, chemo- and siRNA therapy

    Science.gov (United States)

    Savla, Ronak

    Cancer is one of the most insidious diseases. Compromising of over 100 different types and sharing the unifying factors of uncontrolled growth and metastasis, unmet clinical needs in terms of cancer diagnosis and treatment continue to exist. It is widely accepted that most forms of cancer are treatable or even curable if detected before widespread metastasis occurs. Nearly a quarter of deaths in the United States is the result of cancer and it only trails heart disease in terms of annual mortality. Surgery, chemotherapy, and radiation therapy are the primary treatment modalities for cancer. Research in these procedures has resulted in substantial benefits for cancer patients, but there is still room for an improvement. However, a time has been reached at which it appears that the benefits from these modalities have been reached the maximum. Therefore, it is vital to develop new strategies for the diagnosis and treatment of cancer. The field of nanotechnology is concerned with structures in the nanometer size range and holds the potential to drastically impact and improve the lives of patients suffering from cancer. Not only can nanotechnology improve current methods of diagnosis and treatment, it has a possibility of introducing newer and better modalities. The overall purpose of this work is to develop novel nanotechnology-based methodologies for the diagnosis and treatment of various forms of cancers. The first aim of the project is the development of a multifunctional targeted nanosystem for the delivery of siRNA to overcome drug resistance. The second aspect is the synthesis of a quantum dot-based delivery system that releases drug in response to pH changes. The third aim is the development of a targeted, tumor environment responsive magnetic resonance nanoparticle contrast agent coupled with a nanoparticle-based treatment.

  19. Frequency of central nervous system tumors in delta region, Egypt

    Directory of Open Access Journals (Sweden)

    Khaled R Zalata

    2011-01-01

    Full Text Available Introduction and Aim of Work: Central nervous system (CNS tumors represent a major public health problem, and their epidemiological data in Egypt have been rather incomplete except for some regional reports. There are no available frequency-based data on CNS tumors in our locality. The objective of this study was to estimate the frequency of CNS tumors in east delta region, Egypt. Materials and Methods: The data were collected during the 8-year period from January 1999 to December 2007 from Pathology Department, Mansoura University, and other referred pathology labs. Examination of HandE stained sections from retrieved paraffin blocks were done in all cases for histopathologic categorization of C.N.S. tumors. Immunohistochemical studies were applied to confirm final histopathologic diagnosis in problematic cases. Results: Intracranial tumors represented 86.7% of cases in comparison to only 13.3% for spinal tumors. Gliomas were the CNS tumors of the highest frequency (35.2%, followed by meningioma (25.6%, pituitary adenoma (11.6% and nerve sheath tumors (6.6%. 10.25% of tumors were of children <15 years. Conclusion: This study provides the largest series of the relative frequency of CNS tumors in Delta region in Egypt till now and may help to give insight into the epidemiology of CNS tumors in our locality.

  20. A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Paul Savage

    2017-10-01

    Full Text Available Summary: Therapies targeting epidermal growth factor receptor (EGFR have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC patient-derived xenografts (PDXs, we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR. Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster. Sorted EGFRhi subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFRhi cells gave rise to EGFRhi and EGFRlo cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFRhi subpopulations were identified in independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity. This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention. : Savage et al. demonstrate that sensitivity to EGFR inhibitor, gefitinib, in triple-negative breast cancer is paradoxically associated with EGFR heterogeneity. Using single-cell RNA sequencing in conjunction with functional assays, they identify TNBC tumors in which EGFR expression identifies cells with tumor-initiating capacity whose proliferative expansion is sensitive to EGFR inhibition. Keywords: breast cancer, tumor heterogeneity, patient-derived xenograft, single-cell RNA sequencing, EGFR inhibition, therapeutic response, tumor-initiating cell, cell hierarchy, BRCA1 mutation

  1. Beyond the M-CSF receptor - novel therapeutic targets in tumor-associated macrophages.

    Science.gov (United States)

    Bonelli, Stefano; Geeraerts, Xenia; Bolli, Evangelia; Keirsse, Jiri; Kiss, Mate; Pombo Antunes, Ana Rita; Van Damme, Helena; De Vlaminck, Karen; Movahedi, Kiavash; Laoui, Damya; Raes, Geert; Van Ginderachter, Jo A

    2018-02-01

    Tumor-associated macrophages (TAM) are by now established as important regulators of tumor progression by impacting on tumor immunity, angiogenesis, and metastasis. Hence, a multitude of approaches are currently pursued to intervene with TAM's protumor activities, the most advanced of which being a blockade of macrophage-colony stimulating factor (M-CSF)/M-CSF receptor (M-CSFR) signaling. M-CSFR signaling largely impacts on the differentiation of macrophages, including TAM, and hence strongly influences the numbers of these cells in tumors. However, a repolarization of TAM toward a more antitumor phenotype may be more elegant and may yield stronger effects on tumor growth. In this respect, several aspects of TAM behavior could be altered, such as their intratumoral localization, metabolism and regulatory pathways. Intervention strategies could include the use of small molecules but also new generations of biologicals which may complement the current success of immune checkpoint blockers. This review highlights current work on the search for new therapeutic targets in TAM. © 2017 Federation of European Biochemical Societies.

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

    OpenAIRE

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

  3. Novel Therapeutic Targets to Inhibit Tumor Microenvironment-Induced Castration Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    extracted from laser -captured PCa cells from human CRPC tumors revealed that MAPK4 expression is strongly correlated with AR activation (expression...Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and...signaling induced the expression of several AR targets as well as MAPK4 in PCa LNCaP cells, and that MAPK4 induced ligand-independent AR activation in

  4. Peptide ligand and PEG-mediated long-circulating liposome targeted to FGFR overexpressing tumor in vivo

    Directory of Open Access Journals (Sweden)

    Cai L

    2012-08-01

    Full Text Available Lulu Cai,1,3,† Xianhuo Wang,4,† Wenwen Wang,1,† Neng Qiu,1 Jiaolin Wen,1 Xingmei Duan,1 Xia Li,1 Xiang Chen,1 Li Yang,1 Zhiyong Qian,1 Yuquan Wei,1 Lijuan Chen,1,2 1State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, 2State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 3Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Sichuan Chengdu, China; 4Tianjin Medical University Cancer Institute and Hospital, Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China†These authors equally contributed to this researchBackground and methods: Paclitaxel, a widely used antitumor agent, has limited clinical application due to its hydrophobicity and systemic toxicity. To achieve sustained and targeted delivery of paclitaxel to tumor sites, liposomes composed of egg phosphatidylcholine, cholesterol, and distearolyphosphatidyl ethanolamine-N-poly(ethylene glycol (PEG2000 were prepared by a lipid film method. In addition, the liposomes also contained truncated fibroblast growth factor fragment-PEG-cholesterol as a ligand targeting the tumor marker fibroblast growth factor receptor. Physicochemical characteristics, such as particle size, zeta potential, entrapment efficiency, and release profiles were investigated. Pharmacokinetics and biodistribution were evaluated in C57BL/6 J mice bearing B16 melanoma after intravenous injection of paclitaxel formulated in Cremophor EL (free paclitaxel, conventional liposomes (CL-PTX, or in targeted PEGylated liposomes (TL-PTX.Results: Compared with CL-PTX and free paclitaxel, TL-PTX prolonged the half-life of paclitaxel by 2.01-fold and 3.40-fold, respectively, in plasma and improved the AUC0→t values of paclitaxel by

  5. Boron containing magnetic nanoparticles for neutron capture therapy--an innovative approach for specifically targeting tumors.

    Science.gov (United States)

    Tietze, Rainer; Unterweger, Harald; Dürr, Stephan; Lyer, Stefan; Canella, Lea; Kudejova, Petra; Wagner, Franz M; Petry, Winfried; Taccardi, Nicola; Alexiou, Christoph

    2015-12-01

    The selective delivery of (10)B into the tumor tissue remains to be further improved for successful and reliable Boron Neutron Capture Therapy applications. Magnetic Drug Targeting using intraarterially administered superparamagnetic nanoparticles and external magnetic fields already exhibited convincing results in terms of highly efficient and selective drug deposition. Using the same technique for the targeted (10)B delivery is a promising new approach. Here, systematic irradiation experiments of phantom cubes containing different concentrations of boron and nanoparticles as well as varying three-dimensional arrangements have been performed. Copyright © 2015. Published by Elsevier Ltd.

  6. Therapeutic Innovations for Targeting Childhood Neuroblastoma: Implications of the Neurokinin-1 Receptor System.

    Science.gov (United States)

    Berger, Michael; VON Schweinitz, Dietrich

    2017-11-01

    Neuroblastoma is the most common solid extracranial malignant tumor in children. Despite recent advances in the treatment of this heterogenous tumor with surgery and chemotherapy, the prognosis in advanced stages remains poor. Interestingly, neuroblastoma is one of the few solid tumors, to date, in which an effect for targeted immunotherapy has been proven in controlled clinical trials, giving hope for further advances in the treatment of this and other tumors by targeted therapy. A large array of novel therapeutic options for targeted therapy of neuroblastoma is on the horizon. To this repεrtoirε, the neurokinin-1 receptor (NK1R) system was recently added. The present article explores the most recent developments in targeting neuroblastoma cells via the NK1R and how this new knowledge could be helpful to create new anticancer therapies agains neuroblastoma and other cancers. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  7. Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy.

    Science.gov (United States)

    Takara, Kazuhiro; Hatakeyama, Hiroto; Kibria, Golam; Ohga, Noritaka; Hida, Kyoko; Harashima, Hideyoshi

    2012-08-20

    Anti-angiogenic therapy is a potential chemotherapeutic strategy for the treatment of drug resistant cancers. However, a method for delivering such drugs to tumor endothelial cells remains to be a major impediment to the success of anti-angiogenesis therapy. We designed liposomes (LPs) with controlled diameter of around 300 nm, and modified them with a specific ligand and a cell penetrating peptide (CPP) (a dual-ligand LP) for targeting CD13-expressing neovasculature in a renal cell carcinoma (RCC). We modified the LPs with an NGR motif peptide on the top of poly(ethylene glycol) and tetra-arginine (R4) on the surface of the liposome membrane as a specific and CPP ligand, respectively. The large size prevented extravasation of the dual-ligand LP, which allowed it to associate with target vasculature. While a single modification with either the specific or CPP ligand showed no increase in targetability, the dual-ligand enhanced the amount of delivered liposomes after systemic administration to OS-RC-2 xenograft mice. The anti-tumor activity of a dual-ligand LP encapsulating doxorubicin was evaluated and the results were compared with Doxil, which is clinically used to target tumor cells. Even though Doxil showed no anti-tumor activity, the dual-ligand LP suppressed tumor growth because the disruption of tumor vessels was efficiently induced. The comparison showed that tumor endothelial cells (TECs) were more sensitive to doxorubicin by 2 orders than RCC tumor cells, and the disruption of tumor vessels was efficiently induced. Collectively, the dual-ligand LP is promising carrier for the treatment of drug resistant RCC via the disruption of TECs. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Targeting engineering synchronization in chaotic systems

    Science.gov (United States)

    Bhowmick, Sourav K.; Ghosh, Dibakar

    2016-07-01

    A method of targeting engineering synchronization states in two identical and mismatch chaotic systems is explained in detail. The method is proposed using linear feedback controller coupling for engineering synchronization such as mixed synchronization, linear and nonlinear generalized synchronization and targeting fixed point. The general form of coupling design to target any desire synchronization state under unidirectional coupling with the help of Lyapunov function stability theory is derived analytically. A scaling factor is introduced in the coupling definition to smooth control without any loss of synchrony. Numerical results are done on two mismatch Lorenz systems and two identical Sprott oscillators.

  9. A windowless frozen hydrogen target system

    International Nuclear Information System (INIS)

    Knowles, P.E.; Beer, G.A.; Beveridge, J.L.

    1995-06-01

    A cryogenic target system has been constructed in which gaseous mixtures of all three hydrogen isotopes have been frozen onto a thin, 65 mm diameter gold foil. The foil is cooled to 3 K while inside a 70 K radiation shield, all of which is mounted in a vacuum system maintained at 10 -9 torr. Stable multi-layer hydrogen targets of known uniformity and thickness have been maintained for required measurement times of up to several days. To date, hundreds of targets have been successfully used in muon-catalyzed fusion experiments at TRIUMF. (author). 12 refs., 6 figs

  10. Structural study of liposomes loaded with a GM3 lactone analogue for the targeting of tumor epitopes.

    Science.gov (United States)

    Ristori, Sandra; Di Cola, Emanuela; Lunghi, Carlotta; Richichi, Barbara; Nativi, Cristina

    2009-12-01

    Therapeutic vaccination with tumor antigens is a new approach in cancer treatment, which aims at inducing immune response while avoiding the side effects generally associated to many conventional therapies. To improve the efficacy of vaccines, suitable carriers may be used. Herein the insertion of a thioether analogue of GM3 lactone (SNeuAC-C14) into liposomes is reported. SNeuAC-C14 is a potential vaccine for the targeting of saccharide-based tumor epitopes. Different liposome formulations were designed to act as carriers and to generate recognition by tumor epitopes. The structural study of pure and loaded liposomes was carried out by synchrotron Small Angle X-ray Scattering and was complemented by Dynamic Light Scattering and Zeta potential measurements. This provided detailed information on relevant properties of the investigated host-guest structures and showed that the active unit of SNeuAC-C14, i.e. its spiro tricyclic moiety, was located in the polar head region of the liposome bilayer, which is an important requirement for recognition phenomena. Moreover, it was found that most of the SNeuAC-C14/liposome complexes were positively charged. The obtained results allow these systems to be considered as candidates to promote immunoresponse in tumor cells.

  11. T cells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation.

    Science.gov (United States)

    Blachère, Nathalie E; Orange, Dana E; Santomasso, Bianca D; Doerner, Jessica; Foo, Patricia K; Herre, Margaret; Fak, John; Monette, Sébastien; Gantman, Emily C; Frank, Mayu O; Darnell, Robert B

    2014-11-01

    Paraneoplastic neurologic diseases (PND) involving immune responses directed toward intracellular antigens are poorly understood. Here, we examine immunity to the PND antigen Nova2, which is expressed exclusively in central nervous system (CNS) neurons. We hypothesized that ectopic expression of neuronal antigen in the periphery could incite PND. In our C57BL/6 mouse model, CNS antigen expression limits antigen-specific CD4+ and CD8+ T-cell expansion. Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells. CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo. Despite mediating cancer rejection, adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting. Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity. This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled. Since humoral immunity was not required for tumor rejection, B-cell targeting therapy, such as rituximab, may be a rational treatment option for PND that does not hamper tumor immunity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Meeting the challenge of homogenous boron targeting of heterogeneous tumors for effective boron neutron capture therapy (BNCT)

    International Nuclear Information System (INIS)

    Heber, Elisa M.; Trivillin, Veronica A.; Itoiz, Maria E.; Rebagliati, J. Raul; Batistoni, Daniel; Kreimann, Erica L.; Schwint, Amanda E.; Nigg, David W.; Gonzalez, Beatriz N.

    2006-01-01

    BNCT is a tumor cell targeted radiation therapy. Inadequately boron targeted tumor populations jeopardize tumor control. Meeting the to date unresolved challenge of homogeneous targeting of heterogeneous tumors with effective boron carriers would contribute to therapeutic efficacy. The aim of the present study was to evaluate the degree of variation in boron content delivered by boronophenylalanine (BPA), GB-10 (Na 2 10 B 10 H 10 ) and the combined administration of (BPA+GB-10) in different portions of tumor, precancerous tissue around tumor and normal pouch tissue in the hamster cheek pouch oral cancer model. Boron content was evaluated by ICP-AES. The degree of homogeneity in boron targeting was assessed in terms of the coefficient of variation ([S.D./Mean]x100) of boron values. Statistical analysis of the results was performed by one-way ANOVA and the least significant difference test. GB-10 and GB-10 plus BPA achieved respectively a statistically significant 1.8-fold and 3.3-fold increase in targeting homogeneity over BPA. The combined boron compound administration protocol contributes to homogeneous targeting of heterogeneous tumors and would increase therapeutic efficacy of BNCT by exposing all tumor populations to neutron capture reactions in boron. (author)

  13. Allegany Ballistics Lab: sensor test target system

    Science.gov (United States)

    Eaton, Deran S.

    2011-06-01

    Leveraging the Naval Surface Warfare Center, Indian Head Division's historical experience in weapon simulation, Naval Sea Systems Command commissioned development of a remote-controlled, digitally programmable Sensor Test Target as part of a modern, outdoor hardware-in-the-loop test system for ordnance-related guidance, navigation and control systems. The overall Target system design invokes a sciences-based, "design of automated experiments" approach meant to close the logistical distance between sensor engineering and developmental T&E in outdoor conditions over useful real world distances. This enables operating modes that employ broad spectrum electromagnetic energy in many a desired combination, variably generated using a Jet Engine Simulator, a multispectral infrared emitter array, optically enhanced incandescent Flare Simulators, Emitter/Detector mounts, and an RF corner reflector kit. As assembled, the recently tested Sensor Test Target prototype being presented can capably provide a full array of useful RF and infrared target source simulations for RDT&E use with developmental and existing sensors. Certain Target technologies are patent pending, with potential spinoffs in aviation, metallurgy and biofuels processing, while others are variations on well-established technology. The Sensor Test Target System is planned for extended installation at Allegany Ballistics Laboratory (Rocket Center, WV).

  14. Highly Specific PET Imaging of Prostate Tumors in Mice with an Iodine-124-Labeled Antibody Fragment That Targets Phosphatidylserine

    OpenAIRE

    Stafford, Jason H.; Hao, Guiyang; Best, Anne M.; Sun, Xiankai; Thorpe, Philip E.

    2013-01-01

    Phosphatidylserine (PS) is an attractive target for imaging agents that identify tumors and assess their response to therapy. PS is absent from the surface of most cell types, but becomes exposed on tumor cells and tumor vasculature in response to oxidative stresses in the tumor microenvironment and increases in response to therapy. To image exposed PS, we used a fully human PS-targeting antibody fragment, PGN635 F(ab')2, that binds to complexes of PS and β2-glycoprotein I. PGN635 F(ab')2 was...

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

    Science.gov (United States)

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

    2017-08-01

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

  16. Exceptionally Potent Anti-Tumor Bystander Activity of an scFv:sTRAIL Fusion Protein with Specificity for EGP2 Toward Target Antigen-Negative Tumor Cells

    Directory of Open Access Journals (Sweden)

    Edwin Bremer

    2004-09-01

    Full Text Available Previously, we reported on the target cell-restricted fratricide apoptotic activity of scFvC54:sTRAIL, a fusion protein comprising human-soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL genetically linked to the antibody fragment scFvC54 specific for the cell surface target antigen EGP2. In the present study, we report that the selective binding of scFvC54:sTRAIL to EGP2-positive target cells conveys an exceptionally potent pro-apoptotic effect toward neighboring tumor cells that are devoid of EGP2 expression (bystander cells. The anti-tumor bystander activity of scFvC54:sTRAIL was detectable at target-tobystander cell ratios as low as 1:100. Treatment in the presence of EGP2-blocking or TRAIL-neutralizing antibody strongly inhibited apoptosis in both target and bystander tumor cells. In the absence of target cells, bystander cell apoptosis induction was abrogated. The bystander apoptosis activity of scFvC54:sTRAIL did not require internalization, enzymatic conversion, diffusion, or communication (gap junctional intracellular communication between target and bystander cells. Furthermore, scFvC54:sTRAIL showed no detectable signs of innocent bystander activity toward freshly isolated blood cells. Further development of this new principle is warranted for approaches where cancer cells can escape from antibody-based therapy due to partial loss of target antigen expression.

  17. Target system materials and engineering problems

    International Nuclear Information System (INIS)

    Fischer, W.E.

