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，显著提高前列腺癌化疗的治疗指数。假设将肿瘤微环境特异性聚合物偶联物同时靶向血管生成血管和前列腺肿瘤细胞，可显著提高化疗治疗指数。本研究将有三个具体目标：1)合成并表征N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-药物偶联物，其侧链末端为针对前列腺肿瘤新生血管或肿瘤细胞表面受体的肽。模型药物格尔达霉素（GA）具有众所周知的双重作用模式（抗血管生成和抗肿瘤）将通过溶酶体可降解的间隔物附着在共聚物上。结合物将通过物理化学方法进行表征，并在与人血清孵育后评估其稳定性。2)对缀合物进行体外表征。将在人内皮细胞和前列腺肿瘤细胞系上评价这些结合物的结合亲和力。我们将分别在人前列腺内皮细胞和模型前列腺癌细胞株上评价它们的抗血管生成和抗肿瘤作用。结合的特异性将通过比较几种其他细胞类型（如内皮细胞和成纤维细胞、巨噬细胞和白细胞的共培养）的结合试验来评估。3)用生物学方法在体内对缀合物进行表征。在血管生成程度不同的异种前列腺肿瘤小鼠体内静脉给药后，将监测结合物的生物分布、药代动力学和疗效。抗血管生成和抗肿瘤作用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来测量。对结合物的联合治疗效果进行评价。该方案的创新之处在于：a)首次提出了利用HPMA共聚物靶向肿瘤血管的活性药物；b)新型前列腺特异性肽将被偶联到聚合物上，有望对治疗产生更高程度的反应；c)将评估肿瘤生理学对定位的影响，以指导偶联物的设计；d)将评估靶向抗血管生成和抗肿瘤策略的组合。它可以提高前列腺癌化疗的疗效，降低化疗的毒副作用。

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.