基于生物相容和生物可降解聚合物的抗肿瘤前药的合成及性能研究

本项目拟探索具有高载药量、低生物毒性、高体内循环稳定性和易生物降解的抗肿瘤聚合物前药的合成方法及性能。利用开环聚合、"Click"反应及有机化学反应相结合，以临床使用的几种抗肿瘤药物为模型，利用其引发水溶性环状磷酸酯单体聚合、或通过刺激敏感性基团（缩醛基、腙键、二硫键等），将药物与生物可降解性聚合物键合，并加以修饰肿瘤细胞靶向分子，获得一类新型抗肿瘤聚合物前药。这类聚合物前药能够在水溶液中发生自组装，形成以疏水药物为核、亲水聚合物为壳的纳米药物胶束，肿瘤靶向分子位于胶束表面；同时，它们还可以进一步用于包覆疏水性抗癌药物，用以提高载药量、控制药物释放速率和提高药物的生物利用度。系统研究合成聚合物前药的反应条件、聚合物结构与分子量、前药的自组装结构与粒径以及所键合的刺激敏感性基团对药物控释和肿瘤细胞增殖的抑制作用。本项目对于发展新型抗肿瘤聚合物前药，具有重要的理论意义和潜在的应用价值。

The present project aims to explore the synthesis and properties of anti-tumor polymeric prodrugs with high drug loading content, low toxicity, high stability in systemic circulation and favorable biodegradability. A series of novel polymeric prodrugs based on several kinds of clinical anti-tumor drugs can be obtained via a combination of ring-opening polymerization (ROP), "Click" chemistry and other organic reactions. They will be prepared by two synthetic routes, one is the ROP reaction of cyclic phosphoester monomers using the drugs as initiators; the other is the conjugation of drugs with biodegradable polymers using stimuli-responsive bonds (acetal, hydrazone, or disulfide groups) as the linkages. After that, tumor-targeting molecules will be introduced to the polymeric produgs. These polymeric prodrugs can self-assemble in aqueous solution to form the nano-micelles with hydrophobic anti-tumor drug as the core and hydrophilic polymers as the shell, while tumor-targeting molecule is located on the surface of micelles. In addition, they can be further used to encapsulate hydrophobic anti-tumor drugs for the purpose of increasing the drug loading content, controlling drug release and enhancing the drug bioavailability. The effects of several parameters on the drug release and inhibition to proliferation of tumor cells will be systematically studied, including polymerization condition, polymer structure and molecular weight, the morphology and size of self-assembled nanoparticles, and the stimuli-responsive linkage. This project is supposed to have some thoretical significance and practical application in the development of novel anti-tumor polymeric prodrugs.