    1989-01-01

    This paper discusses the common problems of target design. As a model for the discussion, the author considers a spallation source which is fed by a high power proton beam of the order of one megawatt. The materials used for the target station and particularly for the spallation target itself depend on whether the source is built for pulsed, modulated or continuous operation. The difference of materials used is mainly determined by the neutronics considerations. Depending on the choice of materials for the target systems, the characters of material problems met, are of somewhat different nature. It is recognized that for each target version quite specific difficulties have to be overcome. On the other hand, there is a whole set of problems which is common to all target versions. These are: heat load in region of proton beam interactions; thermal stress and cycling; and radiation damage. It is shown that solutions to the whole package of problems up to a beam power of 0 (1MW) have been found. The whole effort concentrates onto the region of the first few centimeters of beam penetration. Two solutions have been proposed: (1) Keep the power of proton beam limited and produce neutrons elsewhere in the target. and (2) Dilute the power by moving mechanically the target and the window. 8 refs., 11 figs

  18. Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD

    Science.gov (United States)

    Wu, Rui; Liang, Yingjian; Lin, Meihua; Liu, Jia; Chan, Chang S.; Hu, Wenwei; Feng, Zhaohui

    2014-01-01

    Cancer cells display enhanced glycolysis to meet their energetic and biosynthetic demands even under normal oxygen concentrations. Recent studies have revealed that tumor suppressor p53 represses glycolysis under normoxia as a novel mechanism for tumor suppression. As the common microenvironmental stress for tumors, hypoxia drives the metabolic switch from the oxidative phosphorylation to glycolysis, which is crucial for survival and proliferation of cancer cells under hypoxia. The p53's role and mechanism in regulating glycolysis under hypoxia is poorly understood. Here, we found that p53 represses hypoxia-stimulated glycolysis in cancer cells through RRAD, a newly-identified p53 target. RRAD expression is frequently decreased in lung cancer. Ectopic expression of RRAD greatly reduces glycolysis whereas knockdown of RRAD promotes glycolysis in lung cancer cells. Furthermore, RRAD represses glycolysis mainly through inhibition of GLUT1 translocation to the plasma membrane. Under hypoxic conditions, p53 induces RRAD, which in turn inhibits the translocation of GLUT1 and represses glycolysis in lung cancer cells. Blocking RRAD by siRNA greatly abolishes p53's function in repressing glycolysis under hypoxia. Taken together, our results revealed an important role and mechanism of p53 in antagonizing the stimulating effect of hypoxia on glycolysis, which contributes to p53's function in tumor suppression. PMID:25114038

  19. Targeting long non-coding RNA-TUG1 inhibits tumor growth and angiogenesis in hepatoblastoma.

    Science.gov (United States)

    Dong, R; Liu, G-B; Liu, B-H; Chen, G; Li, K; Zheng, S; Dong, K-R

    2016-06-30

    Hepatoblastoma is the most common liver tumor of early childhood, which is usually characterized by unusual hypervascularity. Recently, long non-coding RNAs (lncRNA) have emerged as gene regulators and prognostic markers in several cancers, including hepatoblastoma. We previously reveal that lnRNA-TUG1 is upregulated in hepatoblastoma specimens by microarray analysis. In this study, we aim to elucidate the biological and clinical significance of TUG1 upregulation in hepatoblastoma. We show that TUG1 is significantly upregulated in human hepatoblastoma specimens and metastatic hepatoblastoma cell lines. TUG1 knockdown inhibits tumor growth and angiogenesis in vivo, and decreases hepatoblastoma cell viability, proliferation, migration, and invasion in vitro. TUG1, miR-34a-5p, and VEGFA constitutes to a regulatory network, and participates in regulating hepatoblastoma cell function, tumor progression, and tumor angiogenesis. Overall, our findings indicate that TUG1 upregulation contributes to unusual hypervascularity of hepatoblastoma. TUG1 is a promising therapeutic target for aggressive, recurrent, or metastatic hepatoblastoma.

  20. A novel monoclonal antibody targeting coxsackie virus and adenovirus receptor inhibits tumor growth in vivo.

    Science.gov (United States)

    Kawada, Manabu; Inoue, Hiroyuki; Kajikawa, Masunori; Sugiura, Masahito; Sakamoto, Shuichi; Urano, Sakiko; Karasawa, Chigusa; Usami, Ihomi; Futakuchi, Mitsuru; Masuda, Tohru

    2017-01-11

    To create a new anti-tumor antibody, we conducted signal sequence trap by retrovirus-meditated expression method and identified coxsackie virus and adenovirus receptor (CXADR) as an appropriate target. We developed monoclonal antibodies against human CXADR and found that one antibody (6G10A) significantly inhibited the growth of subcutaneous as well as orthotopic xenografts of human prostate cancer cells in vivo. Furthermore, 6G10A also inhibited other cancer xenografts expressing CXADR, such as pancreatic and colorectal cancer cells. Knockdown and overexpression of CXADR confirmed the dependence of its anti-tumor activity on CXADR expression. Our studies of its action demonstrated that 6G10A exerted its anti-tumor activity primarily through both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Moreover, 6G10A reacted with human tumor tissues, such as prostate, lung, and brain, each of which express CXADR. Although we need further evaluation of its reactivity and safety in human tissues, our results show that a novel anti-CXADR antibody may be a feasible candidate for cancer immunotherapy.

  1. Tumor initiating cells and chemoresistance: which is the best strategy to target colon cancer stem cells?

    Science.gov (United States)

    Paldino, Emanuela; Tesori, Valentina; Casalbore, Patrizia; Gasbarrini, Antonio; Puglisi, Maria Ausiliatrice

    2014-01-01

    There is an emerging body of evidence that chemoresistance and minimal residual disease result from selective resistance of a cell subpopulation from the original tumor that is molecularly and phenotypically distinct. These cells are called "cancer stem cells" (CSCs). In this review, we analyze the potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies for metastatic colon cancer. These include induction of terminal epithelial differentiation of CSCs or targeting some genes expressed only in CSCs and involved in self-renewal and chemoresistance. Ideal targets could be cell regulators that simultaneously control the stemness and the resistance of CSCs. Another important aspect of cancer biology, which can also be harnessed to create novel broad-spectrum anticancer agents, is the Warburg effect, also known as aerobic glycolysis. Actually, little is yet known with regard to the metabolism of CSCs population, leaving an exciting unstudied avenue in the dawn of the emerging field of metabolomics.

  2. Programming controlled adhesion of E. coli to target surfaces, cells, and tumors with synthetic adhesins.

    Science.gov (United States)

    Piñero-Lambea, Carlos; Bodelón, Gustavo; Fernández-Periáñez, Rodrigo; Cuesta, Angel M; Álvarez-Vallina, Luis; Fernández, Luis Ángel

    2015-04-17

    In this work we report synthetic adhesins (SAs) enabling the rational design of the adhesion properties of E. coli. SAs have a modular structure comprising a stable β-domain for outer membrane anchoring and surface-exposed immunoglobulin domains with high affinity and specificity that can be selected from large repertoires. SAs are constitutively and stably expressed in an E. coli strain lacking a conserved set of natural adhesins, directing a robust, fast, and specific adhesion of bacteria to target antigenic surfaces and cells. We demonstrate the functionality of SAs in vivo, showing that, compared to wild type E. coli, lower doses of engineered E. coli are sufficient to colonize solid tumors expressing an antigen recognized by the SA. In addition, lower levels of engineered bacteria were found in non-target tissues. Therefore, SAs provide stable and specific adhesion capabilities to E. coli against target surfaces of interest for diverse applications using live bacteria.

  3. The inducible caspase-9 suicide gene system as a ‘safety switch’ to limit on-target, off-tumor toxicities of chimeric antigen receptor T-cells.

    Directory of Open Access Journals (Sweden)

    Tessa eGargett

    2014-10-01

    Full Text Available Immune modulation has become a central element in many cancer treatments, and T cells genetically engineered to express chimeric antigen receptors (CAR may provide a new approach to cancer immunotherapy. Autologous CAR T cells that have been re-directed towards tumor-associated antigens (TAA have shown promising results in phase 1 clinical trials, with some patients undergoing complete tumor regression. However this T-cell therapy must carefully balance effective T-cell activation, to ensure antitumor activity, with the potential for uncontrolled activation that may produce immunopathology. An inducible Caspase 9 (iCasp9 ‘safety switch’ offers a solution that allows for the removal of inappropriately activated CAR T cells. The induction of iCasp9 depends on the administration of the small molecule dimerizer drug AP1903 and dimerization results in rapid induction of apoptosis in transduced cells, preferentially killing activated cells expressing high levels of transgene. The iCasp9 gene has been incorporated into vectors for use in preclinical studies and demonstrates effective and reliable suicide gene activity in phase 1 clinical trials. A third-generation CAR incorporating iCasp9 re-directs T cells towards the GD2 TAA. GD2 is over-expressed in melanoma and other malignancies of neural crest origin and the safety and activity of these GD2-iCAR T cells will be investigated in CARPETS and other actively recruiting phase 1 trials.

  4. Targeted SERS nanosensors measure physicochemical gradients and free energy changes in live 3D tumor spheroids.

    Science.gov (United States)

    Jamieson, Lauren E; Camus, Victoria L; Bagnaninchi, Pierre O; Fisher, Kate M; Stewart, Grant D; Nailon, William H; McLaren, Duncan B; Harrison, David J; Campbell, Colin J

    2016-09-22

    Use of multicellular tumor spheroids (MTS) to investigate therapies has gained impetus because they have potential to mimic factors including zonation, hypoxia and drug-resistance. However, analysis remains difficult and often destroys 3D integrity. Here we report an optical technique using targeted nanosensors that allows in situ 3D mapping of redox potential gradients whilst retaining MTS morphology and function. The magnitude of the redox potential gradient can be quantified as a free energy difference (ΔG) and used as a measurement of MTS viability. We found that by delivering different doses of radiotherapy to MTS we could correlate loss of ΔG with increasing therapeutic dose. In addition, we found that resistance to drug therapy was indicated by an increase in ΔG. This robust and reproducible technique allows interrogation of an in vitro tumor-model's bioenergetic response to therapy, indicating its potential as a tool for therapy development.

  5. A new radiological examination for tumor in the internal auditory canal by combination of air CT cisternography and target imaging

    International Nuclear Information System (INIS)

    Yagishita, Akira; Shiga, Itsuo; Kanzaki, Hitoshi

    1982-01-01

    A 56-year-old man was admitted to the hospital because of progressive right hearing disturbance and tinnitus. An x-ray film of the skull demonstrated dilatation of the right internal auditory canal. Intravcnously enhanced CT didn't reveal any tumor in the right cerebellopontine angle. An intracanalicular tumor was demonstrated by air CT cisternography with target imaging, and confirmed by surgery. This method is useful for the radiological evaluation of the intracanalicular tumors. (author)

  6. Targeting bladder tumor cells in voided urine of Chinese patients with FITC-CSNRDARRC peptide ligand

    Directory of Open Access Journals (Sweden)

    Jia XY

    2012-05-01

    . The advantage was maintained in terms of the detection of invasive tumors between the FITC-CSNRDARRC ligand and UC (90.48% versus 23.81%, P = 0.001 as well as between FISH and UC (85.71% versus 23.81%, P = 0.003. The specificities for the FITC-CSNRDARRC ligand, UC, and FISH were 100%.Conclusion: Results show that the FITC-CSNRDARRC ligand is a promising noninvasive tool for diagnosis and surveillance in patients suspected of having a new bladder tumor.Keywords: bladder tumor, tumor-targeting, FITC-CSNRDARRC ligand, fluorescent probe

  7. Pegylated zinc protoporphyrin: a water-soluble heme oxygenase inhibitor with tumor-targeting capacity.

    Science.gov (United States)

    Sahoo, S K; Sawa, T; Fang, J; Tanaka, S; Miyamoto, Y; Akaike, T; Maeda, H

    2002-01-01

    Heme oxygenase (HO) is a key enzyme in heme metabolism; it oxidatively degrades heme to biliverdin, accompanied by formation of free iron and carbon monoxide. Biliverdin is subsequently reduced by cytosolic biliverdin reductase to form bilirubin, a potent antioxidant. We recently found that tumor cells utilize HO to protect themselves from oxidative stress by producing the antioxidant bilirubin. This result suggested an important potential therapeutic strategy: suppression of bilirubin production with the use of HO inhibitors; hence, cancer cells become vulnerable to oxidative stress induced by anticancer drugs or leukocytes of the host. This concept was validated by using the intraarterial administration of an HO inhibitor, zinc protoporphyrin, in nonphysiological solution. In the present study, zinc protoporphyrin (ZnPP) was conjugated with poly(ethylene glycol) (PEG) with molecular weight of 5000, to make ZnPP, a water-soluble compound (PEG-ZnPP), and to improve its tumor-targeting efficiency. PEG was conjugated to ZnPP through newly introduced amino groups, where ethylenediamine residues were added at C6 and C7 of protoporphyrin. The divalent zinc cation was chelated into the protoporphyrin ring to obtain PEG-ZnPP. PEG-ZnPP did become highly water-soluble, and it formed multimolecular associations with molecules larger than 70 kDa in aqueous media. PEG-ZnPP inhibited splenic microsomal HO activity in vitro in a competitive manner in the presence of hemin, with an apparent inhibitory constant of 0.12 microM. Most important, PEG-ZnPP injected intravenously significantly suppressed intratumor HO activity in a murine solid tumor model, which suggests that tumor-targeted inhibition of HO is possible with the use of PEG-ZnPP.

  8. FDTD analysis of a noninvasive hyperthermia system for brain tumors

    Directory of Open Access Journals (Sweden)

    Yacoob Sulafa M

    2012-08-01

    Full Text Available Abstract Background Hyperthermia is considered one of the new therapeutic modalities for cancer treatment and is based on the difference in thermal sensitivity between healthy tissues and tumors. During hyperthermia treatment, the temperature of the tumor is raised to 40–45°C for a definite period resulting in the destruction of cancer cells. This paper investigates design, modeling and simulation of a new non-invasive hyperthermia applicator system capable of effectively heating deep seated as well as superficial brain tumors using inexpensive, simple, and easy to fabricate components without harming surrounding healthy brain tissues. Methods The proposed hyperthermia applicator system is composed of an air filled partial half ellipsoidal chamber, a patch antenna, and a head model with an embedded tumor at an arbitrary location. The irradiating antenna is placed at one of the foci of the hyperthermia chamber while the center of the brain tumor is placed at the other focus. The finite difference time domain (FDTD method is used to compute both the SAR patterns and the temperature distribution in three different head models due to two different patch antennas at a frequency of 915 MHz. Results The obtained results suggest that by using the proposed noninvasive hyperthermia system it is feasible to achieve sufficient and focused energy deposition and temperature rise to therapeutic values in deep seated as well as superficial brain tumors without harming surrounding healthy tissue. Conclusions The proposed noninvasive hyperthermia system proved suitable for raising the temperature in tumors embedded in the brain to therapeutic values by carefully selecting the systems components. The operator of the system only needs to place the center of the brain tumor at a pre-specified location and excite the antenna at a single frequency of 915 MHz. Our study may provide a basis for a clinical applicator prototype capable of heating brain tumors.

  9. miR-137 suppresses tumor growth of malignant melanoma by targeting aurora kinase A

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Xiao; Zhang, Haiping [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Lian, Shi [Department of Dermatology and Venereal Disease, Capital Medical University, Beijing 100069 (China); Zhu, Wei, E-mail: zhuwei_2020@163.com [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)

    2016-07-01

    As an oncogene, aurora kinase A (AURKA) is overexpressed in various types of human cancers. However, the expression and roles of AURKA in malignant melanoma are largely unknown. In this study, a miR-137-AURKA axis was revealed to regulate melanoma growth. We found a significant increase in levels of AURKA in melanoma. Both genetic knockdown and pharmacologic inhibition of AURKA decreased tumor cell growth in vitro and in vivo. Further found that miR-137 reduced AURKA expression through interaction with its 3′ untranslated region (3′UTR) and that miR-137 was negatively correlated with AURKA expression in melanoma specimens. Overexpression of miR-137 decreased cell proliferation and colony formation in vitro. Notably, re-expression of AURKA significantly rescued miR-137-mediated suppression of cell growth and clonality. In summary, these results reveal that miR-137 functions as a tumor suppressor by targeting AURKA, providing new insights into investigation of therapeutic strategies against malignant melanoma. -- Highlights: •First reported overexpression of AURKA in melanoma. •Targeting AURKA inhibits melanoma growth in vitro and in vivo. •Further found miR-137 suppressed cell growth by binding to AURKA 3′UTR. •Re-expression of AURKA rescued miR-137-mediated suppression. •miR-137-AURKA axis may be potential therapeutic targets of melanoma.

  10. HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples.

    Science.gov (United States)

    Moens, Lotte N J; Falk-Sörqvist, Elin; Ljungström, Viktor; Mattsson, Johanna; Sundström, Magnus; La Fleur, Linnéa; Mathot, Lucy; Micke, Patrick; Nilsson, Mats; Botling, Johan

    2015-11-01

    In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomolecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings. Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  11. Virotherapy targeting cyclin E overexpression in tumors with adenovirus-enhanced cancer-selective promoter.

    Science.gov (United States)

    Cheng, Pei-Hsin; Rao, Xiao-Mei; Duan, Xiaoxian; Li, Xiao-Feng; Egger, Michael E; McMasters, Kelly M; Zhou, H Sam

    2015-02-01

    Oncolytic virotherapy can selectively destroy cancer cells and is a potential approach in cancer treatment. A strategy to increase tumor-specific selectivity is to control the expression of a key regulatory viral gene with a tumor-specific promoter. We have previously found that cyclin E expression is augmented in cancer cells after adenovirus (Ad) infection. Thus, the cyclin E promoter that is further activated by Ad in cancer cells may have unique properties for enhancing oncolytic viral replication. We have shown that high levels of viral E1a gene expression are achieved in cancer cells infected with Ad-cycE, in which the endogenous Ad E1a promoter was replaced with the cyclin E promoter. Ad-cycE shows markedly selective oncolytic efficacy in vitro and destroys various types of cancer cells, including those resistant to ONYX-015/dl1520. Furthermore, Ad-cycE shows a strong capacity to repress A549 xenograft tumor growth in nude mice and significantly prolongs survival. This study suggests the potential of Ad-cycE in cancer therapy and indicates the advantages of using promoters that can be upregulated by virus infection in cancer cells in development of oncolytic viruses. Key messages: Cyclin E promoter activity is high in cancer cells and enhanced by adenovirus infection. Cyclin E promoter is used to control the E1a gene of a tumor-specific oncolytic adenovirus. Ad-cycE efficiently targets cancer cells and induces oncolysis. Ad-cycE significantly repressed xenograft tumor and prolonged survival.

  12. Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-PET in mice

    DEFF Research Database (Denmark)

    Willmann, Jürgen K; Cheng, Zhen; Davis, Corrine

    2008-01-01

    To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice....

  13. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.

    Directory of Open Access Journals (Sweden)

    Kristian Pietras

    2008-01-01

    Full Text Available BACKGROUND: Important support functions, including promotion of tumor growth, angiogenesis, and invasion, have been attributed to the different cell types populating the tumor stroma, i.e., endothelial cells, cancer-associated fibroblasts, pericytes, and infiltrating inflammatory cells. Fibroblasts have long been recognized inside carcinomas and are increasingly implicated as functional participants. The stroma is prominent in cervical carcinoma, and distinguishable from nonmalignant tissue, suggestive of altered (tumor-promoting functions. We postulated that pharmacological targeting of putative stromal support functions, in particular those of cancer-associated fibroblasts, could have therapeutic utility, and sought to assess the possibility in a pre-clinical setting. METHODS AND FINDINGS: We used a genetically engineered mouse model of cervical carcinogenesis to investigate platelet-derived growth factor (PDGF receptor signaling in cancer-associated fibroblasts and pericytes. Pharmacological blockade of PDGF receptor signaling with the clinically approved kinase inhibitor imatinib slowed progression of premalignant cervical lesions in this model, and impaired the growth of preexisting invasive carcinomas. Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2 and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. Treatment with neutralizing antibodies to the PDGF receptors recapitulated these effects. A ligand trap for the FGFs impaired the angiogenic phenotype similarly to imatinib. Thus PDGF ligands expressed by cancerous epithelia evidently stimulate PDGFR-expressing stroma to up-regulate FGFs, promoting angiogenesis and epithelial proliferation, elements of a multicellular signaling network that elicits functional capabilities in the tumor microenvironment

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

    Science.gov (United States)

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

    2017-09-01

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

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

    Science.gov (United States)

    Bao, Qi; Zhao, Yue; Niess, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl-Walter; Huss, Ralf; Nelson, Peter 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 associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host. PMID:22530882

  16. Development of an autonomous target tracking system

    Science.gov (United States)

    Gidda, Venkata Ramaiah

    In recent years, surveillance and border patrol have become one of the key research areas in UAV research. Increase in the computational capability of the computers and embedded electronics, coupled with compatibility of various commercial vision algorithms and commercial off the shelf (COTS) embedded electronics, and has further fuelled the research. The basic task in these applications is perception of environment through the available visual sensors like camera. Visual tracking, as the name implies, is tracking of objects using a camera. The process of autonomous target tracking starts with the selection of the target in a sequence of video frames transmitted from the on-board camera. We use an improved fast dynamic template matching algorithm coupled with Kalman Filter to track the selected target in consecutive video frames. The selected target is saved as a reference template. On the ground station computer, the reference template is overlaid on the live streaming video from the on-board system, starting from the upper left corner of the video frame. The template is slid pixel by pixel over the entire source image. A comparison of the pixels is performed between the template and source image. A confidence value R of the match is calculated at each pixel. Based on the method used to perform the template matching, the best match pixel location is found according to the highest or lowest confidence value R. The best match pixel location is communicated to the on-board gimbal controller over the wireless Xbee network. The software on the controller actuates the pan-tilt servos to continuously to hold the selected target at the center of the video frame. The complete system is a portable control system assembled from commercial off the shelf parts. The tracking system is tested on a target having several motion patterns.

