Polymers for Targeted Delivery of Angiogenic Inhibitors

描述（由申请人提供）：本研究的长期目标是开发新型靶向聚合物递送系统，显著增强前列腺癌化疗的治疗指数。该假设是，通过将肿瘤微环境特异性聚合物缀合物靶向血管生成血管和前列腺肿瘤细胞，可以显著增加化疗治疗指数。本论文的主要目的是：1）合成和表征N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-药物偶联物，其侧链终止于靶向前列腺肿瘤新生血管或肿瘤细胞表面受体的肽。具有众所周知的双重作用模式（抗血管生成和抗肿瘤）的模型药物格尔德霉素（GA）将通过溶酶体可降解的间隔物连接到共聚物上。将通过理化方法表征结合物，并在与人血清孵育后评价其稳定性。2)体外表征结合物。将在人内皮和前列腺肿瘤细胞系上评价缀合物的结合亲和力。将分别在人内皮细胞和模型前列腺癌细胞系中评价其抗血管生成和抗肿瘤功效。将通过比较对几种其他细胞类型（如内皮细胞和成纤维细胞、巨噬细胞和白细胞的共培养物）进行的结合试验，评价结合特异性。3)通过体内生物学方法表征偶联物。在携带前列腺肿瘤异种移植物的小鼠中静脉内施用后，监测缀合物的生物分布、药代动力学和功效，所述前列腺肿瘤异种移植物的血管生成程度不同。将通过血管通透性和微血管密度测量以及肿瘤组织学和免疫组织化学测量抗血管生成和抗肿瘤作用。将评价结合物的联合治疗效果。这一建议的创新之处在于：a）这是首次提出使用HPMA共聚物靶向肿瘤血管生成血管的活性药物，B）新的前列腺特异性肽将与承诺对治疗有更高程度响应的聚合物缀合，c）将评估肿瘤生理学对定位的影响以指导缀合物设计，d）将评价靶向抗血管生成和抗肿瘤策略的组合。其意义在于它可以提高前列腺癌化疗的疗效和降低毒性。

DESCRIPTION (provided by applicant): 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.