具有P-糖蛋白抑制功能的pH-、还原双敏感抗肿瘤载药胶束

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 delivery system to overcome the MDR.

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。

针对耐药肿瘤细胞膜表面高表达P-糖蛋白（P-gp）而导致传统化疗效果不佳的特点，本项目从具有高生物相容性和P-gp抑制能力的药用辅料维生素E聚乙二醇1000琥珀酸酯（TPGS）出发，结合聚合物的刺激响应性，构建完成了3类共聚物药物传递体系：（1）叶酸靶向TPGS-聚（β-氨基酯）（PBAE）pH-、还原双敏感混合胶束；（2）pH敏感壳聚糖接枝TPGS共聚物纳米粒；（3）还原/pH-敏感TPGS前药胶束；对这些材料的化学结构、自组装行为及还原/pH-敏感性进行了详细研究。结果表明，这3个体系均能有效实现对化疗药物的包载，形成直径在100-200nm间的胶束/纳米粒结构，从而通过EPR被动靶向或/和通过叶酸主动靶向于肿瘤组织，经胞吞后对肿瘤细胞内特殊环境产生响应，快速释放出所负载的药物；同时，TPGS发挥P-gp抑制功效，保证药物在耐药肿瘤细胞内的有效蓄积，从而起到克服肿瘤耐药性的作用。相较于普通临床制剂，本项目药物传递体系的耐药肿瘤抑瘤率可提高1倍以上，表现出良好的临床应用前景。