  17. MiR-145 functions as a tumor suppressor targeting NUAK1 in human intrahepatic cholangiocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Xinkui; Sun, Daoyi; Chai, Hao; Shan, Wengang [Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province (China); Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province (China); Yu, Yue [Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province (China); Pu, Liyong [Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province (China); Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province (China); Cheng, Feng, E-mail: docchengfeng@njmu.edu.cn [Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province (China); Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province (China)

    2015-09-18

    The dysregulation of micro (mi)RNAs is associated with cancer development. The miRNA miR-145 is downregulated in intrahepatic cholangiocarcinoma (ICC); however, its precise role in tumor progression has not yet been elucidated. Novel (nua) kinase family (NUAK)1 functions as an oncogene in various cancers and is a putative target of miR-145 regulation. In this study, we investigated the regulation of NUAK1 by miR-145 in ICC. We found that miR-145 level was significantly decreased in ICC tissue and cell lines, which corresponded with an increase in NUAK1 expression. NUAK1 was found to be a direct target of miR-145 regulation. The overexpression of miR-145 in ICC cell lines inhibited proliferation, growth, and invasion by suppressing NUAK1 expression, which was associated with a decrease in Akt signaling and matrix metalloproteinase protein expression. Similar results were observed by inhibiting NUAK1 expression. These results demonstrate that miR-145 can prevent ICC progression by targeting NUAK1 and its downstream effectors, and can therefore be useful for clinical diagnosis and targeted therapy of ICC. - Highlights: • MiR-145 suppresses ICC proliferation and invasion abilities. • We demonstrated that miR-145 directly targets NUAK1 in ICC. • MiR-145 expression in ICC was associated with Akt signaling and MMPs expression.

  18. Recent Advances in Aptamers Targeting Immune System.

    Science.gov (United States)

    Hu, Piao-Ping

    2017-02-01

    The immune system plays important role in protecting the organism by recognizing non-self molecules from pathogen such as bacteria, parasitic worms, and viruses. When the balance of the host defense system is disturbed, immunodeficiency, autoimmunity, and inflammation occur. Nucleic acid aptamers are short single-stranded DNA (ssDNA) or RNA ligands that interact with complementary molecules with high specificity and affinity. Aptamers that target the molecules involved in immune system to modulate their function have great potential to be explored as new diagnostic and therapeutic agents for immune disorders. This review summarizes recent advances in the development of aptamers targeting immune system. The selection of aptamers with superior chemical and biological characteristics will facilitate their application in the diagnosis and treatment of immune disorders.

  19. Development and optimization of targeted radionuclide tumor therapy using folate based radiopharmaceuticals

    CERN Document Server

    Reber, Josefine Astrid

    The folate receptor (FR) has been used for a quarter of a century as a tumor-associated target for selective delivery of drugs and imaging agents to cancer cells. While several folic acid radioconjugates have been successfully employed for imaging purposes in (pre)clinical studies, a therapeutic application of folic acid radioconjugates has not yet reached the critical stage which would allow a clinical translation. Due to a substantial expression of the FR in the proximal tubule cells, radiofolates accumulate in the kidneys which are at risk of damage by particle-radiation. To improve this situation, we aimed to develop and evaluate strategies for the performance of FR-targeted radionuclide therapy by decreasing the renal uptake of radiofolates and thereby reducing potential nephrotoxic effects. Two different strategies were investigated. First, the combination of radiofolates with chemotherapeutic agents such as pemetrexed (PMX) and 5-fluorouracil (5-FU) and secondly, an approach based on radioiodinated fol...

  20. Radionuclide 131I-labeled multifunctional dendrimers for targeted SPECT imaging and radiotherapy of tumors

    Science.gov (United States)

    Zhu, Jingyi; Zhao, Lingzhou; Cheng, Yongjun; Xiong, Zhijuan; Tang, Yueqin; Shen, Mingwu; Zhao, Jinhua; Shi, Xiangyang

    2015-10-01

    We report the synthesis, characterization, and utilization of radioactive 131I-labeled multifunctional dendrimers for targeted single-photon emission computed tomography (SPECT) imaging and radiotherapy of tumors. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) were sequentially modified with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO) and folic acid (FA) linked with polyethylene glycol (PEG), followed by acetylation modification of the dendrimer remaining surface amines and labeling of radioactive iodine-131 (131I). The generated multifunctional 131I-G5.NHAc-HPAO-PEG-FA dendrimers were characterized via different methods. We show that prior to 131I labeling, the G5.NHAc-HPAO-PEG-FA dendrimers conjugated with approximately 9.4 HPAO moieties per dendrimer are noncytotoxic at a concentration up to 20 μM and are able to target cancer cells overexpressing FA receptors (FAR), thanks to the modified FA ligands. In the presence of a phenol group, radioactive 131I is able to be efficiently labeled onto the dendrimer platform with good stability and high radiochemical purity, and render the platform with an ability for targeted SPECT imaging and radiotherapy of an FAR-overexpressing xenografted tumor model in vivo. The designed strategy to use the facile dendrimer nanotechnology may be extended to develop various radioactive theranostic nanoplatforms for targeted SPECT imaging and radiotherapy of different types of cancer.We report the synthesis, characterization, and utilization of radioactive 131I-labeled multifunctional dendrimers for targeted single-photon emission computed tomography (SPECT) imaging and radiotherapy of tumors. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) were sequentially modified with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO) and folic acid (FA) linked with polyethylene glycol (PEG), followed by acetylation modification of the dendrimer remaining surface amines and

  1. An image-guided system for optimized volumetric treatment planning and execution for radiofrequency ablation of liver tumors

    International Nuclear Information System (INIS)

    Banovac, F.; Popa, T.; Cheng, P.; Cleary, K.; Abeledo, H.; Campos-Nanez, E.; Wood, B.J.

    2007-01-01

    Radiofrequency ablation of liver tumors is becoming an increasingly popular option for the treatment of cancer. However, the procedure has several technical challenges, mostly associated with precision targeting of the tumor and ensuring complete ablation coverage. In this paper we describe an image-guided system that we are developing for improved visualization and probe placement during these procedures. The system will include a pre-procedure optimization module and an intra-procedure guidance component. The system concept is explained and some preliminary results are given. While this system is designed for radiofrequency ablation of liver tumors, the methods are applicable to other organs and treatment methods. (orig.)

  2. Galectin-3 as a Potential Therapeutic Target in Tumors Arising from Malignant Endothelia

    Directory of Open Access Journals (Sweden)

    Kim D. Johnson

    2007-08-01

    Full Text Available Angiosarcoma (ASA in humans, hemangiosarcoma (HSA in dogs are deadly neoplastic diseases characterized by an aggressive growth of malignant cells with endothelial phenotype, widespread metastasis, poor response to chemotherapy. Galectin-3 (Gal-3, a p-galactoside-binding lectin implicated in tumor progression, metastasis, endothelial cell biology, angiogenesis, regulation of apoptosis, neoplastic cell response to cytotoxic drugs, has not been studied before in tumors arising from malignant endothelia. Here, we tested the hypothesis that Gal-3 could be widely expressed in human ASA, canine HSA, could play an important role in malignant endothelial cell biology. Immunohistochemical analysis demonstrated that 100% of the human ASA (10 of 10, canine HSA (17 of 17 samples analyzed expressed Gal-3. Two carbohydrate-based Gal-3 inhibitors, modified citrus pectin (MCP, lactulosyl-l-leucine (LL, caused a dose-dependent reduction of SVR murine ASA cell clonogenic survival through the inhibition of Gal-3 antiapoptotic function. Furthermore, both MCP, LL sensitized SVR cells to the cytotoxic drug doxorubicin to a degree sufficient to reduce the in vitro IC50 of doxorubicin by 10.7-fold, 3.64old, respectively. These results highlight the important role of Gal-3 in the biology of ASA, identify Gal-3 as a potential therapeutic target in tumors arising from malignant endothelial cells.

  3. CD47-CAR-T Cells Effectively Kill Target Cancer Cells and Block Pancreatic Tumor Growth.

    Science.gov (United States)

    Golubovskaya, Vita; Berahovich, Robert; Zhou, Hua; Xu, Shirley; Harto, Hizkia; Li, Le; Chao, Cheng-Chi; Mao, Mike Ming; Wu, Lijun

    2017-10-21

    CD47 is a glycoprotein of the immunoglobulin superfamily that is often overexpressed in different types of hematological and solid cancer tumors and plays important role in blocking phagocytosis, increased tumor survival, metastasis and angiogenesis. In the present report, we designed CAR (chimeric antigen receptor)-T cells that bind CD47 antigen. We used ScFv (single chain variable fragment) from mouse CD47 antibody to generate CD47-CAR-T cells for targeting different cancer cell lines. CD47-CAR-T cells effectively killed ovarian, pancreatic and other cancer cells and produced high level of cytokines that correlated with expression of CD47 antigen. In addition, CD47-CAR-T cells significantly blocked BxPC3 pancreatic xenograft tumor growth after intratumoral injection into NSG mice. Moreover, we humanized mouse CD47 ScFv and showed that it effectively bound CD47 antigen. The humanized CD47-CAR-T cells also specifically killed ovarian, pancreatic, and cervical cancer cell lines and produced IL-2 that correlated with expression of CD47. Thus, CD47-CAR-T cells can be used as a novel cellular therapeutic agent for treating different types of cancer.

  4. Tumor Endothelial Cell-Specific Drug Delivery System Using Apelin-Conjugated Liposomes

    Science.gov (United States)

    Kawahara, Hiroki; Naito, Hisamichi; Takara, Kazuhiro; Wakabayashi, Taku; Kidoya, Hiroyasu; Takakura, Nobuyuki

    2013-01-01

    Background A drug delivery system specifically targeting endothelial cells (ECs) in tumors is required to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors. Methods and Results Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe)-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13) were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs. Conclusions ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors. PMID:23799018

  5. Tumor endothelial cell-specific drug delivery system using apelin-conjugated liposomes.

    Directory of Open Access Journals (Sweden)

    Hiroki Kawahara

    Full Text Available BACKGROUND: A drug delivery system specifically targeting endothelial cells (ECs in tumors is required to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors. METHODS AND RESULTS: Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13 were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs. CONCLUSIONS: ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors.

  6. miR-195 Inhibits Tumor Progression by Targeting RPS6KB1 in Human Prostate Cancer.

    Science.gov (United States)

    Cai, Chao; Chen, Qing-Biao; Han, Zhao-Dong; Zhang, Yan-Qiong; He, Hui-Chan; Chen, Jia-Hong; Chen, Yan-Ru; Yang, Sheng-Bang; Wu, Yong-Ding; Zeng, Yan-Ru; Qin, Guo-Qiang; Liang, Yu-Xiang; Dai, Qi-Shan; Jiang, Fu-Neng; Wu, Shu-lin; Zeng, Guo-Hua; Zhong, Wei-De; Wu, Chin-Lee

    2015-11-01

    To investigate the involvement of hsa-miRNA-195-5p (miR-195) in progression and prognosis of human prostate cancer. qRT-PCR was performed to detect miR-195 expression in both prostate cancer cell lines and clinical tissue samples. Its clinical significance was statistically analyzed. The roles of miR-195 and its candidate target gene, ribosomal protein S6 kinase, 70 kDa, polypeptide 1 (RPS6KB1) in prostate cancer progression were confirmed on the basis of both in vitro and in vivo systems. miR-195 downregulation in prostate cancer tissues was significantly associated with high Gleason score (P = 0.001), positive metastasis failure (P biochemical recurrence (BCR, P cancer patients (P = 0.022). Then, we confirmed the tumor suppressive role of miR-195 through prostate cancer cell invasion, migration, and apoptosis assays in vitro, along with tumor xenograft growth, angiogenesis, and invasion in vivo according to both gain-of-function and loss-of-function experiments. In addition, RPS6KB1 was identified as a novel direct target of miR-195 through proteomic expression profiling combined with bioinformatic target prediction and luciferase reporter assay. Moreover, the reexpression and knockdown of RPS6KB1 could respectively rescue and imitate the effects induced by miR-195. Importantly, RPS6KB1 expression was closely correlated with aggressive progression and poor prognosis in prostate cancer patients as opposed to miR-195. Furthermore, we identified MMP-9, VEGF, BAD, and E-cadherin as the downstream effectors of miR-195-RPS6KB1 axis. The newly identified miR-195-RPS6KB1 axis partially illustrates the molecular mechanism of prostate cancer progression and represents a novel potential therapeutic target for prostate cancer treatment. ©2015 American Association for Cancer Research.

  7. Solute carrier transporters: potential targets for digestive system neoplasms

    Directory of Open Access Journals (Sweden)

    Xie J

    2018-01-01

    application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms. Keywords: solute carrier, digestive system neoplasms, carcinogenesis, tumor progression, chemoresistance, small molecule modulators

  8. Advantage of lutetium-177 versus radioiodine immunoconjugate in targeted radionuclide therapy of b-cell tumors.

    Science.gov (United States)

    Repetto-Llamazares, Ada; Abbas, Nasir; Bruland, Øyvind S; Dahle, Jostein; Larsen, Roy H

    2014-07-01

    We herein report a comparison of the radiolabels 177Lu and 125I bound to the monoclonal antibody HH1 that targets the CD37 antigen expressed on non-Hodgkin B-cell lymphomas. Mixtures of 177Lu and 125I-labeled HH1 antibody were co-injected into nude mice carrying Ramos xenografts and the biodistribution using the paired label format allowing tracer comparisons in each individual mouse. Products of the two radionuclides had very similar immunoractivity in vitro but showed different properties in vivo. Both products had relevant stability in blood and most normal tissues in nude mice carrying subcutaneous Ramos xenografts. However, both the tumor uptake and retention were significantly higher for 177Lu vs. 125I labeled HH1. The tumor to normal tissue ratios were several-fold improved for 177Lu compared to radioiodine labeled antibodies. The data presented herein support the evaluation of CD37 as a target for clinical 177Lu-based radioimmunotherapy against b-cell malignancies. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. Evaluation of radioiodinated curcumin for its potential as a tumor-targeting radiopharmaceutical

    International Nuclear Information System (INIS)

    Kumar, Chandan; Subramanian, Suresh; Samuel, Grace

    2016-01-01

    Curcumin, a component of the spice turmeric has widely reported anticancer properties in several types of cancer. The differential accumulation and mechanism of its action in normal and cancer cells have proven its potential in targeting tumor. Therefore, it was of interest to label curcumin with a suitable radionuclide and explore its potential for use in nuclear medicine. Curcumin was labeled with 125 I by iodogen method. The radiochemical purity was analyzed by paper electrophoresis and high-performance liquid chromatography (HPLC) method. Cell binding was carried out in murine lymphoma and melanoma cell lines. Bioevaluation and pharmacokinetics of radioiodinated curcumin was carried out in lymphoma-bearing mice for various time points (1, 3, 24, and 48 h). The efficiency of labeling was >75% and the radiochemical purity postpurification was >95%. The maximum uptake (∼7% at 2 h, 37°C using 5 X 10 5 cells) was observed in EL4 cells. Significant tumor uptake in lymphoma-bearing mice was observed at 180 min (3.3 ± 0.76% ID/g). In addition, pharmacokinetics of radioiodinated curcumin is fast, with the majority of the preparation out of the bloodstream in 3 h. The results of these studies suggest that curcumin has the potential for targeting lymphomas, which may be used as diagnostic/therapeutic agent by labeling with other radionuclides. (author)

  10. Chrysin inhibited tumor glycolysis and induced apoptosis in hepatocellular carcinoma by targeting hexokinase-2.

    Science.gov (United States)

    Xu, Dong; Jin, Junzhe; Yu, Hao; Zhao, Zheming; Ma, Dongyan; Zhang, Chundong; Jiang, Honglei

    2017-03-20

    Hexokinase-2(HK-2) plays dual roles in glucose metabolism and mediation of cell apoptosis, making it an attractive target for cancer therapy. Chrysin is a natural flavone found in plant extracts which are widely used as herb medicine in China. In the present study, we investigated the antitumor activity of chrysin against hepatocellular carcinoma (HCC) and the role of HK-2 played for chrysin to exert its function. The expression of HK-2 in HCC cell line and tumor tissue was examined by western blotting and immunohistochemistry staining. The activities of chrysin against HCC cell proliferation and tumor glycolysis were investigated. Chrysin-induced apoptosis was analyzed by flow cytometry. The effect of chrysin on HK-2 expression and the underlying mechanisms by which induced HCC cell apoptosis were studied. In HK-2 exogenous overexpression cell, the changes of chrysin-induced cell apoptosis and glycolysis suppression were investigated. HCC cell xenograft model was used to confirm the antitumor activity of chrysin in vivo and the effect on HK-2 was tested in chrysin-treated tumor tissue. In contrast with normal cell lines and tissue, HK-2 expression was substantially elevated in the majority of tested HCC cell lines and tumor tissue. Owing to the decrease of HK-2 expression, glucose uptake and lactate production in HCC cells were substantially inhibited after exposure to chrysin. After chrysin treatment, HK-2 which combined with VDAC-1 on mitochondria was significantly declined, resulting in the transfer of Bax from cytoplasm to mitochondria and induction of cell apoptosis. Chrysin-mediated cell apoptosis and glycolysis suppression were dramatically impaired in HK-2 exogenous overexpression cells. Tumor growth in HCC xenograft models was significantly restrained after chrysin treatment and significant decrease of HK-2 expression was observed in chrysin-treated tumor tissue. Through suppressing glycolysis and inducing apoptosis in HCC, chrysin, or its derivative has

  11. A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Claudia Gaspar

    2009-07-01

    Full Text Available Germline mutations in the adenomatous polyposis coli (APC gene are responsible for familial adenomatous polyposis (FAP, an autosomal dominant hereditary predisposition to the development of multiple colorectal adenomas and of a broad spectrum of extra-intestinal tumors. Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers. Notwithstanding its multifunctional nature, the main tumor suppressing activity of the APC gene resides in its ability to regulate Wnt/beta-catenin signaling. Notably, genotype-phenotype correlations have been established at the APC gene between the length and stability of the truncated proteins encoded by different mutant alleles, the corresponding levels of Wnt/beta-catenin signaling activity they encode for, and the incidence and distribution of intestinal and extra-intestinal tumors. Here, we report a novel mouse model, Apc1572T, obtained by targeting a truncated mutation at codon 1572 in the endogenous Apc gene. This hypomorphic mutant allele results in intermediate levels of Wnt/beta-catenin signaling activation when compared with other Apc mutations associated with multifocal intestinal tumors. Notwithstanding the constitutive nature of the mutation, Apc(+/1572T mice have no predisposition to intestinal cancer but develop multifocal mammary adenocarcinomas and subsequent pulmonary metastases in both genders. The histology of the Apc1572T primary mammary tumours is highly heterogeneous with luminal, myoepithelial, and squamous lineages and is reminiscent of metaplastic carcinoma of the breast in humans. The striking phenotype of Apc(+/1572T mice suggests that specific dosages of Wnt/beta-catenin signaling activity differentially affect tissue homeostasis and initiate tumorigenesis in an organ-specific fashion.

  12. Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

    Directory of Open Access Journals (Sweden)

    Erbao Chen

    2018-02-01

    Full Text Available Background/Aims: Breast cancer is a common cause of cancer mortality throughout the world. The cross-talk between cancer cells and interstitial cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. CXC is one of four chemokine families involved in mediating survival, angiogenesis, and immunosensitization by chemoattracting leukocytes, and it incentivizes tumor cell growth, invasion and metastasis in the tumor microenvironment. However, the differential expression profiles and prognostic values of these chemokines remains to be elucidated. Methods: In this study, we compared transcriptional CXC chemokines and survival data of patients with breast carcinoma (BC using the ONCOMINE dataset, Kaplan-Meier Plotter, TCGA and cBioPortal. Results: We discovered increased mRNA levels for CXCL8/10/11/16/17, whereas mRNA expression of CXCL1/2/3/4/5/6/7/12/14 was lower in BC patients compared to non-tumor tissues. Kaplan-Meier plots revealed that high mRNA levels of CXCL1/2/3/4/5/6/7/12/14 correlate with relapse-free survival (RFS in all types of BC patients. Conversely, high CXCL8/10/11 predicted worse RFS in BC patients. Significantly, high transcription levels of CXCL9/12/13/14 conferred an overall survival (OS advantage in BC patients, while high levels of CXCL8 demonstrated shorter OS in all BC sufferers. Conclusions: Integrative bioinformatics analysis suggests that CXCL8/12/14 are potential suitable targets for precision therapy in BC patients compared to other CXC chemokines.

