药物相互作用对共包载盐霉素和siRNA纳米给药系统抗肿瘤效应的影响及其分子机制研究

Cancer heterogeneities are major obstacles for effective cancer chemotherapy. Multifunctional targeted drug delivery system represents a potentially powerful strategy for the treatment of cancer. This project is to develop self-assembled multifunctional nanoparticles for co-delivery of negative charged siRNA (targeting to EGFR gene) and hydrophobic drug (salinomycin). A novel amphiphilic and cationic diblock copolymer named PCL-S-S-PDMAEMA was designed and synthesized to form the nanoparticles. The nanoparticles were decorated with AS1411, a DNA aptamer specifically binding to nucleolin which is highly expressed in the plasma membrane of cancer cells. AS1411 was conjugated to TPGS forming a TPGS-AS1411 complex, and then modified to the surface of nanoparticles. This system was aimed to increase the efficiency of cancer treatment by multi-target therapeutics. After fundamental understanding the construction and quality control of the nanoparticles we will focus on two key factors. One is the enhancement of siRNA-mediated gene silencing through co-loading of salinomycin, and the other is effect of EGFR downregulated expression on anti-cancer efficacy of salinomycin. Our initial fundamental studies will give important insights that might clarify the molecular mechanisms of synergistic anti-tumor efficacy of gene medicine and chemotherapeutics. This project will also provide new a new route to completely cure tumor based on multifunctional drug delivery systems.

肿瘤异质性给肿瘤治疗带来了巨大挑战，设计和构建多功能载基因药物系统可能是肿瘤彻底治疗的一种新策略。本项目以新设计合成的两亲性阳离子嵌段聚合物PCL-S-S-PDMAEMA自组装形成胶束纳米载体，同时包载靶向肿瘤相关基因（如EGFR）的负电性siRNA和靶向肿瘤干细胞的疏水性药物盐霉素，并修饰TPGS偶联AS1411为靶向配体，构建多功能纳米载药系统，以研究多靶点抗肿瘤效果。在获得构建该纳米系统的基本规律与质控特点的基础上，重点研究考察盐霉素共包载能否增强siRNA基因沉默效应? EGFR等表达下调能否增强盐霉素抗肿瘤干细胞效应？课题将首次探索基因药物与肿瘤干细胞杀灭药物协同抗肿瘤作用的分子机制，研究结果将为“根治”肿瘤的多功能载药系统研究提供新思路。

本研究设计了多种肿瘤微环境敏感性共聚物材料，如：[PCL-PMAA-PDMAEMA]4，PEG-BHyd-dC12，PEOz-PLA等，以靶向配体精胺或亚精胺等进行化学修饰增强其细胞摄取，利用共聚物材料两亲性特征自组装成纳米胶束，表面精胺或亚精胺修饰可促进纳米粒的细胞主动摄取，将紫杉醇等化疗药物包载于疏水核心，可在肿瘤微环境中迅速释放起效，亲水层的阳离子片段则可递送siRNA发挥基因沉默效应，体内外的药效学评价均显示这些纳米载体具有较好的抗肿瘤效应。同时我们还探讨了不同大小共聚物片段对胶束/siRNA复合物结构和转染效率的影响，为该类型纳米粒的合理设计提供参考。这些研究以肿瘤微环境触发为中心，围绕解析材料结构与功能间的关系、药物抗肿瘤分子机制这两个基本点，探讨了构建肿瘤微环境敏感纳米载体的设计规律，为改善临床肿瘤治疗效果提供科学依据。该课题相关研究成果已发表在《ACS Nano》、《International Journal of Pharmaceutics》、《European Journal of Pharmaceutical Sciences》、《RSC Advances》、 《International Journal of Nanomedicine》等SCI收录杂志，共发表SCI论文7篇, 2016年至今培养2名博士生和1名硕士生。