受体介导的胞内酶敏感型纳米载体的构建及其联合载药抗肿瘤功效研究

Targeted co-delivery multiple drugs is an important strategy for improving tumor therapy. This project is to develop a transferrin receptor-mediated intracellular enzyme-response biodegradable multifunctional nanocarrier for targeted co-delivery of chemical drug and siRNA during treatment of cancer. A novel amphiphilic bioreducible cholesterol graft poly(amido amine)s containing multiple disulfide linkages (SS-PAA-g-Chol) is synthesized and used to form the positive-charged polymer micelles containing lipophilic chemical drug and hydrophilic siRNA, and the coating of liposome by electrostatic interaction further enhances the stability of nanocarriers.Also,the nanocarrier modified with T7 peptide (HAIYPRH) could exhibit good targeted delivery efficiency by transferrin receptor-mediated endocytosis in tumor cells, and the internalized nanocarriers are further rapidly disintegrated and releasing drugs into cytosol due to the cleavage of disulfide-bonds in the reducing enviroment.The project is to explore the relationship of anticancer activity and strucutre of this nanocarrier. Each component of this nanocarrier has good biocompatibility. Based on good preliminary basis, this project has good feasibility and it will be completed successfully by our research team.

靶向联合给药是改善肿瘤治疗效果的重要策略。本项目利用两亲性聚合物胆固醇修饰的含二硫键超支化聚（酰胺-胺）（SS-PAA-g-Chol）自组装形成的胶束同时包载疏水性化学药物和亲水性siRNA，胶束外层包被脂膜可进一步提高纳米载体稳定性，并利用脂膜上修饰的导向化合物DSPE-PEG-T7(T7肽:HAIYPRH）在转铁蛋白受体介导下实现抗肿瘤药物靶向联合递送。聚合物中二硫键在胞内还原酶作用下断裂而使得复合物解聚释放出所包载的siRNA和化学药物，因此获得多靶点联合治疗肿瘤的效应。本项目旨在探索这种新型的胞内酶敏感型靶向纳米载体联合给药抗肿瘤治疗效应，用跨学科研究手段阐明相关科学问题，具有较好的科学意义。本研究设计思路目前国内外未见报道。本项目新颖性较好，研究力量较强，科研条件具备，工作基础较扎实，部分前期研究结果表明本项目的可行性较好。

本课题研究目标是构建高效低毒的受体介导的胞内酶敏感型纳米联合载药系统，以期利用所载siRNA与化学药物同步靶向肿瘤部位，实现肿瘤多靶点同步治疗效应。本研究设计开发了至少两种胞内酶敏感型SS-PAA-g-Chol, ssGLCL材料，利用材料两亲性在水相介质中形成自组装纳米颗粒并包载递送siRNA。我们利用T7肽和伐普肽（Vap）等多肽配体修饰的靶向载体用于siRNA与化疗药物的联合递送。体内外的抗肿瘤评价结果表明这些胞内酶敏感型共递送载药系统具有较好抗肿瘤治疗效应。这些研究围绕着结构-效应相关性及抗肿瘤分子作用机制，将有利于揭示出多靶点抗肿瘤治疗药物制剂的设计规律，并为进一步应用研究提供理论基础和实践参考。目前，该课题相关研究结果已发表在《Biomaterials》、《Journal of Controlled Release》、《European Journal of Pharmaceutical Sciences》等杂志上，共发表SCI学术论文7篇及国内核心期刊5篇（均标注基金号），申请并获得专利1项，培养博士生3名，硕士生6名。