  13. Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis.

    Science.gov (United States)

    Chen, Erbao; Qin, Xuan; Peng, Ke; Xu, Xiaojing; Li, Wei; Cheng, Xi; Tang, Cheng; Cui, Yuehong; Wang, Zhiming; Liu, Tianshu

    2018-02-23

    Breast cancer is a common cause of cancer mortality throughout the world. The cross-talk between cancer cells and interstitial cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. CXC is one of four chemokine families involved in mediating survival, angiogenesis, and immunosensitization by chemoattracting leukocytes, and it incentivizes tumor cell growth, invasion and metastasis in the tumor microenvironment. However, the differential expression profiles and prognostic values of these chemokines remains to be elucidated. In this study, we compared transcriptional CXC chemokines and survival data of patients with breast carcinoma (BC) using the ONCOMINE dataset, Kaplan-Meier Plotter, TCGA and cBioPortal. We discovered increased mRNA levels for CXCL8/10/11/16/17, whereas mRNA expression of CXCL1/2/3/4/5/6/7/12/14 was lower in BC patients compared to non-tumor tissues. Kaplan-Meier plots revealed that high mRNA levels of CXCL1/2/3/4/5/6/7/12/14 correlate with relapse-free survival (RFS) in all types of BC patients. Conversely, high CXCL8/10/11 predicted worse RFS in BC patients. Significantly, high transcription levels of CXCL9/12/13/14 conferred an overall survival (OS) advantage in BC patients, while high levels of CXCL8 demonstrated shorter OS in all BC sufferers. Integrative bioinformatics analysis suggests that CXCL8/12/14 are potential suitable targets for precision therapy in BC patients compared to other CXC chemokines. © 2018 The Author(s). Published by S. Karger AG, Basel.

  14. The distribution of BRAF gene fusions in solid tumors and response to targeted therapy.

    Science.gov (United States)

    Ross, Jeffrey S; Wang, Kai; Chmielecki, Juliann; Gay, Laurie; Johnson, Adrienne; Chudnovsky, Jacob; Yelensky, Roman; Lipson, Doron; Ali, Siraj M; Elvin, Julia A; Vergilio, Jo-Anne; Roels, Steven; Miller, Vincent A; Nakamura, Brooke N; Gray, Adam; Wong, Michael K; Stephens, Philip J

    2016-02-15

    Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 (0.3%) of 20,573 tumors, across 12 distinct tumor types, including 20 novel BRAF fusions. These comprised 29 unique 5' fusion partners, of which 31% (9) were known and 69% (20) were novel. BRAF fusions included 3% (14/531) of melanomas; 2% (15/701) of gliomas; 1.0% (3/294) of thyroid cancers; 0.3% (3/1,062) pancreatic carcinomas; 0.2% (8/4,013) nonsmall-cell lung cancers and 0.2% (4/2,154) of colorectal cancers, and were enriched in pilocytic (30%) vs. nonpilocytic gliomas (1%; p < 0.0001), Spitzoid (75%) vs. nonSpitzoid melanomas (1%; p = 0.0001), acinar (67%) vs. nonacinar pancreatic cancers (<1%; p < 0.0001) and papillary (3%) vs. nonpapillary thyroid cancers (0%; p < 0.03). Clinical responses to trametinib and sorafenib are presented. In conclusion, BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms, but enriched in Spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers. © 2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  15. Conceptual design study of IFMIF target system

    International Nuclear Information System (INIS)

    Kato, Y.; Nakamura, H.; Ida, M.; Maekawa, H.; Katsuta, H.; Hua, T.; Cevolani, S.

    1997-01-01

    IFMIF-CDA (International Fusion Materials Irradiation Facility - Conceptual Design Activity) had been carried out during 1995 and 1996, under the auspices of the IEA. The mission of this facility is to provide an accelerator based deuterium-lithium (D-Li) neutron source to test the candidate materials of radiation - resistant and low - activation materials up to about a full lifetime of anticipated use in fusion energy reactors. The neutrons of about 14 MeV are obtained by the stripping reaction of the deuteron of Max. 40 MeV with target lithium. Total deuteron beam current is about 250 mA and beam footprint is 20 cm x 5 cm on the free surface of lithium jet. In this report general characteristics of the target lithium system and the results of thermal and flow analysis for the target lithium jet are described. (author)

  16. Elimination of Tumor Cells Using Folate Receptor Targeting by Antibody-Conjugated, Gold-Coated Magnetite Nanoparticles in a Murine Breast Cancer Model

    Directory of Open Access Journals (Sweden)

    Evan S. Krystofiak

    2012-01-01

    Full Text Available Background. The chemotherapeutic treatment of cancer suffers from poor specificity for targeting the tumor cells and often results in adverse effects such as systemic toxicity, damage to nontarget tissues, and development of drug-resistant tumors in patients. Increasingly, drug nanocarriers have been explored as a way of lessening or overcoming these problems. In this study, antibody-conjugated Au-coated magnetite nanoparticles, in conjunction with inductive heating produced by exposure to an oscillating magnetic field (OMF, were evaluated for their effects on the viability of tumor cells in a murine model of breast cancer. Treatment effects were evaluated by light microscopy and SEM. Results. 4T1 mammary epithelial carcinoma cells overexpressing the folate receptor were targeted with an anti-folate receptor primary antibody, followed by labeling with secondary antibody-conjugated Au-coated magnetite nanoparticles. In the absence of OMF exposure, nanoparticle labeling had no effect on 4T1 cell viability. However, following OMF treatment, many of the labeled 4T1 cells showed extensive membrane damage by SEM analysis, and dramatically reduced viability as assessed using a live/dead staining assay. Conclusions. These results demonstrate that Au-coated magnetite targeted to tumor cells through binding to an overexpressed surface receptor, in the presence of an OMF, can lead to tumor cell death.

  17. Tumor Acidity/NIR Controlled Interaction of Transformable Nanoparticle with Biological Systems for Cancer Therapy.

    Science.gov (United States)

    Li, Dongdong; Ma, Yinchu; Du, Jinzhi; Tao, Wei; Du, Xiaojiao; Yang, Xianzhu; Wang, Jun

    2017-05-10

    Precisely controlling the interaction of nanoparticles with biological systems (nanobio interactions) from the injection site to biological targets shows great potential for biomedical applications. Inspired by the ability of nanoparticles to alter their physicochemical properties according to different stimuli, we explored the tumor acidity and near-infrared (NIR) light activated transformable nanoparticle DA TAT-NP IR&DOX . This nanoparticle consists of a tumor acidity-activated TAT [the TAT lysine residues' amines was modified with 2,3-dimethylmaleic anhydride (DA)], a flexible chain polyphosphoester core coencapsulated a NIR dye IR-780, and DOX (doxorubicin). The physicochemical properties of the nanoparticle can be controlled in a stepwise fashion using tumor acidity and NIR light, resulting in adjustable nanobio interactions. The resulting transformable nanoparticle DA TAT-NP IR&DOX efficiently avoids the interaction with mononuclear phagocyte system (MPS) ("stealth" state) due to the masking of the TAT peptide during blood circulation. Once it has accumulated in the tumor tissues, DA TAT-NP IR&DOX is reactivated by tumor acidity and transformed into the "recognize" state in order to promote interaction with tumor cells and enhance cellular internalization. Then, this nanoparticle is transformed into "attack" state under NIR irradiation, achieving the supersensitive DOX release from the flexible chain polyphosphoester core in order to increase the DOX-DNA interaction. This concept provides new avenues for the creation of transformable drug delivery systems that have the ability to control nanobio interactions.

  18. A Context Dependent Automatic Target Recognition System

    Science.gov (United States)

    Kim, J. H.; Payton, D. W.; Olin, K. E.; Tseng, D. Y.

    1984-06-01

    This paper describes a new approach to automatic target recognizer (ATR) development utilizing artificial intelligent techniques. The ATR system exploits contextual information in its detection and classification processes to provide a high degree of robustness and adaptability. In the system, knowledge about domain objects and their contextual relationships is encoded in frames, separating it from low level image processing algorithms. This knowledge-based system demonstrates an improvement over the conventional statistical approach through the exploitation of diverse forms of knowledge in its decision-making process.

  19. Fatty acid synthase is a key target in multiple essential tumor functions of prostate cancer: uptake of radiolabeled acetate as a predictor of the targeted therapy outcome.

    Directory of Open Access Journals (Sweden)

    Yukie Yoshii

    Full Text Available Fatty acid synthase (FASN expression is elevated in several cancers, and this over-expression is associated with poor prognosis. Inhibitors of FASN, such as orlistat, reportedly show antitumor effects against cancers that over-express FASN, making FASN a promising therapeutic target. However, large variations in FASN expression levels in individual tumors have been observed, and methods to predict FASN-targeted therapy outcome before treatment are required to avoid unnecessary treatment. In addition, how FASN inhibition affects tumor progression remains unclear. Here, we showed the method to predict FASN-targeted therapy outcome using radiolabeled acetate uptake and presented mechanisms of FASN inhibition with human prostate cancer cell lines, to provide the treatment strategy of FASN-targeted therapy. We revealed that tumor uptake of radiolabeled acetate reflected the FASN expression levels and sensitivity to FASN-targeted therapy with orlistat in vitro and in vivo. FASN-targeted therapy was noticeably effective against tumors with high FASN expression, which was indicated by high acetate uptake. To examine mechanisms, we established FASN knockdown prostate cancer cells by transduction of short-hairpin RNA against FASN and investigated the characteristics by analyses on morphology and cell behavior and microarray-based gene expression profiling. FASN inhibition not only suppressed cell proliferation but prevented pseudopodia formation and suppressed cell adhesion, migration, and invasion. FASN inhibition also suppressed genes involved in production of intracellular second messenger arachidonic acid and androgen hormones, both of which promote tumor progression. Collectively, our data demonstrated that uptake of radiolabeled acetate is a useful predictor of FASN-targeted therapy outcome. This suggests that [1-(11C]acetate positron emission tomography (PET could be a powerful tool to accomplish personalized FASN-targeted therapy by non

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Tumor targeting efficiency of bare nanoparticles does not mean the efficacy of loaded anticancer drugs: importance of radionuclide imaging for optimization of highly selective tumor targeting polymeric nanoparticles with or without drug.

    Science.gov (United States)

    Lee, Beom Suk; Park, Kyeongsoon; Park, Sangjin; Kim, Gui Chul; Kim, Hyo Jung; Lee, Sangjoo; Kil, Heeseup; Oh, Seung Jun; Chi, Daeyoon; Kim, Kwangmeyung; Choi, Kuiwon; Kwon, Ick Chan; Kim, Sang Yoon

    2010-10-15

    The better understanding of polymeric nanoparticles as a drug delivery carrier is a decisive factor to get more efficient therapeutic response in vivo. Here, we report the non-invasive imaging of bare polymeric nanoparticles and drug-loaded polymeric nanoparticles to evaluate biodistribution in tumor bearing mice. To make nano-sized drug delivery carrier, glycol chitosan was modified with different degrees of hydrophobic N-acetyl histidine (NAcHis-GC-1, -2, and -3). The biodistribution of polymeric nanoparticles and drug was confirmed by using gamma camera with (131)I-labeled NAcHis-GC and (131)I-labeled doxorubicin (DOX) and by using in vivo live animal imaging with near-infrared fluorescence Cy5.5-labeled NAcHis-GC. Among bare nanoparticles, NAcHis-GC3 (7.8% NAcHis content) showed much higher tumor targeting efficiency than NAcHis-GC1 (3.3% NAcHis content) and NAcHis-GC2 (6.8% NAcHis content). In contrast, for drug-loaded nanoparticles, DOX-NAcHis-GC1 displayed two-fold higher tumor targeting property than DOX-NAcHis-GC3. These data imply that the biodistribution and tumor targeting efficiency between bare and drug-loaded nanoparticles may be greatly different. Therapeutic responses for NAcHis-GC nanoparticles after drug loading were also evaluated. In xenograft animal model, we could find out that DOX-NAcHis-GC1 with higher tumor targeting of DOX has more excellent therapeutic effect than DOX-NAcHis-GC3 and free DOX. These results mean that the hydrophobic core stability might be a critical factor for tumor targeting efficiency of nanoparticles. The present study indicates that by using molecular imaging, we can select more appropriate nanoparticles with the highest tumor targeting properties, leading to exerting more excellent therapeutic results in cancer therapy. Copyright © 2010 Elsevier B.V. All rights reserved.

  2. The role of the immune system in neurofibromatosis type 1-associated nervous system tumors.

    Science.gov (United States)

    Karmakar, Souvik; Reilly, Karlyne M

    2017-01-01

    With the recent development of new anticancer therapies targeting the immune system, it is important to understand which immune cell types and cytokines play critical roles in suppressing or promoting tumorigenesis. The role of mast cells in promoting neurofibroma growth in neurofibromatosis type 1 (NF1) patients was hypothesized decades ago. More recent experiments in mouse models have demonstrated the causal role of mast cells in neurofibroma development and of microglia in optic pathway glioma development. We review here what is known about the role of NF1 mutation in immune cell function and the role of immune cells in promoting tumorigenesis in NF1. We also review the therapies targeting immune cell pathways and their promise in NF1 tumors.

  3. Evaluation of potential internal target volume of liver tumors using cine-MRI

    Energy Technology Data Exchange (ETDEWEB)

    Akino, Yuichi, E-mail: akino@radonc.med.osaka-u.ac.jp [Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan and Miyakojima IGRT Clinic, Miyakojima-ku, Osaka 5340021 (Japan); Oh, Ryoong-Jin; Masai, Norihisa; Shiomi, Hiroya; Inoue, Toshihiko [Miyakojima IGRT Clinic, Miyakojima-ku, Osaka 5340021 (Japan)

    2014-11-01

    Purpose: Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. Methods: The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquired for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas–Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV {sub Potential}). The concordance between ITV {sub Potential} and ITV estimated with 4DCT (ITV {sub 4DCT}) was evaluated using the Dice’s similarity coefficient (DSC). Results

  4. Evaluation of potential internal target volume of liver tumors using cine-MRI.

    Science.gov (United States)

    Akino, Yuichi; Oh, Ryoong-Jin; Masai, Norihisa; Shiomi, Hiroya; Inoue, Toshihiko

    2014-11-01

    Four-dimensional computed tomography (4DCT) is widely used for evaluating moving tumors, including lung and liver cancers. For patients with unstable respiration, however, the 4DCT may not visualize tumor motion properly. High-speed magnetic resonance imaging (MRI) sequences (cine-MRI) permit direct visualization of respiratory motion of liver tumors without considering radiation dose exposure to patients. Here, the authors demonstrated a technique for evaluating internal target volume (ITV) with consideration of respiratory variation using cine-MRI. The authors retrospectively evaluated six patients who received stereotactic body radiotherapy (SBRT) to hepatocellular carcinoma. Before acquiring planning CT, sagittal and coronal cine-MRI images were acquired for 30 s with a frame rate of 2 frames/s. The patient immobilization was conducted under the same condition as SBRT. Planning CT images were then acquired within 15 min from cine-MRI image acquisitions, followed by a 4DCT scan. To calculate tumor motion, the motion vectors between two continuous frames of cine-MRI images were calculated for each frame using the pyramidal Lucas-Kanade method. The target contour was delineated on one frame, and each vertex of the contour was shifted and copied onto the following frame using neighboring motion vectors. 3D trajectory data were generated with the centroid of the contours on sagittal and coronal images. To evaluate the accuracy of the tracking method, the motion of clearly visible blood vessel was analyzed with the motion tracking and manual detection techniques. The target volume delineated on the 50% (end-exhale) phase of 4DCT was translated with the trajectory data, and the distribution of the occupancy probability of target volume was calculated as potential ITV (ITV Potential). The concordance between ITV Potential and ITV estimated with 4DCT (ITV 4DCT) was evaluated using the Dice's similarity coefficient (DSC). The distance between blood vessel positions

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

    International Nuclear Information System (INIS)

    Park, Ji-Ae; Lee, Yong Jin; Ko, In Ok; Kim, Tae-Jeong; Chang, Yongmin; Lim, Sang Moo; Kim, Kyeong Min; Kim, Jung Young

    2014-01-01

    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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-12-12

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

  7. Enhancing Tumor Detection in IR-UWB Breast Cancer System.

    Science.gov (United States)

    Fouad, Sara; Ghoname, Reda; Elmahdy, Abd Elmonem; Zekry, Abd Elhalim

    2017-01-01

    An ultra-wideband (UWB) microwave system for breast cancer detection is presented. The proposed system includes monocycle pulse generator, antipodal Vivaldi antenna, breast model, and calibration algorithm for tumor detection. Firstly, our pulse generator employs transmission gate in glitch generator to achieve several advantages such as low power consumption and low ringing level. Secondly, the antipodal Vivaldi antenna is designed assuming FR4 dielectric substrate material, and developed antenna element (80 × 80 mm 2 ) features a -10 dB return loss and bandwidth ranges from 2.3 GHz to more than 11 GHz. Thirdly, the phantom breast can be modeled as a layer of skin, fat, and then tumor is inserted in this layer. Finally, subtract and add algorithm (SAD) is used as a calibration algorithm in tumor detection system. The proposed system suggested that horizontal antenna position with 90° between transmitting and receiving antennas is localized as a suitable antenna position with different rotating location and a 0.5 cm near to phantom. The mean advantages of this localization and tracking position around breast is a high received power signal approximately around mv as a higher recognized signal in tumor detection. Using our proposed system we can detect tumor in 5 mm diameter.

  8. A tri-modality image fusion method for target delineation of brain tumors in radiotherapy.

    Directory of Open Access Journals (Sweden)

    Lu Guo

    Full Text Available To develop a tri-modality image fusion method for better target delineation in image-guided radiotherapy for patients with brain tumors.A new method of tri-modality image fusion was developed, which can fuse and display all image sets in one panel and one operation. And a feasibility study in gross tumor volume (GTV delineation using data from three patients with brain tumors was conducted, which included images of simulation CT, MRI, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET examinations before radiotherapy. Tri-modality image fusion was implemented after image registrations of CT+PET and CT+MRI, and the transparency weight of each modality could be adjusted and set by users. Three radiation oncologists delineated GTVs for all patients using dual-modality (MRI/CT and tri-modality (MRI/CT/PET image fusion respectively. Inter-observer variation was assessed by the coefficient of variation (COV, the average distance between surface and centroid (ADSC, and the local standard deviation (SDlocal. Analysis of COV was also performed to evaluate intra-observer volume variation.The inter-observer variation analysis showed that, the mean COV was 0.14(± 0.09 and 0.07(± 0.01 for dual-modality and tri-modality respectively; the standard deviation of ADSC was significantly reduced (p<0.05 with tri-modality; SDlocal averaged over median GTV surface was reduced in patient 2 (from 0.57 cm to 0.39 cm and patient 3 (from 0.42 cm to 0.36 cm with the new method. The intra-observer volume variation was also significantly reduced (p = 0.00 with the tri-modality method as compared with using the dual-modality method.With the new tri-modality image fusion method smaller inter- and intra-observer variation in GTV definition for the brain tumors can be achieved, which improves the consistency and accuracy for target delineation in individualized radiotherapy.

  9. Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma.

