具有P-糖蛋白抑制功能的pH-、还原双敏感抗肿瘤载药胶束

项目名称： 具有P-糖蛋白抑制功能的pH-、还原双敏感抗肿瘤载药胶束

项目编号： No.21204024

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 高分子科学

项目作者： 谭松巍

作者单位： 华中科技大学

项目金额： 25万元

中文摘要： 细胞膜上高表达的P-糖蛋白（P-gp）是肿瘤产生耐药性的一个重要原因，也是化疗成功的主要障碍。针对这个问题，本项目拟合成一种能同步实现P-gp抑制和药物快速释放的新型pH-、还原双敏感接枝共聚物，用于化疗药的输送。该聚合物以能抑制P-gp的维生素E聚乙二醇1000琥珀酸酯（TPGS）为侧链，通过还原敏感的二硫键与pH敏感聚（β-氨基酯）（PBAE）主链连接。这种PBAE-g-TPGS共聚物可通过共混形成含靶向基团的混合胶束，再通过EPR效应富集于肿瘤组织，经受体介导胞吞进入肿瘤细胞。在内涵体弱酸性条件下，PBAE主链质子化，通过"质子海绵"效应致使内涵体破裂，快速释放包载的药物；同时，TPGS在胞内还原环境中从共聚物上解离，与P-gp结合，抑制其对药物的泵出。从而实现更高的肿瘤杀伤效果，降低所需药物剂量，为环境敏感型高分子药物传输系统逆转肿瘤多药耐药性的研究提供有价值的基础研究结果。

中文关键词： pH敏感；还原敏感；P-糖蛋白；肿瘤；胶束

英文摘要： Overexpression of the drug-efflux transporter P-glycoprotein (P-gp) is a key factor responsible for tumor multi-drug resistance (MDR). To solve this problem, a novel pH- and reduction dual-sensitive copolymer, poly (β-amino ester)-graft-vitamin E polyethylene glycol 1000 succinate (PBAE-g-TPGS) with intracellular drug burst releasing and P-gp inhibiting activity are designed for anticancer drug delivery. PBAE responses to the weakly acidic environment in cancer cells. TPGS is conjugated with PBEA through reduction-sensitive disulfide bridge and serves as the P-gp inhibitor. It could self-assemble into mixed micelles with targeting moieties by blending with folate-PEG-b-PBAE. These micelles could be accumulated in tumor tissues through EPR effect and be phagocytized into tumor cells via receptor mediated endocytosis. Under the mild acid condition in endosomes, PBAE is protonated, releases carried drugs quickly and further facilitates their escape from the endosomes by proton sponge effect. Meanwhile, TPGS can be dissociated from the copolymer in the reduction environment, inhibits P-gp activity thus leads to high levels of cellular drug accumulation. Therefore, a better anti-tumor efficacy of chemotherapeutics could be achieved. This project would give some valuable research results about stimuli-responsive drug

英文关键词： pH-sensitive；Redox-sensitive；P-glycoprotein；tumor；Micelle