目前，针对肿瘤氧化还原微环境敏感的化学桥连主要以硫键为主，开发新型智能响应型敏感键具有重要的科学意义和实用价值。本课题拟基于肿瘤微环境构建氧化还原双重响应型前药自组装纳米递药系统。设计合成含有不同化学桥连（单硫键、单硒键、二硫键和二硒键）的紫杉醇-香茅醇小分子前药，并制备前药自组装纳米粒，通过高载药量（>50%）、体内长循环和EPR效应实现肿瘤靶向高效药物递送。在肿瘤部位，前药结构中的化学桥连会在肿瘤细胞高表达的活性氧和谷胱甘肽的作用下快速断裂，实现肿瘤细胞内快速释药，进而提高紫杉醇的抗肿瘤效果并降低毒副作用。同时，解析含有不同化学桥连前药的氧化还原敏感释药机制，并考察化学桥连的引入对前药的自组装、纳米粒的稳定性、氧化还原敏感释药能力、细胞毒性、药动学、组织分布以及药效学的影响。本课题将丰富智能响应型化学桥连的设计理论，为开发肿瘤微环境智能响应型药物递送系统提供新的策略和思路。

The development of novel redox-responsive linkages has long been a focus of research in cancer therapy, as the current state is mainly based on the sulfide bonds. In the present study, a serious of paclitaxel-citronellol prodrugs were developed, using thioether bond, selenium bond, disulfide bond and diselenide bond as linkages. The prodrugs can self-assemble into uniform size nanoparticles with impressive high drug loading (>50%). The prodrug nanoassemblies exhibited improved tumor accumulation through the long circulation time and EPR effects. Besides, the linkages showed distinct redox dual-responsive property, with on-demand drug release in the present of the over expressed reactive oxygen species (ROS) and glutathione (GSH) in tumor cells. The mechanism of redox-responsive drug release of the sulfur/selenium bond bridged prodrug nanoassemblies were investigated, and the influence of linkages on the self-assemble ability, colloidal stability, redox-dual responsive drug release, cytotoxicity, pharmacokinetics, tissue distribution and antitumor efficiency were also studied. Our findings give new insight into the effects of linkages in prodrug-based drug delivery systems (DDS), and provide a good foundation for the development of novel redox dual-responsive DDS for cancer therapy.