    Science.gov (United States)

    Liang, Chao; Li, Fangfei; Wang, Luyao; Zhang, Zong-Kang; Wang, Chao; He, Bing; Li, Jie; Chen, Zhihao; Shaikh, Atik Badshah; Liu, Jin; Wu, Xiaohao; Peng, Songlin; Dang, Lei; Guo, Baosheng; He, Xiaojuan; Au, D W T; Lu, Cheng; Zhu, Hailong; Zhang, Bao-Ting; Lu, Aiping; Zhang, Ge

    2017-12-01

    Osteosarcoma (OS) is a highly aggressive pediatric cancer, characterized by frequent lung metastasis and pathologic bone destruction. Vascular endothelial growth factor A (VEGFA), highly expressed in OS, not only contributes to angiogenesis within the tumor microenvironment via paracrine stimulation of vascular endothelial cells, but also acts as an autocrine survival factor for tumor cell themselves, thus making it a promising therapeutic target for OS. CRISPR/Cas9 is a versatile genome editing technology and holds tremendous promise for cancer treatment. However, a major bottleneck to achieve the therapeutic potential of the CRISPR/Cas9 is the lack of in vivo tumor-targeted delivery systems. Here, we screened an OS cell-specific aptamer (LC09) and developed a LC09-functionalized PEG-PEI-Cholesterol (PPC) lipopolymer encapsulating CRISPR/Cas9 plasmids encoding VEGFA gRNA and Cas9. Our results demonstrated that LC09 facilitated selective distribution of CRISPR/Cas9 in both orthotopic OS and lung metastasis, leading to effective VEGFA genome editing in tumor, decreased VEGFA expression and secretion, inhibited orthotopic OS malignancy and lung metastasis, as well as reduced angiogenesis and bone lesion with no detectable toxicity. The delivery system simultaneously restrained autocrine and paracrine VEGFA signaling in tumor cells and could facilitate translating CRISPR-Cas9 into clinical cancer treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Moving target acquisition and tracking system

    Science.gov (United States)

    Klein, Michael D.; Budenske, John; Richardson, Russell D.

    1990-09-01

    Imaging Systems have traditionally required large development cycles to transition from non-real-time implementations on general purpose computers to final real-time system prototypes using custom hardware. This paper presents a flexible realtime prototyping approach for the Conceptual Definition, Demonstration and Validation phases of development for imaging system applications such as forward observe, perimeterdefense, or "mobile barrier." A target acquisition and tracking system that has utilized this approach will be discussed and tracking system that has utilized this approach will be discussed and used to compare hardware, software, resources and schedule factors to other imaging system development programs. The testbed is shown to maintain a high degree of algorithm flexibility allowing field test experiences to be rapidly incorporated into the system. The entire system is programmable using high order languages to minimize software costs and enhance maintainability. This system was developed and integrated into a mobile lab for field testing. During real-time testing the system was upgraded and modified to provide high detection performance with low false alarm rates. This approach has led to a more complete understanding of the problem being addressed and has positioned this system closer to its final product form.

  11. Polymeric micelles of zinc protoporphyrin for tumor targeted delivery based on EPR effect and singlet oxygen generation.

    Science.gov (United States)

    Iyer, Arun K; Greish, Khaled; Seki, Takahiro; Okazaki, Shoko; Fang, Jun; Takeshita, Keizo; Maeda, Hiroshi

    2007-01-01

    Polymeric micelles of zinc protoporphyrin (ZnPP) with water soluble biocompatible and amphiphilic polymer, polyethylene glycol (PEG) demonstrated unique characteristics to target tumor tissues selectively based on the enhanced permeability and retention (EPR) effect. The micellar macromolecular drug of ZnPP (SMA-ZnPP and PEG-ZnPP) previously showed notable anticancer activity as a consequence of selective tumor targeting ability and its potent HO-1 inhibitory potential, resulting in suppressed biliverdin/bilirubin production in tumors thereby leading to oxystress induced tumor cell killing. Furthermore, recent findings also showed that ZnPP efficiently generated reactive singlet oxygen under illumination of visible light, laser, or xenon light source, which could augment its oxystress induced cell killing abilities. In the present paper, we report the synergistic effects of light induced photosensitizing capabilities and HO-1 inhibitory potentials of these unique micelles when tested in vitro and in vivo on tumor models under localized, mild illumination conditions using a tungsten-xenon light source. The results indicate that these water soluble polymeric micelles of ZnPP portend to be promising candidates for targeted chemotherapy as well as photodynamic therapy against superficial tumors as well as solid tumors located at light penetrable depths.

  12. Nano-engineered mesenchymal stem cells increase therapeutic efficacy of anticancer drug through true active tumor targeting.

    Science.gov (United States)

    Layek, Buddhadev; Sadhukha, Tanmoy; Panyam, Jayanth; Prabha, Swayam

    2018-03-28

    Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor targeting strategy that relies on engineering mesenchymal stem cells (MSCs) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Further, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUClung of PTX (1.5 µg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 µg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs. Copyright ©2018, American Association for Cancer Research.

  13. Current opinions on radiotherapy of pediatric central nervous system tumors

    International Nuclear Information System (INIS)

    Chojnacka, M.; Skowronska-Gardas, A.

    2006-01-01

    Primary central nervous system (CNS) neoplasms are the most frequent solid tumors in childhood accounting for 20% of all pediatric malignancies. Despite developments in neurosurgery, radiotherapy and chemotherapy, a significant proportion of these patients suffer progressive disease. A good treatment management strategy should consider not only survival but also the quality of life of the child. Irradiation is ann essential part of the management of the majority of CNS tumors. During then last decade, there significant advances in the technology of planning and delivery of radiation treatment. These new radiotherapy techniques such as conformal, intensity modulated photon beam and stereotactic methods allow a high homogenous dose to the tumor region with minimal doses to normal tissue. This is particularly important in children with localized low-grade tumors, whose prognosis of long-term survival is often excellent and should be accompanied by smallest risk of treatment toxicity. For small tumors fractionated radiotherapy stereotactic radiotherapy using multiple fixed non-coplanar beams is an appropriate treatment. Modification of craniospinal technique, lowering of the total craniospinal dose with adjuvant chemotherapy, new radiotherapy modalities to treat the posterior fossa may be employed to possibly decrease the late rectifies of radiation therapy. For malignant glioma and brain stem tumors we need new approaches, as chemo sensitization, angiogenesis inhibitors and gene therapies. These new methods in therapy of pediatric brain tumors and our experience in treatment of children with medulloblastoma, low-grade astrocytoma, craniopharyngioma and brain stem tumors are presented. We summarize therapeutic aspects of most childhood brain tumors. (author)

  14. Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral Analysis

    Directory of Open Access Journals (Sweden)

    Yunzhou Shi

    2017-11-01

    Full Text Available The effect of anti-angiogenic agents on tumor oxygenation has been in question for a number of years, where both increases and decreases in tumor pO2 have been observed. This dichotomy in results may be explained by the role of vessel normalization in the response of tumors to anti-angiogenic therapy, where anti-angiogenic therapies may initially improve both the structure and the function of tumor vessels, but more sustained or potent anti-angiogenic treatments will produce an anti-vascular response, producing a more hypoxic environment. The first goal of this study was to employ multispectral (MS 19F–MRI to noninvasively quantify viable tumor pO2 and evaluate the ability of a high dose of an antibody to vascular endothelial growth factor (VEGF to produce a strong and prolonged anti-vascular response that results in significant tumor hypoxia. The second goal of this study was to target the anti-VEGF induced hypoxic tumor micro-environment with an agent, tirapazamine (TPZ, which has been designed to target hypoxic regions of tumors. These goals have been successfully met, where an antibody that blocks both murine and human VEGF-A (B20.4.1.1 was found by MS 19F–MRI to produce a strong anti-vascular response and reduce viable tumor pO2 in an HM-7 xenograft model. TPZ was then employed to target the anti-VEGF-induced hypoxic region. The combination of anti-VEGF and TPZ strongly suppressed HM-7 tumor growth and was superior to control and both monotherapies. This study provides evidence that clinical trials combining anti-vascular agents with hypoxia-activated prodrugs should be considered to improved efficacy in cancer patients.

  15. Targeted Mesoporous Iron Oxide Nanoparticles-Encapsulated Perfluorohexane and a Hydrophobic Drug for Deep Tumor Penetration and Therapy.

    Science.gov (United States)

    Su, Yu-Lin; Fang, Jen-Hung; Liao, Chia-Ying; Lin, Chein-Ting; Li, Yun-Ting; Hu, Shang-Hsiu

    2015-01-01

    A magneto-responsive energy/drug carrier that enhances deep tumor penetration with a porous nano-composite is constructed by using a tumor-targeted lactoferrin (Lf) bio-gate as a cap on mesoporous iron oxide nanoparticles (MIONs). With a large payload of a gas-generated molecule, perfluorohexane (PFH), and a hydrophobic anti-cancer drug, paclitaxel (PTX), Lf-MIONs can simultaneously perform bursting gas generation and on-demand drug release upon high-frequency magnetic field (MF) exposure. Biocompatible PFH was chosen and encapsulated in MIONs due to its favorable phase transition temperature (56 °C) and its hydrophobicity. After a short-duration MF treatment induces heat generation, the local pressure increase via the gasifying of the PFH embedded in MION can substantially rupture the three-dimensional tumor spheroids in vitro as well as enhance drug and carrier penetration. As the MF treatment duration increases, Lf-MIONs entering the tumor spheroids provide an intense heat and burst-like drug release, leading to superior drug delivery and deep tumor thermo-chemo-therapy. With their high efficiency for targeting tumors, Lf-MIONs/PTX-PFH suppressed subcutaneous tumors in 16 days after a single MF exposure. This work presents the first study of using MF-induced PFH gasification as a deep tumor-penetrating agent for drug delivery.

  16. Threshold for extinction and survival in stochastic tumor immune system

    Science.gov (United States)

    Li, Dongxi; Cheng, Fangjuan

    2017-10-01

    This paper mainly investigates the stochastic character of tumor growth and extinction in the presence of immune response of a host organism. Firstly, the mathematical model describing the interaction and competition between the tumor cells and immune system is established based on the Michaelis-Menten enzyme kinetics. Then, the threshold conditions for extinction, weak persistence and stochastic persistence of tumor cells are derived by the rigorous theoretical proofs. Finally, stochastic simulation are taken to substantiate and illustrate the conclusion we have derived. The modeling results will be beneficial to understand to concept of immunoediting, and develop the cancer immunotherapy. Besides, our simple theoretical model can help to obtain new insight into the complexity of tumor growth.

  17. Self-Assembly of Gold Nanoparticles Shows Microenvironment-Mediated Dynamic Switching and Enhanced Brain Tumor Targeting.

    Science.gov (United States)

    Feng, Qishuai; Shen, Yajing; Fu, Yingjie; Muroski, Megan E; Zhang, Peng; Wang, Qiaoyue; Xu, Chang; Lesniak, Maciej S; Li, Gang; Cheng, Yu

    2017-01-01

    Inorganic nanoparticles with unique physical properties have been explored as nanomedicines for brain tumor treatment. However, the clinical applications of the inorganic formulations are often hindered by the biological barriers and failure to be bioeliminated. The size of the nanoparticle is an essential design parameter which plays a significant role to affect the tumor targeting and biodistribution. Here, we report a feasible approach for the assembly of gold nanoparticles into ~80 nm nanospheres as a drug delivery platform for enhanced retention in brain tumors with the ability to be dynamically switched into the single formulation for excretion. These nanoassemblies can target epidermal growth factor receptors on cancer cells and are responsive to tumor microenvironmental characteristics, including high vascular permeability and acidic and redox conditions. Anticancer drug release was controlled by a pH-responsive mechanism. Intracellular L-glutathione (GSH) triggered the complete breakdown of nanoassemblies to single gold nanoparticles. Furthermore, in vivo studies have shown that nanospheres display enhanced tumor-targeting efficiency and therapeutic effects relative to single-nanoparticle formulations. Hence, gold nanoassemblies present an effective targeting strategy for brain tumor treatment.

  18. ERK5/BMK1 Is a Novel Target of the Tumor Suppressor VHL: Implication in Clear Cell Renal Carcinoma

    Directory of Open Access Journals (Sweden)

    Laura Arias-González

    2013-06-01

    Full Text Available Extracellular signal-regulated kinase 5 (ERK5, also known as big mitogen-activated protein kinase (MAPK 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas.

  19. Non-invasive synergistic treatment of brain tumors by targeted chemotherapeutic delivery and amplified focused ultrasound-hyperthermia using magnetic nanographene oxide.

    Science.gov (United States)

    Yang, Hung-Wei; Hua, Mu-Yi; Hwang, Tsong-Long; Lin, Kun-Ju; Huang, Chiung-Yin; Tsai, Rung-Ywan; Ma, Chen-Chi M; Hsu, Po-Hung; Wey, Shiaw-Pyng; Hsu, Peng-Wei; Chen, Pin-Yuan; Huang, Yin-Cheng; Lu, Yu-Jen; Yen, Tzu-Chen; Feng, Li-Ying; Lin, Chih-Wen; Liu, Hao-Li; Wei, Kuo-Chen

    2013-07-12

    The combination of chemo-thermal therapy is the best strategy to ablate tumors, but how to heat deep tumor tissues effectively without side-damage is a challenge. Here, a systemically delivered nanocarrier is designed with multiple advantages, including superior heat absorption, highly efficient hyperthermia, high drug capacity, specific targeting ability, and molecular imaging, to achieve both high antitumor efficacy and effective amplification of hyperthermia with minimal side effects. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Combining radiation and immunotherapy: a new systemic therapy for solid tumors?

    Science.gov (United States)

    Tang, Chad; Wang, Xiaohong; Soh, Hendrick; Seyedin, Steven; Cortez, Maria Angelica; Krishnan, Sunil; Massarelli, Erminia; Hong, David; Naing, Aung; Diab, Adi; Gomez, Daniel; Ye, Huiping; Heymach, John; Komaki, Ristuko; Allison, James P; Sharma, Padmanee; Welsh, James W

    2014-09-01

    With the recent success of checkpoint inhibitors and other immunomodulating agents, there has been renewed interest in the combination of such agents with radiation. The biologic premise behind such a strategy is that the tumor-antigen release achieved by localized radiation will promote specific tumor targeting by the adaptive immune system, which can be augmented further by systemic immune-stimulating agents. In this manner, clinicians hope to induce a phenomenon known as the abscopal effect, whereby localized radiation results in immune-mediated tumor regression in disease sites well outside of the radiation field. Herein, we present a comprehensive overview of the early clinical and preclinical evidence behind this approach. ©2014 American Association for Cancer Research.

  1. Tumor Initiating Cells and Chemoresistance: Which Is the Best Strategy to Target Colon Cancer Stem Cells?

    Directory of Open Access Journals (Sweden)

    Emanuela Paldino

    2014-01-01

    Full Text Available There is an emerging body of evidence that chemoresistance and minimal residual disease result from selective resistance of a cell subpopulation from the original tumor that is molecularly and phenotypically distinct. These cells are called “cancer stem cells” (CSCs. In this review, we analyze the potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies for metastatic colon cancer. These include induction of terminal epithelial differentiation of CSCs or targeting some genes expressed only in CSCs and involved in self-renewal and chemoresistance. Ideal targets could be cell regulators that simultaneously control the stemness and the resistance of CSCs. Another important aspect of cancer biology, which can also be harnessed to create novel broad-spectrum anticancer agents, is the Warburg effect, also known as aerobic glycolysis. Actually, little is yet known with regard to the metabolism of CSCs population, leaving an exciting unstudied avenue in the dawn of the emerging field of metabolomics.

  2. Tumor-homing peptides as tools for targeted delivery of payloads to the placenta

    Science.gov (United States)

    King, Anna; Ndifon, Cornelia; Lui, Sylvia; Widdows, Kate; Kotamraju, Venkata R.; Agemy, Lilach; Teesalu, Tambet; Glazier, Jocelyn D.; Cellesi, Francesco; Tirelli, Nicola; Aplin, John D.; Ruoslahti, Erkki; Harris, Lynda K.

    2016-01-01

    The availability of therapeutics to treat pregnancy complications is severely lacking mainly because of the risk of causing harm to the fetus. As enhancement of placental growth and function can alleviate maternal symptoms and improve fetal growth in animal models, we have developed a method for targeted delivery of payloads to the placenta. We show that the tumor-homing peptide sequences CGKRK and iRGD bind selectively to the placental surface of humans and mice and do not interfere with normal development. Peptide-coated nanoparticles intravenously injected into pregnant mice accumulated within the mouse placenta, whereas control nanoparticles exhibited reduced binding and/or fetal transfer. We used targeted liposomes to efficiently deliver cargoes of carboxyfluorescein and insulin-like growth factor 2 to the mouse placenta; the latter significantly increased mean placental weight when administered to healthy animals and significantly improved fetal weight distribution in a well-characterized model of fetal growth restriction. These data provide proof of principle for targeted delivery of drugs to the placenta and provide a novel platform for the development of placenta-specific therapeutics. PMID:27386551

  3. Targeting of systemically-delivered magnetic nanoparticle hyperthermia using a noninvasive, static, external magnetic field

    Science.gov (United States)

    Zulauf, Grayson D.; Trembly, B. Stuart; Giustini, Andrew J.; Flint, Brian R.; Strawbridge, Rendall R.; Hoopes, P. Jack

    2013-01-01

    One of the greatest challenges of nanoparticle cancer therapy is the delivery of adequate numbers of nanoparticles to the tumor site. Iron oxide nanoparticles (IONPs) have many favorable qualities, including their nontoxic composition, the wide range of diameters in which they can be produced, the cell-specific cytotoxic heating that results from their absorption of energy from a nontoxic, external alternating magnetic field (AMF), and the wide variety of functional coatings that can be applied. Although IONPs can be delivered via an intra-tumoral injection to some tumors, the resulting tumor IONP distribution is generally inadequate; additionally, local tumor injections do not allow for the treatment of systemic or multifocal disease. Consequently, the ultimate success of nanoparticle based cancer therapy likely rests with successful systemic, tumor-targeted IONP delivery. In this study, we used a surface-based, bilateral, noninvasive static magnetic field gradient produced by neodymium-boron-iron magnets (80 T/m to 130 T/m in central plane between magnets), a rabbit ear model, and systemically-delivered starch-coated 100 nm magnetic (iron oxide) nanoparticles to demonstrate a spatially-defined increase in the local tissue accumulation of IONPs. In this non-tumor model, the IONPs remained within the local vascular space. It is anticipated that this technique can be used to enhance IONP delivery significantly to the tumor parenchyma/cells. PMID:24073325

  4. Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

    Directory of Open Access Journals (Sweden)

    Hua-Sheng Chiu

    2018-04-01

    Full Text Available Summary: Long noncoding RNAs (lncRNAs are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor and TUG1 and WT1-AS (inferred onco-lncRNAs dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts. : Chiu et al. present a pan-cancer analysis of lncRNA regulatory interactions. They suggest that the dysregulation of hundreds of lncRNAs target and alter the expression of cancer genes and pathways in each tumor context. This implies that hundreds of lncRNAs can alter tumor phenotypes in each tumor context. Keywords: lncRNA, regulation, modulation, cancer gene, pan-cancer, noncoding RNA, microRNA, RNA-binding proteins, interactome

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

    Directory of Open Access Journals (Sweden)

    Xu J

    2012-01-01

    Full Text Available 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-loaded atactic poly(D,L-lactic acid nanoparticles (ORI-PLA-NPs. Surface cross-linking with the peptide Arg-Gly-Asp (RGD further modified the ORI-PLA-NPs, generating ORI-PLA-RGD-NPs. The NPs were characterized and release experiments were performed in vitro. The pharmacokinetics, tissue distribution, and antitumor activity of the NPs were studied in mice bearing hepatocarcinoma 22 (H22-derived tumors.Results: The ORI-PLA-NPs and ORI-PLA-RGD-NPs were smooth, sphere-like, and relatively uniform in size. The RGD surface modification slightly increased the mean particle size (95.8 nm for ORI-PLA-NPs versus 105.2 nm for ORI-PLA-RGD-NPs and considerably altered the surface electrical property (-10.19 mV for ORI-PLA-NPs versus -21.95 mV for ORI-PLA-RGD-NPs, but it had no obvious influence on ORI loading (8.23% ± 0.35% for ORI-PLA-NPs versus 8.02% ± 0.38% for ORI-PLA-RGD-NPs, entrapment efficiency (28.86% ± 0.93% for ORI-PLA-NPs versus 28.24% ± 0.81% for ORI-PLA-RGD-NPs, or the release of ORI. The pharmacokinetic properties of free ORI were improved by encapsulation in NPs, as shown by increased area under the concentration-time curve (11.89 ± 0.35 µg·mL-1 · h for ORI solution versus 22.03 ± 0.01 µg · mL-1 · h for ORI-PLA-RGD-NPs and prolonged mean retention time (2.03 ± 0.09 hours for ORI solution versus 8.68 ± 0.66 hours for ORI-PLA-RGD-NPs. In the tissue distribution study, more ORI targeted tumor tissue in the mice treated with ORI-PLA-RGD-NPs than with ORI

  6. RI and Target recovery system of Lanthanides

    Energy Technology Data Exchange (ETDEWEB)

    Choi, K. H.; Park, U. J.; Jung, S. H.; Kim, J. B.; Moon, J. H.; Nam, S. S.; Jang, K. D. [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2015-10-15

    Separation of adjacent lanthanides is complicated process to obtain pure target nuclide. Several papers have reported that the ionic character change of lanthanides with appropriate chelating agents can isolate the target lanthanides. These specific agents to the metal ion are called as complexing agents including-HIBA, tartaric acid, mandelic acid, lactic acid etc. Radioisotope research division of KAERI has developed separating technique for target lanthanides, total 20mg scale, by using complexing agents and ion-pairing agents in cold state. The reactor-produced radiolanthanides have been pivotal for development of therapeutic radiopharmaceuticals. Some radiolanthanides show excellent theranostic effects in that they have proper Let (Linear Energy Transfer) to induce apoptosis for cancer treatment and gamma ray to use as a tracer for cancer diagnosis. This system was designed for automated separation of the (n,γ) reaction product. Especially, we are focused on getting the carrier free Ho-166 which is the first attempt at KAERI. Even though we have already developed to produce c.a Ho-166(carrier added form), we did not try to develop to produce carrier free Ho-166 since the separating process is difficult as well as production process follows double (n,γ) reaction. After HANARO is re-operated, we are schedule to produce n.c.a Ho by using this recovery system.

