The long-term Goal of this research is to develop novel targeted polymeric delivery systems that significantly enhance the therapeutic index of prostate cancer chemotherapy. The hypothesis is that chemotherapy therapeutic index can be significantly increased by targeting tumor microenvironment - specific polymeric conjugates to both angiogenic blood vessels and prostate tumor cells.
Three Specific Aims will be pursued: 1) To synthesize and characterize N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates with side-chains terminated in peptides targeted to prostate tumor neovasculature or tumor cell surface receptors. A model drug Geldanamycin (GA) with well known dual mode of action (antiangiogenic and antitumor) will be attached to the copolymers via lysosome degradable spacers. The conjugates will be characterized by physico-chemical methods and their stability evaluated after incubation with human serum. 2) To characterize the conjugates in vitro. The binding affinity of the conjugates will be evaluated on human endothelial and prostate tumor cell lines. Their antiangiogenic and antitumor efficacy will be evaluated in human endothelial and model prostate cancer cell lines respectively. The specificity of binding will be evaluated by comparing binding assays performed on several other cell types such as co-cultures of endothelial cells and fibroblasts, macrophages and leukocytes. 3) To characterize the conjugates by biological methods in vivo. The biodistribution, pharmacokinetics and efficacy of the conjugates will be monitored following intravenous administration in mice bearing prostate tumor xenografts varying in their degree of angiogenesis. Antiangiogenic and antitumor effects will be measured by vascular permeability and microvessel density measurements as well as by tumor histology and immunohistochemistry. The effect of combination therapy will be evaluated for the conjugates. This proposal is innovative in that: a) it is the first time active drug targeting to tumor angiogenic blood vessels using HPMA copolymers is proposed, b) novel prostate-specific peptides will be conjugated to the polymers that promise a higher degree of response to therapy, c) the influence of tumor physiology on localization will be evaluated to guide conjugate design, d) combination of targeted antiangiogenic and antitumor strategies will be evaluated. It is significant in that it can increase efficacy and reduce toxicity of prostate cancer chemotherapy. ? ? ?
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