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Advanced Drug Delivery Reviews (v.64, #8)
Therapeutic strategies for controlling the metastasis and recurrence of cancers: contribution of drug delivery technologies by Yasufumi Kaneda (pp. 707-709).
Cancer therapy; Drug delivery system; Gene therapy
Cancer stromal targeting (CAST) therapy by Yasuhiro Matsumura (pp. 710-719).
Despite great advances in cell and molecular biology, pharmacology and medicine, there is to date no antitumor drug available which can specifically kill tumor cells in the human body without damaging normal tissue, because it has not been possible to find a truly cancer specific molecule to target.Low molecular weight (MW) anticancer drugs extravasate easily from normal vessels in the body causing drug adverse effects. Conversely, high MW anti-tumor agents including antibodies against cancer cell antigens, accumulate selectively in tumors because of their leaky vasculature. However, most human solid tumors possess abundant intercellular connective tissue, hindering diffusion of such macromolecules. That is why immunoconjugate therapy for stroma rich common solid cancer has not yet proved successful in clinics. In this review, I describe a successful new strategy that overcomes the above contradictory drawbacks by conjugating a small MW cyototoxic drug with an antibody against particular components of tumor stroma. Stroma-targeting immunconjugates bound to the stroma to create a scaffold, from which sustained release of cytotoxic agent occurred and subsequently diffused throughout the tumor tissue to damage both tumor cells and tumor vessels. Cancer-stroma targeting (CAST) therapy was thus validated as a new modality of oncological therapy, especially for refractory, stromal-rich cancers.Display Omitted
Keywords: Cancer stromal targeting; Blood coagulation; Fibrin; Collagen 4; Immunoconjugate
Evolution of oncolytic adenovirus for cancer treatment by Joung-Woo Choi; Jung-Sun Lee; Sung Wan Kim; Chae-Ok Yun (pp. 720-729).
Oncolytic adenovirus (Ad) has been used in cancer gene therapy largely due to its ability to selectively infect and replicate in tumor cells. However, because the oncolytic antitumor activity is insufficient to effectively eliminate tumors, various strategies have been devised to improve the therapeutic efficacy. Single-vector Ads “armed” with short hairpin RNA, cytokines, or matrix-modulating proteins have been developed. Two clear advantages are viral amplification of the therapeutic gene, and the additive effects of oncolytic and therapeutic gene-mediated antitumor activities. To develop systemically injectable Ad carriers, strategies to modify the Ad surface with polymers, liposomes, or nanoparticles have been shown to extend circulation time, reduce immunogenicity, and result in increased antitumor effect as well as lower accumulation and toxicity in liver. Specific targeting platforms for tumor-selective oncolytic therapies against both primary and metastatic cancers have been developed. This review will focus on updated strategies to develop potent oncolytic Ads for use in cancer treatment.Display Omitted
Keywords: Abbreviations; ABP; arginine-grafted bioreducible polymer; Ad; adenovirus; APC; antigen-presenting cell; CD or poly(CBA-DAH); poly(cystaminebisacrylamide-diaminohexane); CAR; coxsackievirus and adenovirus receptors; DC; dendritic cell; E1A- and E1B-double mutant oncolytic Ad; Ad-ΔB7; ECM; extracellular matrix; FA; folic acid; GM-CSF; granulocyte-macrophage colony-stimulating factor; HRE; hypoxia response element; IL; interleukin; PEG; polyethylene glycol; PSA; prostate-specific antigen; PSMA; prostate-specific membrane antigen; RGD; arginyl-glycyl-aspartic acid; shRNA; short hairpin RNA; VEGF; vascular endothelial growth factorSystemic adenovirus delivery; Polymer; Nano material; Nanocomplex; Gene therapy; Efficacy
Virosome: A novel vector to enable multi-modal strategies for cancer therapy by Yasufumi Kaneda (pp. 730-738).