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

    Science.gov (United States)

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

    2017-02-15

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

  8. New Aspects of an Old Drug – Diclofenac Targets MYC and Glucose Metabolism in Tumor Cells

    Science.gov (United States)

    Gottfried, Eva; Lang, Sven A.; Renner, Kathrin; Bosserhoff, Anja; Gronwald, Wolfram; Rehli, Michael; Einhell, Sabine; Gedig, Isabel; Singer, Katrin; Seilbeck, Anton; Mackensen, Andreas; Grauer, Oliver; Hau, Peter; Dettmer, Katja; Andreesen, Reinhard; Oefner, Peter J.; Kreutz, Marina

    2013-01-01

    Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor α-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies. PMID:23874405

  9. New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells.

    Directory of Open Access Journals (Sweden)

    Eva Gottfried

    Full Text Available Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1, lactate dehydrogenase A (LDHA, and monocarboxylate transporter 1 (MCT1 gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor α-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies.

  10. Glutathione S-conjugates as prodrugs to target drug-resistant tumors

    Directory of Open Access Journals (Sweden)

    Emma E. Ramsay

    2014-08-01

    Full Text Available Living organisms are continuously exposed to xenobiotics. The major phase of enzymatic detoxification in many species is the conjugation of activated xenobiotics to reduced glutathione (GSH catalyzed by the glutathione-S-transferase (GST. It has been reported that some compounds, once transformed into glutathione S-conjugates, enter the mercapturic acid pathway whose end products are highly reactive and toxic for the cell responsible for their production. The cytotoxicity of these GSH conjugates depends essentially on GST and γ-glutamyl transferases (γGT, the enzymes which initiate the mercapturic acid synthesis pathway. Numerous studies support the view that the expression of GST and γGT in cancer cells represents an important factor in the appearance of a more aggressive and resistant phenotype. High levels of tumor GST and γGT expression were employed to selectively target tumor with GST- or γGT-activated drugs. This strategy, explored over the last two decades, has recently been successful using GST-activated nitrogen mustard (TLK286 and γGT-activated arsenic-based (GSAO and Darinaparsin prodrugs confirming the potential of GSH-conjugates as anticancer drugs.

  11. Quantitative multi-target RNA profiling in Epstein-Barr virus infected tumor cells.

    Science.gov (United States)

    Greijer, A E; Ramayanti, O; Verkuijlen, S A W M; Novalić, Z; Juwana, H; Middeldorp, J M

    2017-03-01

    Epstein-Barr virus (EBV) is etiologically linked to multiple acute, chronic and malignant diseases. Detection of EBV-RNA transcripts in tissues or biofluids besides EBV-DNA can help in diagnosing EBV related syndromes. Sensitive EBV transcription profiling yields new insights on its pathogenic role and may be useful for monitoring virus targeted therapy. Here we describe a multi-gene quantitative RT-PCR profiling method that simultaneously detects a broad spectrum (n=16) of crucial latent and lytic EBV transcripts. These transcripts include (but are not restricted to), EBNA1, EBNA2, LMP1, LMP2, BARTs, EBER1, BARF1 and ZEBRA, Rta, BGLF4 (PK), BXLF1 (TK) and BFRF3 (VCAp18) all of which have been implicated in EBV-driven oncogenesis and viral replication. With this method we determine the amount of RNA copies per infected (tumor) cell in bulk populations of various origin. While we confirm the expected RNA profiles within classic EBV latency programs, this sensitive quantitative approach revealed the presence of rare cells undergoing lytic replication. Inducing lytic replication in EBV tumor cells supports apoptosis and is considered as therapeutic approach to treat EBV-driven malignancies. This sensitive multi-primed quantitative RT-PCR approach can provide broader understanding of transcriptional activity in latent and lytic EBV infection and is suitable for monitoring virus-specific therapy responses in patients with EBV associated cancers. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  12. The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors.

    Science.gov (United States)

    Castelletti, Deborah; Fiaschetti, Giulio; Di Dato, Valeria; Ziegler, Urs; Kumps, Candy; De Preter, Katleen; Zollo, Massimo; Speleman, Frank; Shalaby, Tarek; De Martino, Daniela; Berg, Thorsten; Eggert, Angelika; Arcaro, Alexandre; Grotzer, Michael A

    2010-12-01

    The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort 7to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong antiproliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G(1)/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both eukaryotic translation initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with 2 main proproliferative signaling pathways, that is, the AKT and the MEK/extracellular signal-regulated kinase pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong antitumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET.

  13. RORα, a Potential Tumor Suppressor and Therapeutic Target of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jun Du

    2012-11-01

    Full Text Available The function of the nuclear receptor (NR in breast cancer progression has been investigated for decades. The majority of the nuclear receptors have well characterized natural ligands, but a few of them are orphan receptors for which no ligand has been identified. RORα, one member of the retinoid orphan nuclear receptor (ROR subfamily of orphan receptors, regulates various cellular and pathological activities. RORα is commonly down-regulated and/or hypoactivated in breast cancer compared to normal mammary tissue. Expression of RORα suppresses malignant phenotypes in breast cancer cells, in vitro and in vivo. Activity of RORα can be categorized into the canonical and non-canonical nuclear receptor pathways, which in turn regulate various breast cancer cellular function, including cell proliferation, apoptosis and invasion. This information suggests that RORα is a potent tumor suppressor and a potential therapeutic target for breast cancer.

  14. Synthesis of Specific Nanoparticles for Targeting and Imaging Tumor Angiogenesis Using Electron-Beam Irradiation

    International Nuclear Information System (INIS)

    Rizza, G.; Deshayes, S.; Maurizot, V.; Clochard, M.-C.; Berthelot, T.; Baudin, C.; Déléris, G.

    2010-01-01

    We have succeeded to synthesize PVDF nanoparticles by nanoemulsion polymerization and their functionalization with a peptide that presents an anti-angiogenic activity. Resulted nanoparticles present a radius of 60 nm. From FESEM images and light scattering measurements, we deduced that they were spherical and monodisperse. The alkyl radicals induced from electron beam irradiation combine immediately with the oxygen to form peroxide radicals. Because of a high specific area and small crystallite size, the radical decay with time is evidenced from EPR measurements. Despite this radical decay, electron beam irradiation allows us to graft PAA by radical polymerization onto freshly irradiated PVDF nanoparticles and then to immobilize CBO-P11 by click chemistry via a spacer arm. Evidences of grafting were shown using HRMAS NMR and MALDI-TOF mass spectrometry. Nanoparticles functionalized with an angiogenesis-targeting agent are an attractive option for anti-tumor therapy

  15. Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism.

    Directory of Open Access Journals (Sweden)

    Sarah Garrido-Urbani

    Full Text Available Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.

  16. Chondroitin Sulfate Proteoglycan 4 and Its Potential As an Antibody Immunotherapy Target across Different Tumor Types

    Directory of Open Access Journals (Sweden)

    Kristina M. Ilieva

    2018-01-01

    Full Text Available Overexpression of the chondroitin sulfate proteoglycan 4 (CSPG4 has been associated with the pathology of multiple types of such as melanoma, breast cancer, squamous cell carcinoma, mesothelioma, neuroblastoma, adult and pediatric sarcomas, and some hematological cancers. CSPG4 has been reported to exhibit a role in the growth and survival as well as in the spreading and metastasis of tumor cells. CSPG4 is overexpressed in several malignant diseases, while it is thought to have restricted and low expression in normal tissues. Thus, CSPG4 has become the target of numerous anticancer treatment approaches, including monoclonal antibody-based therapies. This study reviews key potential anti-CSPG4 antibody and immune-based therapies and examines their direct antiproliferative/metastatic and immune activating mechanisms of action.

  17. Microenvironment of Tumor-Draining Lymph Nodes: Opportunities for Liposome-Based Targeted Therapy

    Directory of Open Access Journals (Sweden)

    Siddarth Chandrasekaran

    2014-11-01

    Full Text Available The World Health Organization (WHO recently reported that the total number of global cancer cases in 2013 reached 14 million, a 10% rise since 2008, while the total number of cancer deaths reached 8.2 million, a 5.2% increase since 2008. Metastasis is the major cause of death from cancer, accounting for 90% of all cancer related deaths. Tumor-draining lymph nodes (TDLN, the sentinel nodes, are the first organs of metastasis in several types of cancers. The extent of metastasis in the TDLN is often used in disease staging and prognosis evaluation in cancer patients. Here, we describe the microenvironment of the TDLN and review the recent literature on liposome-based therapies directed to immune cells within the TDLN with the intent to target cancer cells.

  18. Targeting herpesvirus reliance of the chemokine system

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Kledal, Thomas N

    2006-01-01

    Viral infections depend on an intimate relationship between the infectious agent and the host cells. Viruses need the host cells for replication, while the innate- and adaptive- immunesystem of the host is fighting to kill the infected cell in order to clear out the pathogen and survive...... the infection. However, since both virus and host exist, the organisms struggle must reach an ecological equilibrium. Among the best-studied interactions between viruses and the host immune system are those between herpesviruses and their hosts. Herpesviruses are known to devote a significant part...... acquired homologs of both chemokines and chemokine receptors belonging to the 7 transmembrane (7TM) spanning, G protein-coupled receptor family. 7TM receptors are very efficient drug targets and are currently the most popular class of investigational drug targets. A notable trait for the virus encoded...

  19. Achromatic illumination system for small targets

    International Nuclear Information System (INIS)

    Sigler, R.D.

    1979-01-01

    A pair of light beams is directed to provide illumination that is substantially uniform from all directions on a small target by a system comprising a pair of corrector windows, a pair of planar reflecting surfaces, a pair of paraboloidal mirrors and a reflecting mirror cavity. The components are arranged so that each of the beams passes through a corrector and is reflected from the planar surface to the paraboloidal mirror, from which it is focused through a hole in the planar surface to the interior of the cavity. The surface of the interior portion of the cavity is shaped to reflect the focused beam three times before the focused reflected beam strikes the target

  20. Synthesis and characterization of ZnS:Mn/ZnS core/shell nanoparticles for tumor targeting and imaging in vivo.

    Science.gov (United States)

    Yu, Zhangsen; Ma, Xiying; Yu, Bin; Pan, Yuefang; Liu, Zhaogang

    2013-08-01

    Fluorescence imaging technique has been used for imaging of biological cells and tissues in vivo. The Cd-free luminescent quantum dots conjugating with a cancer targeting ligand has been taken as a promising biocompatibility and low cytotoxicity system for targeted cancer imaging. This work reports the synthesis of fluorescent-doped core/shell quantum dots of water-soluble manganese-doped zinc sulfide. Quantum dots of manganese-doped zinc sulfide were prepared by nucleation doping strategy, with 3-mercaptopropionic acid as stabilizer at 90 in aqueous solution. The manganese-doped zinc sulfide nanoparticles exhibit strong orange fluorescence under UV irradiation, resistance to photo-bleaching, and low-cytotoxicity to HeLa cells. The structure and optical properties of nanoparticles were characterized by scanning electron microscope, X-ray diffraction, dynamic light scattering, and photoluminescence emission spectroscopy. Manganese-doped zinc sulfide nanoparticles conjugated with folic acid using 2,2'-(ethylenedioxy)-bis-(ethylamine) as the linker. The covalent binding of both 2,2'-(ethylenedioxy)-bis-(ethylamine) and folic acid on the surface of manganese-doped zinc sulfide nanoparticles probed by Fourier transform infrared spectroscopy detection. Furthermore, in vitro cytotoxicity assessment of manganese-doped zinc sulfide-folic acid probes use HeLa cells. The obtained fluorescent probes (manganese-doped zinc sulfide) were used for tumor targeting and imaging in vivo. The manganese-doped zinc sulfide-folic acid fluorescent probes which targeting the tumor cells in the body of nude mouse tumor model would emit orange fluorescence, when exposed to a 365 nm lamp. We investigate the biodistribution of the manganese-doped zinc sulfide-folic acid fluorescent probes in tumor mouse model by measuring zinc concentration in tissues. These studies demonstrate the practicality of manganese-doped zinc sulfide-folic acid fluorescent probes as promising platform for tumor

  1. Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression

    Directory of Open Access Journals (Sweden)

    Triche Timothy

    2009-12-01

    Full Text Available Abstract Background Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Results Using parallel oligonucleotide array platforms, shared orthologues between species were identified and normalized. The osteosarcoma expression signatures could not distinguish the canine and human diseases by hierarchical clustering. Cross-species target mining identified two genes, interleukin-8 (IL-8 and solute carrier family 1 (glial high affinity glutamate transporter, member 3 (SLC1A3, which were uniformly expressed in dog but not in all pediatric osteosarcoma patient samples. Expression of these genes in an independent population of pediatric osteosarcoma patients was associated with poor outcome (p = 0.020 and p = 0.026, respectively. Validation of IL-8 and SLC1A3 protein expression in pediatric osteosarcoma tissues further supported the potential value of these novel targets. Ongoing evaluation will validate the biological significance of these targets and their associated pathways. Conclusions Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapies.

  2. Cyclin D1 is a direct transcriptional target of GATA3 in neuroblastoma tumor cells

    NARCIS (Netherlands)

    Molenaar, J. J.; Ebus, M. E.; Koster, J.; Santo, E.; Geerts, D.; Versteeg, R.; Caron, H. N.

    2010-01-01

    Almost all neuroblastoma tumors express excess levels of Cyclin D1 (CCND1) compared to normal tissues and other tumor types. Only a small percentage of these neuroblastoma tumors have high-level amplification of the Cyclin D1 gene. The other neuroblastoma tumors have equally high Cyclin D1

  3. High Shear Stresses under Exercise Condition Destroy Circulating Tumor Cells in a Microfluidic System

    OpenAIRE

    Regmi, Sagar; Fu, Afu; Luo, Kathy Qian

    2017-01-01

    Circulating tumor cells (CTCs) are the primary targets of cancer treatment as they cause distal metastasis. However, how CTCs response to exercise-induced high shear stress is largely unknown. To study the effects of hemodynamic microenvironment on CTCs, we designed a microfluidic circulatory system that produces exercise relevant shear stresses. We explore the effects of shear stresses on breast cancer cells with different metastatic abilities, cancer cells of ovarian, lung and leukemic orig...

  4. Somatic mutation detection using various targeted detection assays in paired samples of circulating tumor DNA, primary tumor and metastases from patients undergoing resection of colorectal liver metastases.

    Science.gov (United States)

    Beije, Nick; Helmijr, Jean C; Weerts, Marjolein J A; Beaufort, Corine M; Wiggin, Matthew; Marziali, Andre; Verhoef, Cornelis; Sleijfer, Stefan; Jansen, Maurice P H M; Martens, John W M

    2016-12-01

    Assessing circulating tumor DNA (ctDNA) is a promising method to evaluate somatic mutations from solid tumors in a minimally-invasive way. In a group of twelve metastatic colorectal cancer (mCRC) patients undergoing liver metastasectomy, from each patient DNA from cell-free DNA (cfDNA), the primary tumor, metastatic liver tissue, normal tumor-adjacent colon or liver tissue, and whole blood were obtained. Investigated was the feasibility of a targeted NGS approach to identify somatic mutations in ctDNA. This targeted NGS approach was also compared with NGS preceded by mutant allele enrichment using synchronous coefficient of drag alteration technology embodied in the OnTarget assay, and for selected mutations with digital PCR (dPCR). All tissue and cfDNA samples underwent IonPGM sequencing for a CRC-specific 21-gene panel, which was analyzed using a standard and a modified calling pipeline. In addition, cfDNA, whole blood and normal tissue DNA were analyzed with the OnTarget assay and with dPCR for specific mutations in cfDNA as detected in the corresponding primary and/or metastatic tumor tissue. NGS with modified calling was superior to standard calling and detected ctDNA in the cfDNA of 10 patients harboring mutations in APC, ATM, CREBBP, FBXW7, KRAS, KMT2D, PIK3CA and TP53. Using this approach, variant allele frequencies in plasma ranged predominantly from 1 to 10%, resulting in limited concordance between ctDNA and the primary tumor (39%) and the metastases (55%). Concordance between ctDNA and tissue markedly improved when ctDNA was evaluated for KRAS, PIK3CA and TP53 mutations by the OnTarget assay (80%) and digital PCR (93%). Additionally, using these techniques mutations were observed in tumor-adjacent tissue with normal morphology in the majority of patients, which were not observed in whole blood. In conclusion, in these mCRC patients with oligometastatic disease NGS on cfDNA was feasible, but had limited sensitivity to detect all somatic mutations present

  5. Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery.

    Science.gov (United States)

    de Geus, Susanna W L; Boogerd, Leonora S F; Swijnenburg, Rutger-Jan; Mieog, J Sven D; Tummers, Willemieke S F J; Prevoo, Hendrica A J M; Sier, Cornelis F M; Morreau, Hans; Bonsing, Bert A; van de Velde, Cornelis J H; Vahrmeijer, Alexander L; Kuppen, Peter J K

    2016-12-01

    The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma. The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)-score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma. Integrin α v β 6 , carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p < 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients. The results of this study show that integrin α v β 6 , CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma.

  6. MicroRNA targeting microtubule cross-linked protein (MACF1) would suppress the invasion and metastasis of malignant tumor.

    Science.gov (United States)

    Zhao, Wenpeng; Qian, Huiming; Zhang, Ruisan; Gao, Xingchun; Gou, Xingchun

    2017-07-01

    Cancer is one of the most serious diseases that endanger human health in the world today, and the incidence and mortality of cancer increases year by year. Invasion and metastasis is the most prominent feature of malignant tumors, but also becomes the primary factor of threatening patient's health. Tumor cell invasion and metastasis which closely related to the dynamic changes of the cytoskeleton is an important factor influencing the survival of patients. Therefore, inhibition of tumor cell invasion and metastasis is a key strategy for the treatment of cancer. MACF1 is a microtubule microfilament cross-linking factor that plays an important role in cell polarization, cell migration, and maintenance of tissue integrity. A lot of studies have shown that microRNAs play an important role in tumorigenesis, invasion and metastasis. Therefore, we propose the following scientific assumptions: MACF1, an important molecule in adjusting the invasion and metastasis of tumor cells, regulates microfilaments, microtubules participating in cytoskeleton dynamics to promote malignant tumor cell migration and invasion; MicroRNA targeting MACF1 can decrease the expression of MACF1 and thus disrupt the dynamic balance of microtubule or microfilaments as an effective way to inhibit the invasion and metastasis of tumor cells. So we can use it as a new target for clinical early diagnosis and treatment of malignant tumor invasion and metastasis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Imatinib and gastrointestinal stromal tumor (GIST: a selective targeted therapy Imatinib y tumor del estroma gastrointestinal (GIST: un tratamiento selectivo frente a una diana molecular

    Directory of Open Access Journals (Sweden)

    A. Fernández

    2004-10-01

    Full Text Available Gastrointestinal stromal tumors are the most frequent mesenchymal tumors in the gastrointestinal tract. They originate from the interstitial cells of Cajal and are characterized by an anomalous receptor for a growth factor with tyrosine-kinase activity (c-kit. This anomaly causes a permanent activation of the receptor and uncontrolled cell growth. These tumors show a poor response to traditional chemotherapy drugs, and are thus associated with low survival in cases of advanced disease. Imatinib, a tyrosine kinase inhibitor, is an example of selective targeted oncologic therapy that induces improved survival in these patients. We discuss two cases of metastatic gastrointestinal stromal tumors with a good response to imatinib, and also review the pathophysiology and treatment-related outcome of this type of tumors. We include results from clinical phase-III studies.Los tumores del estroma gastrointestinal son los tumores mesenquimales más frecuentes del tracto digestivo y se originan de las células intersticiales de Cajal. Se caracterizan por presentar un receptor para el factor de crecimiento con actividad tirosin kinasa (c-kit anómalo que condiciona su activación permanente y un crecimiento celular incontrolado. Tienen una baja supervivencia en casos de enfermedad avanzada, con escasa respuesta a los agentes quimioterápicos tradicionales. El imatinib es un fármaco inhibidor de la tirosín kinasa y un ejemplo de terapia oncológica selectiva que condiciona un importante aumento en la supervivencia de estos pacientes. Se presentan 2 casos de enfermedad metastásica con buena respuesta a imatinib, así como una revisión sobre la fisiopatología y evolución en el tratamiento de este tipo de tumores, incluyendo resultados de estudios en fase III.

