可同步运载MDR-1 siRNA和阿霉素的多功能聚合物胶束及其逆转肿瘤多药耐药性的研究

恶性肿瘤是严重威胁人类生命健康的常见病、多发病，化疗仍然是其主要的临床治疗手段，但其效果却受到了肿瘤细胞耐药性的限制。在申请者前期工作的基础上，本项目拟构建一类多功能聚合物胶束用于同步运输anti-mdr1 siRNA和阿霉素，以实现逆转肿瘤多药耐药性并提高肿瘤治疗效果的目的。我们通过开环聚合结合点击化学等后修饰方法合成一系列官能化的聚环氧乙烷-聚ε-己内酯共聚物基元，然后筛选不同功能的聚合物基元与siRNA自组装形成共载药胶束。该系统可同时具有主动靶向肿瘤细胞、促进载体跨膜吸收和程序性释放药物等多重功能，并充分发挥不同组装基元间的协同增效作用。采用跨学科的先进研究手段深入探索这类载体系统在结构和功能上的相关性，建立适合的体内外模型评价其作用机制和治疗效果，为进一步的应用打下良好的基础。本项目设计思路新颖，相关基础工作扎实，具有较好的可行性。

Cancer is one of the major causes of death worldwide and chemotherapy is a major therapeutic approach for the treatment which may be used alone or combined with other forms of therapy. However, conventional chemotherapy suffers multidrug resistance. Herein we report on the development of polymeric micelles that can integrate multiple functions in one system, including the capability to accommodate a combination of therapeutic entities with different physicochemical properties, active cancer targeting, cell membrane translocation, and tunable drug release. This system was used to improve the efficacy of DOX in tumor models by simultaneous intracellular delivery of DOX and mdr-1 siRNA against the multidrug resistance. Such micellar system was constructed from degradable poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) block copolymers with functional groups on both blocks synthesized by ring opening polymerization combined with click chemistry. We will focus our efforts on performing a detailed structure/activity relationship analysis in terms of siRNA complexation, particulate properties, controlled self-assemble ability, receptor mediated endocytosis, intracellular transportation and gene silencing to gain a better insight and understanding of this micellar system. Based on our previous work, we think this multifunctional polymeric micellar system should hold great potential for the inhibition of P-gp-mediated DOX resistance in vitro and targeting of αvβ3-positive tumors in vivo.