Despite advancements in treatments, cancer remains a life-threatening disease that is resistant to therapy. Single-modal cancer therapy is often insufficient to provide complete remission. A revolution in cancer therapy may someday be provided by vector-based gene and drug delivery systems. However, it remains difficult to achieve this aim because viral and non-viral vectors have their own advantages and limitations. To overcome these limitations, virosomes have been constructed by combining viral components with non-viral vectors or by using pseudovirions without viral genome replication. Viruses, such as influenza virus, HVJ (hemagglutinating virus of Japan; Sendai virus) and hepatitis B virus, have been used in the construction of virosomes. The HVJ-derived vector is particularly promising due to its highly efficient delivery of DNA, siRNA, proteins and anti-cancer drugs. Furthermore, the HVJ envelope (HVJ-E) vector has intrinsic anti-tumor activities including the activation of multiple anti-tumor immunities and the induction of cancer-selective apoptosis. HVJ-E is currently being clinically used for the treatment of melanoma. A promising multi-modal cancer therapy will be achieved when virosomes with intrinsic anti-tumor activities are utilized as vectors for the delivery of anti-tumor drugs and genes.Display Omitted
Keywords: Pseudovirion; Synthetic vector; Virus; Anti-tumor immunity; Apoptosis; RNA; Fusion protein
Mesenchymal stem cells engineered for cancer therapy by Khalid Shah (pp. 739-748).
Recent pre-clinical and clinical studies have shown that stem cell-based therapies hold tremendous promise for the treatment of human disease. Mesenchymal stem cells (MSC) are emerging as promising anti-cancer agents which have an enormous potential to be utilized to treat a number of different cancer types. MSC have inherent tumor-trophic migratory properties, which allows them to serve as vehicles for delivering effective, targeted therapy to isolated tumors and metastatic disease. MSC have been readily engineered to express anti-proliferative, pro-apoptotic, anti-angiogenic agents that specifically target different cancer types. Many of these strategies have been validated in a wide range of studies evaluating treatment feasibility or efficacy, as well as establishing methods for real-time monitoring of stem cell migration in vivo for optimal therapy surveillance and accelerated development. This review aims to provide an in depth status of current MSC-based cancer therapies, as well as the prospects for their clinical translation.Display Omitted
Keywords: Mesenchymal stem cells; Cancer therapy; Migration; Delivery vehicles; Targeting; Molecular imaging
Combination of pet imaging with viral vectors for identification of cancer metastases by Peter Brader; Richard J. Wong; Gilad Horowitz; Ziv Gil (pp. 749-755).
There are three main ways for dissemination of solid tumors: direct invasion, lymphatic spread and hematogenic spread. The presence of metastases is the most significant factor in predicting prognosis and therefore evidence of metastases will influence decision-making regarding treatment. Conventional imaging techniques are limited in the evaluation and localization of metastases due to their restricted ability to identify subcentimeter neoplastic disease. Hence, there is a need for an effective noninvasive modality that can accurately identify occult metastases in cancer patients. One such method is the combination of positron emission tomography (PET) with vectors designed for delivery of reporter genes into target cells. Vectors expressing the herpes simplex virus-1 thymidine kinase ( HSV1-tk) reporter system have recently been shown to allow localization of micrometastases in animal models of cancer using non invasive imaging. Combination of HSV1-tk and PET imaging is based on the virtues of vectors which can carry and selectively express the HSV1- tk reporter gene in a variety of cancer cells but not in normal tissue. A radioactive tracer which is applied systemically is phosphorylated by the HSV1-tk enzyme, and as a consequence, the tracer accumulates in proportion to the level of HSV1-tk expression which can be imaged by PET.In this paper we review the recent developments in molecular imaging of micrometastases using replication-competent viral or nonviral vectors carrying the HSV1-tk gene using PET imaging. These diagnostic paradigms introduce an advantageous new concept in noninvasive molecular imaging with the potential benefits for improving patient care by providing guidance for therapy to patients with risk for metastases.Display Omitted
Keywords: Positron emission tomography; Oncolytic virus; Melanoma; Lymph node metastases; Molecular imaging; Gene therapy; Reporter genes
Genetic engineering with T cell receptors by Ling Zhang; Richard A. Morgan (pp. 756-762).
In the past two decades, human gene transfer research has been translated from a laboratory technology to clinical evaluation. The success of adoptive transfer of tumor-reactive lymphocytes to treat the patients with metastatic melanoma has led to new strategies to redirect normal T cells to recognize tumor antigens by genetic engineering with tumor antigen-specific T cell receptor (TCR) genes. This new strategy can generate large numbers of defined antigen-specific cells for therapeutic application. Much progress has been made to TCR gene transfer systems by optimizing gene expression and gene transfer protocols. Vector and protein modifications have enabled excellent expression of introduced TCR chains in human lymphocytes with reduced mis-pairing between the introduced and endogenous TCR chains. Initial clinical studies have demonstrated that TCR gene-engineered T cells could mediate tumor regression in vivo. In this review, we discuss the progress and prospects of TCR gene-engineered T cells as a therapeutic strategy for treating patients with melanoma and other cancers.Display Omitted
Keywords: T cell receptor; Gene therapy; Cancer immunotherapy