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

    Science.gov (United States)

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

    2017-12-19

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

  9. Development of a New Positron Emission Tomography Tracer for Targeting Tumor Angiogenesis: Synthesis, Small Animal Imaging, and Radiation Dosimetry

    Directory of Open Access Journals (Sweden)

    David S. Lalush

    2013-05-01

    Full Text Available Angiogenesis plays a key role in cancer progression and correlates with disease aggressiveness and poor clinical outcomes. Affinity ligands discovered by screening phage display random peptide libraries can be engineered to molecularly target tumor blood vessels for noninvasive imaging and early detection of tumor aggressiveness. In this study, we tested the ability of a phage-display-selected peptide sequence recognizing specifically bone marrow- derived pro-angiogenic tumor-homing cells, the QFP-peptide, radiolabeled with 64Cu radioisotope to selectively image tumor vasculature in vivo by positron emission tomography (PET. To prepare the targeted PET tracer we modified QFP-phage with the DOTA chelator and radiolabeled the purified QFP-phage-DOTA intermediate with 64Cu to obtain QFP-targeted radioconjugate with high radiopharmaceutical yield and specific activity. We evaluated the new PET tracer in vivo in a subcutaneous (s.c. Lewis lung carcinoma (LLC mouse model and conducted tissue distribution, small animal PET/CT imaging study, autoradiography, histology, fluorescence imaging, and dosimetry assessments. The results from this study show that, in the context of the s.c. LLC immunocompetent mouse model, the QFP-tracer can target tumor blood vessels selectively. However, further optimization of the biodistribution and dosimetry profile of the tracer is necessary to ensure efficient radiopharmaceutical applications enabled by the biological specificity of the QFP-peptide.

  10. Vascular targeted therapy with anti-prostate-specific membrane antigen monoclonal antibody J591 in advanced solid tumors.

    Science.gov (United States)

    Milowsky, Matthew I; Nanus, David M; Kostakoglu, Lale; Sheehan, Christine E; Vallabhajosula, Shankar; Goldsmith, Stanley J; Ross, Jeffrey S; Bander, Neil H

    2007-02-10

    Based on prostate-specific membrane antigen (PSMA) expression on the vasculature of solid tumors, we performed a phase I trial of antibody J591, targeting the extracellular domain of PSMA, in patients with advanced solid tumor malignancies. This was a proof-of-principle evaluation of PSMA as a potential neovascular target. The primary end points were targeting,toxicity, maximum-tolerated dose, pharmacokinetics (PK), and human antihuman antibody (HAHA) response. Patients had advanced solid tumors previously shown to express PSMA on the neovasculature. They received 111Indium (111ln)-J591 for scintigraphy and PK, followed 2 weeks later by J591 with a reduced amount of 111In for additional PK measurements. J591 dose levels were 5, 10, 20, 40, and 80 mg. The protocol was amended for six weekly administrations of unchelated J591. Patients with a response or stable disease were eligible for re-treatment. Immunohistochemistry assessed PSMA expression in tumor tissues. Twenty-seven patients received monoclonal antibody (mAb) J591. Treatment was well tolerated. Twenty (74%) of 27 patients had at least one area of known metastatic disease targeted by 111In-J591, with positive imaging seen in patients with kidney, bladder, lung, breast, colorectal, and pancreatic cancers, and melanoma. Seven of 10 patient specimens available for immunohistochemical assessment of PSMA expression in tumor-associated vasculature demonstrated PSMA staining. No HAHA response was seen. Three patients of 27 with stable disease received re-treatment. Acceptable toxicity and excellent targeting of known sites of metastases were demonstrated in patients with multiple solid tumor types, highlighting a potential role for the anti-PSMA antibody J591 as a vascular-targeting agent.

  11. Studies on Preparation of Photosensitizer Loaded Magnetic Silica Nanoparticles and Their Anti-Tumor Effects for Targeting Photodynamic Therapy

    Directory of Open Access Journals (Sweden)

    Chen Zhi-Long

    2009-01-01

    Full Text Available Abstract As a fast developing alternative of traditional therapeutics, photodynamic therapy (PDT is an effective, noninvasive, nontoxic therapeutics for cancer, senile macular degeneration, and so on. But the efficacy of PDT was compromised by insufficient selectivity and low solubility. In this study, novel multifunctional silica-based magnetic nanoparticles (SMNPs were strategically designed and prepared as targeting drug delivery system to achieve higher specificity and better solubility. 2,7,12,18-Tetramethyl-3,8-di-(1-propoxyethyl-13,17-bis-(3-hydroxypropyl porphyrin, shorted as PHPP, was used as photosensitizer, which was first synthesized by our lab with good PDT effects. Magnetite nanoparticles (Fe3O4 and PHPP were incorporated into silica nanoparticles by microemulsion and sol–gel methods. The prepared nanoparticles were characterized by transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy and fluorescence spectroscopy. The nanoparticles were approximately spherical with 20–30 nm diameter. Intense fluorescence of PHPP was monitored in the cytoplasm of SW480 cells. The nanoparticles possessed good biocompatibility and could generate singlet oxygen to cause remarkable photodynamic anti-tumor effects. These suggested that PHPP-SMNPs had great potential as effective drug delivery system in targeting photodynamic therapy, diagnostic magnetic resonance imaging and magnetic hyperthermia therapy.

  12. MicroRNA-198 inhibited tumorous behaviors of human osteosarcoma through directly targeting ROCK1

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Shilian, E-mail: shilian_zhang@126.com; Zhao, Yuehua; Wang, Lijie

    2016-04-08

    Osteosarcoma is an aggressive primary sarcoma of bone and occurs mainly in adolescents and young adults. The prognosis of OS remains poor, and most of them will die due to local relapse or metastases. The discovery of microRNAs provides a new possibility for the early diagnosis and treatment of OS. Thus, the aim of this study was to explore the expression and functions of microRNA-198 (miR-198) in osteosarcoma. The expression levels of miR-198 were determined by qRT-PCR in osteosarcoma tissues and cell lines. Cell proliferation assays, migration and invasion assays were adopted to investigate the effects of miR-198 on tumorous behaviors of osteosarcoma cells. The results showed that miR-198 expression levels were lower in osteosarcoma tissues and cell lines. In addition, low miR-198 expression levels were correlated with TNM stage and distant metastasis. After miR-198 mimics transfection, cell proliferation, migration and invasion were significantly suppressed in the osteosarcoma cells. Furthermore, ROCK1 was identified as a novel direct target of miR-198 in osteosarcoma. These findings suggested that miR-198 may act not only as a novel prognostic marker, but also as a potential target for molecular therapy of osteosarcoma.

  13. Cancer systems biology in the genome sequencing era: part 2, evolutionary dynamics of tumor clonal networks and drug resistance.

    Science.gov (United States)

    Wang, Edwin; Zou, Jinfeng; Zaman, Naif; Beitel, Lenore K; Trifiro, Mark; Paliouras, Miltiadis

    2013-08-01

    A tumor often consists of multiple cell subpopulations (clones). Current chemo-treatments often target one clone of a tumor. Although the drug kills that clone, other clones overtake it and the tumor recurs. Genome sequencing and computational analysis allows to computational dissection of clones from tumors, while singe-cell genome sequencing including RNA-Seq allows profiling of these clones. This opens a new window for treating a tumor as a system in which clones are evolving. Future cancer systems biology studies should consider a tumor as an evolving system with multiple clones. Therefore, topics discussed in Part 2 of this review include evolutionary dynamics of clonal networks, early-warning signals (e.g., genome duplication events) for formation of fast-growing clones, dissecting tumor heterogeneity, and modeling of clone-clone-stroma interactions for drug resistance. The ultimate goal of the future systems biology analysis is to obtain a 'whole-system' understanding of a tumor and therefore provides a more efficient and personalized management strategies for cancer patients. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  14. Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context.

    Science.gov (United States)

    Chiu, Hua-Sheng; Somvanshi, Sonal; Patel, Ektaben; Chen, Ting-Wen; Singh, Vivek P; Zorman, Barry; Patil, Sagar L; Pan, Yinghong; Chatterjee, Sujash S; Sood, Anil K; Gunaratne, Preethi H; Sumazin, Pavel

    2018-04-03

    Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  15. Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies.

    Science.gov (United States)

    Shariatpanahi, Seyed Peyman; Shariatpanahi, Seyed Pooya; Madjidzadeh, Keivan; Hassan, Moustapha; Abedi-Valugerdi, Manuchehr

    2018-04-07

    Myeloid-derived suppressor cells (MDSCs) belong to immature myeloid cells that are generated and accumulated during the tumor development. MDSCs strongly suppress the anti-tumor immunity and provide conditions for tumor progression and metastasis. In this study, we present a mathematical model based on ordinary differential equations (ODE) to describe tumor-induced immunosuppression caused by MDSCs. The model consists of four equations and incorporates tumor cells, cytotoxic T cells (CTLs), natural killer (NK) cells and MDSCs. We also provide simulation models that evaluate or predict the effects of anti-MDSC drugs (e.g., l-arginine and 5-Fluorouracil (5-FU)) on the tumor growth and the restoration of anti-tumor immunity. The simulated results obtained using our model were in good agreement with the corresponding experimental findings on the expansion of splenic MDSCs, immunosuppressive effects of these cells at the tumor site and effectiveness of l-arginine and 5-FU on the re-establishment of antitumor immunity. Regarding this latter issue, our predictive simulation results demonstrated that intermittent therapy with low-dose 5-FU alone could eradicate the tumors irrespective of their origins and types. Furthermore, at the time of tumor eradication, the number of CTLs prevailed over that of cancer cells and the number of splenic MDSCs returned to the normal levels. Finally, our predictive simulation results also showed that the addition of l-arginine supplementation to the intermittent 5-FU therapy reduced the time of the tumor eradication and the number of iterations for 5-FU treatment. Thus, the present mathematical model provides important implications for designing new therapeutic strategies that aim to restore antitumor immunity by targeting MDSCs. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Breast Tumor Detection Utilizing Novel in situ Amplication Systems

    National Research Council Canada - National Science Library

    Smith, Cassandra L

    1998-01-01

    ... other. This work will take advantage of the known high specificities of single-stranded DNA to bind its complement to form double-stranded structures, of streptavidin to bind biotin, and of pairs of leucine zipppers to dimerize. This project will focus on optimizing the method in model systems and on tumor cells in culture.

  17. Tumor glycolysis as a target for cancer therapy: progress and prospects

    Science.gov (United States)

    2013-01-01

    Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the “hallmarks of cancer”. This metabolic phenotype is characterized by preferential dependence on glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image

  18. Targeted Therapy of Cancer Using Photodynamic Therapy in Combination with Multi-faceted Anti-Tumor Modalities

    Directory of Open Access Journals (Sweden)

    Malini Olivo

    2010-05-01

    Full Text Available Photodynamic therapy (PDT has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS, which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS, that attack key structural entities within the targeted cells, ultimately resulting in necrosis or apoptosis. Though PDT is a selective modality, it can be further enhanced by combining other targeted therapeutic strategies that include the use of synthetic peptides and nanoparticles for selective delivery of photosensitizers. Another potentially promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. Vascular disrupting agents that eradicate tumor vasculature during PDT and anti-angiogenic agents that targets specific molecular pathways and prevent the formation of new blood vessels are novel therapeutic approaches that have been shown to improve treatment outcome. In addition to the well-documented mechanisms of direct cell killing and damage to the tumor vasculature, PDT can also activate the body’s immune response against tumors. Numerous pre-clinical studies and clinical observations have demonstrated the immuno-stimulatory capability of PDT. Herein, we aim to integrate the most important findings with regard to the combination of PDT and other novel targeted therapy approaches, detailing its potential in cancer photomedicine.

  19. Toxicology and efficacy of tumor-targetingSalmonella typhimuriumA1-R compared to VNP 20009 in a syngeneic mouse tumor model in immunocompetent mice.

    Science.gov (United States)

    Zhang, Yong; Cao, Wenluo; Toneri, Makoto; Zhang, Nan; Kiyuna, Tasuku; Murakami, Takashi; Nelson, Scott D; Dry, Sarah M; Li, Yunfeng; Li, Shukuan; Wang, Xiaoen; Ma, Huaiyu; Singh, Arun S; Eilber, Fritz C; Hoffman, Robert M; Zhao, Ming

    2017-08-15

    Salmonella typhimurium A1-R ( S. typhimurium A1-R) attenuated by leu and arg auxotrophy has been shown to target multiple types of cancer in mouse models. In the present study, toxicologic and biodistribution studies of tumor-targeting S. typhimurium A1-R and S. typhimurium VNP20009 (VNP 20009) were performed in a syngeneic tumor model growing in immunocompetent BALB/c mice. Single or multiple doses of S. typhimurium A1-R of 2.5 × 10 5 and 5 × 10 5 were tolerated. A single dose of 1 × 10 6 resulted in mouse death. S. typhimurium A1-R (5 × 10 5 CFU) was eliminated from the circulation, liver and spleen approximately 3-5 days after bacterial administration via the tail vein, but remained in the tumor in high amounts. S. typhimurium A1-R was cleared from other organs much more rapidly. S. typhimurium A1-R and VNP 20009 toxicity to the spleen and liver was minimal. S. typhimurium A1-R showed higher selective targeting to the necrotic areas of the tumors than VNP20009. S. typhimurium A1-R inhibited the growth of CT26 colon carcinoma to a greater extent at the same dose of VNP20009. In conclusion, we have determined a safe dose and schedule of S. typhimurium A1-R administration in BALB/c mice, which is also efficacious against tumor growth. The results of the present report indicate similar toxicity of S. typhimurium A1-R and VNP20009, but greater antitumor efficacy of S. typhimurium A1-R in an immunocompetent animal. Since VNP2009 has already proven safe in a Phase I clinical trial, the present results indicate the high clinical potential of S. typhimurium A1-R.

  20. Development and evaluation of novel tumor-targeting paclitaxel-loaded nano-carriers for ovarian cancer treatment: in vitro and in vivo.

    Science.gov (United States)

    Yao, Shu; Li, Li; Su, Xuan-Tao; Wang, Kai; Lu, Zai-Jun; Yuan, Cun-Zhong; Feng, Jin-Bo; Yan, Shi; Kong, Bei-Hua; Song, Kun

    2018-02-26

    Ovarian cancer is the most leading cause of death and the third most common gynecologic malignancy in women. Traditional chemotherapy has inevitable drawbacks of nonspecific tumor targeting, high toxicity, and poor therapeutic efficiency. In order to overcome such shortcomings, we prepared a novel nano-carrier drug-delivery system to enhance the anti-tumor efficiency. In vitro characterizations of nano-carriers were determined by TEM, DLS. Cell viability was measured by MTT method. RT-PCR was performed to measure the expression of FARα in three ovarian cancer cell lines. The drug-release study and the uptaken study were measured in vitro. The pharmacokinetic and the drug distribution study were verified by HPLC methods in vivo. The enhanced anti-tumor efficiency of FA-NP was evaluated by the tumor inhibitory rate in vivo. Paclitaxel (PTX)-loaded nanoparticles (NPs) (PTX-PEG-PLA-NP and PTX-PEG-PLA-FA-NP) were prepared successfully, and the drug-release study showed that the cumulative release rates of NP groups were much less than free PTX group. The pharmacokinetic study showed that the elimination phase of two kinds of NP groups were much longer than that of PTX group. The drug distribution in different tissues showed that the peak-reach time was 2 h in the PTX group and 6 h in both NP groups. All of these results confirmed the excellent slow-release effects of both kinds of nano-carriers. More importantly, we confirmed that PTX-PEG-PLA-FA-NP had greater uptake by SK-OV-3 cells than PTX-PEG-PLA-NP and free PTX in vitro. A drug-distribution study of tumor-bearing mice demonstrated that the PTX concentration of tumor tissues in the PTX-PEG-PLA-FA-NP group was 3 times higher than the other two groups. PTX-PEG-PLA-FA-NP was uptaken much more by SK-OV-3 cells than PTX-PEG-PLA-NP and free PTX. Eventually, based on the slow-release effect and tumor-targeting characteristics of PTX-PEG-PLA-FA-NP, a cytotoxicity test indicated that PTX-PEG-PLA-FA-NP was much more toxic

  1. Photoirradiation system for solid tumors in photodynamic therapy

    International Nuclear Information System (INIS)

    Pacheco, L.; Stolik, S.; Rosa, J.M. de la

    2012-01-01

    Photodynamic therapy (PDT) is a clinical procedure which induces cell death for destroying cancerous tissues mostly. This is accomplished by photochemical reaction produced by the combined action of three elements: photo sensitizer, light and oxygen. One aspect of the development of PDT is focused on the treatment of solid and deep tumors, where a set of delivering-light probes are placed into the tumor mass. However, this technique still has several challenges, for although certain parameters involved in the procedure may be adjusted, the complex geometry and non-homogeneity of a tumor difficult to establish the appropriate treatment planning. This paper addresses an overview of interstitial PDT and presents our proposal of photo irradiation system. (Author)

  2. Benign skin tumors in association with systemic malignancy

    Directory of Open Access Journals (Sweden)

    K. Didem Yazganoğlu

    2013-12-01

    Full Text Available There are various types of benign skin tumors in association with the complex nature of the skin. A minor part of them may be associated with visceral malignancies. This review focuses on the benign skin tumors that are described to have well-known associations with systemic malignancies or those with controversial associations. These tumors and the associated conditions are as follows: seborrheic keratosis/ Leser-Trélat sign, lentigo simplex/Peutz Jeghers and Carney syndrome, sebaceous tumors/ Muir-Torre syndrome, fibrofolliculoma- trichodiskoma/ Birt-Hogg-Dubé syndrome, trichoepitheliomacylindroma- spiradenoma/ Brooke-Spiegler syndrome, leiomyoma/multiple cutaneous and uterin leiomyomatosis syndrome, glomeruloid hemangioma/ POEMS syndrome, venous malformation/ Maffucci syndrome, mucosal neuroma/ multiple endocrine neoplasia type 2B, juvenile xanthogranuloma/ juvenile chronic myeloid leukemia. It is important to know the skin tumors related with visceral malignancies in part of a syndrome or in association with a sign as this may yield an earlier recognition of these malignancies.

  3. Overcoming photodynamic resistance and tumor targeting dual-therapy mediated by indocyanine green conjugated gold nanospheres.

    Science.gov (United States)

    Li, Wei; Guo, Xiaomeng; Kong, Fenfen; Zhang, Hanbo; Luo, Lihua; Li, Qingpo; Zhu, Chunqi; Yang, Jie; Du, Yongzhong; You, Jian

    2017-07-28

    Photodynamic therapy (PDT) and photothermal therapy (PTT) have captured much attention due to the great potential to cure malignant tumor. Nevertheless, photodynamic resistance of cancer cells has limited the further efficacy of PDT. Unfortunately, the resistance mechanism and efforts to overcome the resistance still have been rarely reported so far. Here, we report a nanosystem with specific tumor targeting for combined PDT and PTT mediated by near-infrared (NIR) light, which was established by covalently conjugating indocyanine green (ICG) and TNYL peptide onto the surface of hollow gold nanospheres (HAuNS). Our nanosystem (TNYL-ICG-HAuNS) was proved to possess significantly increased light stability, reactive oxygen species (ROS) production and photothermal effect under NIR light irradiation, thus presenting a remarkably enhanced antitumor efficacy. The up-regulation of nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) in cancer cells during PDT induced a significant increase of ABCG2, NQO-1 and HIF-1α expression, causing PDT resistance of the cells. Interestingly, ABCG2 expression could almost keep a normal level in the whole PDT process mediated by TNYL-ICG-HAuNS. After repeated irradiations, TNYL-ICG-HAuNS could still produce almost constant ROS in cells while the Nrf2 expression reduced significantly. Furthermore, PDT resistance induced an obvious decrease of the internalization of free ICG, but didn't influence the cell uptake of TNYL-ICG-HAuNS. Our data explained that TNYL-ICG-HAuNS could overcome the photodynamic resistance of cancer cells, acting as a promising modality for simultaneous photothermal and photodynamic cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Tumour targeting with systemically administered bacteria.

    LENUS (Irish Health Repository)

    Morrissey, David

    2012-01-31

    Challenges for oncology practitioners and researchers include specific treatment and detection of tumours. The ideal anti-cancer therapy would selectively eradicate tumour cells, whilst minimising side effects to normal tissue. Bacteria have emerged as biological gene vectors with natural tumour specificity, capable of homing to tumours and replicating locally to high levels when systemically administered. This property enables targeting of both the primary tumour and secondary metastases. In the case of invasive pathogenic species, this targeting strategy can be used to deliver genes intracellularly for tumour cell expression, while non-invasive species transformed with plasmids suitable for bacterial expression of heterologous genes can secrete therapeutic proteins locally within the tumour environment (cell therapy approach). Many bacterial genera have been demonstrated to localise to and replicate to high levels within tumour tissue when intravenously (IV) administered in rodent models and reporter gene tagging of bacteria has permitted real-time visualisation of this phenomenon. Live imaging of tumour colonising bacteria also presents diagnostic potential for this approach. The nature of tumour selective bacterial colonisation appears to be tumour origin- and bacterial species- independent. While originally a correlation was drawn between anaerobic bacterial colonisation and the hypoxic nature of solid tumours, it is recently becoming apparent that other elements of the unique microenvironment within solid tumours, including aberrant neovasculature and local immune suppression, may be responsible. Here, we consider the pre-clinical data supporting the use of bacteria as a tumour-targeting tool, recent advances in the area, and future work required to develop it into a beneficial clinical tool.

  5. A system for tumor heterogeneity evaluation and diagnosis based on tumor markers measured routinely in the laboratory.

    Science.gov (United States)

    Hui, Liu; Rixv, Liu; Xiuying, Zhou

    2015-12-01

    To develop an efficient and reliable approach to estimate tumor heterogeneity and improve tumor diagnosis using multiple tumor markers measured routinely in the clinical laboratory. A total of 161 patients with different cancers were recruited as the cancer group, and 91 patients with non-oncological conditions were required as the non-oncological disease group. The control group comprised 90 randomly selected healthy subjects. AFP, CEA, CYFRA, CA125, CA153, CA199, CA724, and NSE levels were measured in all these subjects with a chemiluminescent microparticle immunoassay. The tumor marker with the maximum S/CO value (sample test value:cutoff value for discriminating individuals with and without tumors) was considered as a specific tumor marker (STM) for an individual. Tumor heterogeneity index (THI)=N/P (N: number of STMs; P: percentage of individuals with STMs in a certain tumor population) was used to quantify tumor heterogeneity: high THI indicated high tumor heterogeneity. The tumor marker index (TMI), TMI = STM×(number of positive tumor markers+1), was used for diagnosis. The THIs of lung, gastric, and liver cancers were 8.33, 9.63, and 5.2, respectively, while the ROC-areas under the curve for TMI were 0.862, 0.809, and 0.966. In this study, we developed a novel index for tumor heterogeneity based on the expression of various routinely evaluated serum tumor markers. Development of an evaluation system for tumor heterogeneity on the basis of this index could provide an effective diagnostic tool for some cancers. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  6. STAT5b as Molecular Target in Pancreatic Cancer—Inhibition of Tumor Growth, Angiogenesis, and Metastases

    Directory of Open Access Journals (Sweden)

    Christian Moser

    2012-10-01

    Full Text Available The prognosis of patients suffering from pancreatic cancer is still poor and novel therapeutic options are urgently needed. Recently, the transcription factor signal transducer and activator of transcription 5b (STAT5b was associated with tumor progression in human solid cancer. Hence, we assessed whether STAT5b might serve as an anticancer target in ductal pancreatic adenocarcinoma (DPAC. We found that nuclear expression of STAT5b can be detected in approximately 50% of DPAC. Blockade of STAT5b by stable shRNA-mediated knockdown showed no effects on tumor cell growth in vitro. However, inhibition of tumor cell motility was found even in response to stimulation with epidermal growth factor or interleukin-6. These findings were paralleled by a reduction of prometastatic and proangiogenic factors in vitro. Subsequent in vivo experiments revealed a strong growth inhibition on STAT5b blockade in subcutaneous and orthotopic models. These findings were paralleled by impaired tumor angiogenesis in vivo. In contrast to the subcutaneous model, the orthotopic model revealed a strong reduction of tumor cell proliferation that emphasizes the meaning of assessing targets in an appropriate microenvironment. Taken together, our results suggest that STAT5b might be a potential novel target for human DPAC.

  7. Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors

    Directory of Open Access Journals (Sweden)

    Rossmeisl JH

    2017-04-01

    Full Text Available John H Rossmeisl,1–3 Kelli Hall-Manning,4 John L Robertson,1,3,5 Jamie N King,1,2 Rafael V Davalos,3,5 Waldemar Debinski,3 Subbiah Elankumaran6,† 1Veterinary and Comparative Neuro-Oncology Laboratory, 2Department of Small Animal Clinical Sciences, 3The Brain Tumor Center of Excellence, Wake Forest Baptist Medical Center Comprehensive Cancer Center, Winston-Salem, NC, 4Virginia Tech Animal Laboratory Services, Virginia-Maryland College of Veterinary Medicine, 5Department of Biomedical Engineering and Mechanics, Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Virginia Tech, 6Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA†The authors regret to advise of the passing of Dr Subbiah Elankumaran prior to publicationBackground: The expression of the urokinase plasminogen activator receptor (uPAR, a glycosylphosphatidylinositol-anchored protein family member, and the activity of its ligand, urokinase-type plasminogen activator (uPA, have been associated with the invasive and metastatic potentials of a variety of human brain tumors through their regulation of extracellular matrix degradation. Domesticated dogs develop naturally occurring brain tumors that share many clinical, phenotypic, molecular, and genetic features with their human counterparts, which has prompted the use of the dogs with spontaneous brain tumors as models to expedite the translation of novel brain tumor therapeutics to humans. There is currently little known regarding the role of the uPA system in canine brain tumorigenesis. The objective of this study was to characterize the expression of uPAR and the activity of uPA in canine brain tumors as justification for the development of uPAR-targeted brain tumor therapeutics in dogs.Methods: We investigated the expression of uPAR in 37 primary canine brain tumors using immunohistochemistry, Western blotting, real

  8. Mercury erosion experiments for spallation target system

    International Nuclear Information System (INIS)

    Kinoshita, Hidetaka; Kaminaga, Masanori; Haga, Katsuhiro; Hino, Ryutaro

    2003-01-01

    The Japan Atomic Energy Research Institute (JAERI) and the High Energy Accelerator Research Organization (KEK) are promoting a plan to construct the spallation neutron source at the Tokai Research Establishment, JAERI, under the High-Intensity Proton Accelerator Project (J-PARC). A mercury circulation system has been designed so as to supply mercury to the target stably under the rated flow rate of 41 m 3 /hr. Then, it was necessary to confirm a mercury pump performance from the viewpoint of making the mercury circulation system feasible, and more, to investigate erosion rate under the mercury flow as well as an amount of mercury remained on the surface after drain from the viewpoints of mechanical strength relating to the lifetime and remote handling of mercury components. The mercury pump performance was tested under the mercury flow conditions by using an experimental gear pump, which had almost the same structure as a practical mercury pump to be expected in the mercury circulation system, and the erosion rates in a mercury pipeline as well as the amount of mercury remained on the surface were also investigated. The discharged flow rates of the experimental gear pump increased linearly with the rotation speed, so that the gear pump would work as the flow meter. Erosion rates obtained under the mercury velocity less than 1.6 m/s was found to be so small that decrease of pipeline wall thickness would be 390 μm after 30-year operation under the rated mercury velocity of 0.7 m/s. For the amount of remaining mercury on the pipeline, remaining rates of weight and volume were estimated at 50.7 g/m 2 and 3.74 Hg-cm 3 /m 2 , respectively. Applying these remaining rates of weight and volume to the mercury target, the remaining mercury was estimated at about 106.5 g and 7.9 cm 3 . Radioactivity of this remaining mercury volume was found to be three-order lower than that of the target casing. (author)

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

    Directory of Open Access Journals (Sweden)

    Bian X

    2016-05-01

    Full Text Available Xinyu Bian,* Puyuan Wu,* Huizi Sha, Hanqing Qian, Qing Wang, Lei Cheng, Yang Yang, Mi Yang, Baorui LiuComprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China*These authors contributed equally to this workAbstract: 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. Keywords: EGFR, nanobody, iRGD, recombinant protein, targeting drug carriers, antitumor efficiency

  10. Tumor cell-specific photothermal killing by SELEX-derived DNA aptamer-targeted gold nanorods

    Science.gov (United States)

    Chandrasekaran, Ramya; Lee, Alexander Sheng Wei; Yap, Lim Wei; Jans, David A.; Wagstaff, Kylie M.; Cheng, Wenlong

    2015-12-01

    Despite widespread availability of cytotoxic chemotherapeutic agents, the killing of tumour cells without affecting healthy surrounding tissue remains elusive, although recent developments in terms of plasmonic nanoparticles capable of photothermal killing have some promise. Here we describe novel DNA aptamer-tethered gold nanorods (GNRs) that act as efficient photothermal therapeutics against tumour cells, but not their isogenic normal cell counterparts. A modified Cell-SELEX process was developed to select a novel DNA aptamer (KW16-13) that specifically recognised and was internalised by cells of the MCF10CA1h human breast ductal carcinoma line but not by those of its isogenic normal counterpart (MCF10A). GNRs conjugated to KW16-13 were readily internalized by the MCF10CA1h tumour cells with minimal uptake by MCF10A normal cells. Upon near infrared (NIR) light irradiation, tumour cell death of >96%, could be effected, compared to 71-fold tumor cell death than GNRs-targeted with a previously described aptamer. This demonstrates the significant potential for aptamer functionalised-GNRs to be used effective and above all selective anti-cancer photothermal therapeutics.Despite widespread availability of cytotoxic chemotherapeutic agents, the killing of tumour cells without affecting healthy surrounding tissue remains elusive, although recent developments in terms of plasmonic nanoparticles capable of photothermal killing have some promise. Here we describe novel DNA aptamer-tethered gold nanorods (GNRs) that act as efficient photothermal therapeutics against tumour cells, but not their isogenic normal cell counterparts. A modified Cell-SELEX process was developed to select a novel DNA aptamer (KW16-13) that specifically recognised and was internalised by cells of the MCF10CA1h human breast ductal carcinoma line but not by those of its isogenic normal counterpart (MCF10A). GNRs conjugated to KW16-13 were readily internalized by the MCF10CA1h tumour cells with minimal

  11. Solute carrier transporters: potential targets for digestive system neoplasms.

    Science.gov (United States)

    Xie, Jing; Zhu, Xiao Yan; Liu, Lu Ming; Meng, Zhi Qiang

    2018-01-01

    Digestive system neoplasms are the leading causes of cancer-related death all over the world. Solute carrier (SLC) superfamily is composed of a series of transporters that are ubiquitously expressed in organs and tissues of digestive systems and mediate specific uptake of small molecule substrates in facilitative manner. Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies. In this review, we critically summarized the recent advances in understanding the role of SLC proteins in digestive system neoplasms. We highlighted that several SLC subfamilies, including metal ion transporters, transporters of glucose and other sugars, transporters of urea, neurotransmitters and biogenic amines, ammonium and choline, inorganic cation/anion transporters, transporters of nucleotide, amino acid and oligopeptide organic anion transporters, transporters of vitamins and cofactors and mitochondrial carrier, may play important roles in mediating the initiation, progression, metastasis, and chemoresistance of digestive system neoplasms. Proteins in these SLC subfamilies may also have diagnostic and prognostic values to particular cancer types. Differential expression of SLC proteins in tumors of digestive system was analyzed by extracting data from human cancer database, which revealed that the roles of SLC proteins may either be dependent on the substrates they transport or be tissue specific. In addition, small molecule modulators that pharmacologically regulate the functions of SLC proteins were discussed for their possible application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-03-15

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

  13. Resveratrol-Loaded Albumin Nanoparticles with Prolonged Blood Circulation and Improved Biocompatibility for Highly Effective Targeted Pancreatic Tumor Therapy

    Science.gov (United States)

    Geng, Tao; Zhao, Xia; Ma, Meng; Zhu, Gang; Yin, Ling

    2017-06-01

    Human serum albumin (HSA) is an intrinsic protein and important carrier that transports endogenous as well as exogenous substances across cell membranes. Herein, we have designed and prepared resveratrol (RV)-loaded HSA nanoparticles conjugating RGD (arginine-glycine-aspartate) via a polyethylene glycol (PEG) "bridge" (HRP-RGD NPs) for highly effective targeted pancreatic tumor therapy. HRP-RGD NPs possess an average size of 120 ± 2.6 nm with a narrow distribution, a homodisperse spherical shape, a RV encapsulation efficiency of 62.5 ± 4.21%, and a maximum RV release ratio of 58.4.2 ± 2.8% at pH 5.0 and 37 °C. In vitro biocompatibility of RV is improved after coating with HSA and PEG. Confocal fluorescence images show that HRP-RGD NPs have the highest cellular uptake ratio of 47.3 ± 4.6% compared to HRP NPs and HRP-RGD NPs with free RGD blocking, attributing to an RGD-mediated effect. A cell counting kit-8 (CCK-8) assay indicates that HRP-RGD NPs without RV (HP-RGD NPs) have nearly no cytotoxicity, but HRP-RGD NPs are significantly more cytotoxic to PANC-1 cells compared to free RV and HRP NPs in a concentration dependent manner, showing apoptotic morphology. Furthermore, with a formulated PEG and HSA coating, HRP-RGD NPs prolong the blood circulation of RV, increasing approximately 5.43-fold (t1/2). After intravenous injection into tumor-bearing mice, the content of HRP-RGD NPs in tumor tissue was proven to be approximately 3.01- and 8.1-fold higher than that of HRP NPs and free RV, respectively. Based on these results, HRP-RGD NPs were used in an in vivo anti-cancer study and demonstrated the best tumor growth suppression effect of all tested drugs with no relapse, high in vivo biocompatibility, and no significant systemic toxicity over 35 days treatment. These results demonstrate that HRP-RGD NPs with prolonged blood circulation and improved biocompatibility have high anti-cancer effects with promising future applications in cancer therapy.

  14. Cell Cycle Regulating Kinase Cdk4 as a Potential Target for Tumor Cell Treatment and Tumor Imaging

    Directory of Open Access Journals (Sweden)

    Franziska Graf

    2009-01-01

    Full Text Available The cyclin-dependent kinase (Cdk-cyclin D/retinoblastoma (pRb/E2F cascade, which controls the G1/S transition of cell cycle, has been found to be altered in many neoplasias. Inhibition of this pathway by using, for example, selective Cdk4 inhibitors has been suggested to be a promising approach for cancer therapy. We hypothesized that appropriately radiolabeled Cdk4 inhibitors are suitable probes for tumor imaging and may be helpful studying cell proliferation processes in vivo by positron emission tomography. Herein, we report the synthesis and biological, biochemical, and radiopharmacological characterizations of two I124-labeled small molecule Cdk4 inhibitors (8-cyclopentyl-6-iodo-5-methyl-2-(4-piperazin-1-yl-phenylamino-8H-pyrido[2,3-d]-pyrimidin-7-one (CKIA and 8-cyclopentyl-6-iodo-5-methyl-2-(5-(piperazin-1-yl-pyridin-2-yl-amino-8H-pyrido[2,3-d]pyrimidin-7-one (CKIB. Our data demonstrate a defined and specific inhibition of tumor cell proliferation through CKIA and CKIB by inhibition of the Cdk4/pRb/E2F pathway emphasizing potential therapeutic benefit of CKIA and CKIB. Furthermore, radiopharmacological properties of [I124]CKIA and [I124]CKIB observed in human tumor cells are promising prerequisites for in vivo biodistribution and imaging studies.

  15. Fluorescent nanodiamonds engage innate immune effector cells: A potential vehicle for targeted anti-tumor immunotherapy.

    Science.gov (United States)

    Suarez-Kelly, Lorena P; Campbell, Amanda R; Rampersaud, Isaac V; Bumb, Ambika; Wang, Min S; Butchar, Jonathan P; Tridandapani, Susheela; Yu, Lianbo; Rampersaud, Arfaan A; Carson, William E

    2017-04-01

    Fluorescent nanodiamonds (FNDs) are nontoxic, infinitely photostable, and emit fluorescence in the near infrared region. Natural killer (NK) cells and monocytes are part of the innate immune system and are crucial to the control of carcinogenesis. FND-mediated stimulation of these cells may serve as a strategy to enhance anti-tumor activity. FNDs were fabricated with a diameter of 70±28 nm. Innate immune cell FND uptake, viability, surface marker expression, and cytokine production were evaluated in vitro. Evaluation of fluorescence emission from the FNDs was conducted in an animal model. In vitro results demonstrated that treatment of immune cells with FNDs resulted in significant dose-dependent FND uptake, no compromise in cell viability, and immune cell activation. FNDs were visualized in an animal model. Hence, FNDs may serve as novel agents with "track and trace" capabilities to stimulate innate immune cell anti-tumor responses, especially as FNDs are amenable to surface-conjugation with immunomodulatory molecules. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

    Science.gov (United States)

    Priceman, Saul J; Gerdts, Ethan A; Tilakawardane, Dileshni; Kennewick, Kelly T; Murad, John P; Park, Anthony K; Jeang, Brook; Yamaguchi, Yukiko; Yang, Xin; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E; Wu, Anna M; Brown, Christine E; Forman, Stephen J

    2018-01-01

    Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.

  17. From Chemotherapy to Combined Targeted Therapeutics: In Vitro and in Vivo Models to Decipher Intra-tumor Heterogeneity

    Directory of Open Access Journals (Sweden)

    Guido Gambara

    2018-02-01

    Full Text Available Recent advances in next-generation sequencing and other omics technologies capable to map cell fate provide increasing evidence on the crucial role of intra-tumor heterogeneity (ITH for cancer progression. The different facets of ITH, from genomic to microenvironmental heterogeneity and the hierarchical cellular architecture originating from the cancer stem cell compartment, contribute to the range of tumor phenotypes. Decoding these complex data resulting from the analysis of tumor tissue complexity poses a challenge for developing novel therapeutic strategies that can counteract tumor evolution and cellular plasticity. To achieve this aim, the development of in vitro and in vivo cancer models that resemble the complexity of ITH is crucial in understanding the interplay of cells and their (microenvironment and, consequently, in testing the efficacy of new targeted treatments and novel strategies of tailoring combinations of treatments to the individual composition of the tumor. This challenging approach may be an important cornerstone in overcoming the development of pharmaco-resistances during multiple lines of treatment. In this paper, we report the latest advances in patient-derived 3D (PD3D cell cultures and patient-derived tumor xenografts (PDX as in vitro and in vivo models that can retain the genetic and phenotypic heterogeneity of the tumor tissue.

  18. 4-Bromophenylhydrazinyl benzenesulfonylphenylureas as indoleamine 2,3-dioxygenase inhibitors with in vivo target inhibition and anti-tumor efficacy.

    Science.gov (United States)

    Lin, Shu-Yu; Yeh, Teng-Kuang; Song, Jen-Shin; Hung, Ming-Shiu; Cheng, Ming-Fu; Liao, Fang-Yu; Li, An-Shiou; Cheng, Shu-Ying; Lin, Li-Mei; Chiu, Chun-Hsien; Wu, Mine-Hsine; Lin, Yi-Jyun; Hsiao, Wenchi; Sun, Manwu; Wang, Yi-Hsin; Huang, Chin-Hsiang; Tang, Ya-Chu; Chang, Hsin-Huei; Huang, Zih-Ting; Chao, Yu-Sheng; Shih, Chuan; Pan, Shiow-Lin; Wu, Su-Ying; Kuo, Ching-Chuan; Ueng, Shau-Hua

    2018-02-12

    Indoleamine 2,3-dioxygenase is a heme-containing enzyme implicated in the down regulation of the anti-tumor immune response, and considered a promising anti-cancer drug target. Several pharmaceutical companies, including Pfizer, Merck, and Bristol-Myers Squibb, are known to be in pursuit of IDO inhibitors, and Incyte recently reported good results in the phase II clinical trial of the IDO inhibitor Epacadostat. In previous work, we developed a series of IDO inhibitors based on