光敏性聚氨基酸共聚物及其多重响应性纳米医学系统

How to realize the efficient accumulation and quick drug-release of the anticancer drugs in the cancer sites and their cells is one of the key basic questions for polymeric biomaterials and nanomedicine. Therefore, to prepare and fabricate stimuli-responsive,targeted, and high drug-loaded biodegradable nanomedicine (or nanoscale drug delivery system), will provide a practicable tool for the efficient therapy of cancer and other rare illness. This project utilizes both the passive targeting of nanomicelles and the active targeting of biomolecules to realize the efficient accumulation of drugs; in order to realize the quick drug-release of the drugs into cells, both UV- and NIR-sensitive polypeptide copolymers that can adjust the drug-release properties of the hydrophobic anticancer drug-loaded nanomicelles, will be designed and synthesized; to utilize the reduction-responsive disulfide in vivo for controlling the interlayer cross-linking of nanomicelles, which will reduce the drug-release loss of drug-loaded nanomicelles during the blood circulation; to integrate all of the above-mentioned functions into nanomicelles, the photo-sensitive, targeted, reduction-responsive, and interlayer cross-linked polypeptide copolymers' nanomedicine can be fabricated. The main contents include: the design and synthesis of sugar-terminated photo-sensitive polypeptide-b-poly(ethylene oxide)copolymer, physical properties and self-assembly; the integrated functions into nanomicelles, the cooperative effect of these anticancer functions, and the biological assay.

如何实现抗癌药在癌症部位及其细胞内的高效富集与快速释放，是高分子生物材料及其纳米医学的关键科学问题之一。因此，制备与组装刺激响应性、靶向性、高载药量的生物降解高分子纳米医学系统（或纳米药物控释系统），为癌症等疑难疾病的高效治疗提供了切实可行的途径。本研究利用纳米胶束的被动靶向性与生物分子的主动靶向性，以实现药物在细胞内的高效富集；把紫外与近红外光敏性基团引入聚氨基酸共聚物，调节纳米胶束对于疏水性抗癌药物的释放性能，以实现药物在细胞内的快速释放；利用生物体内还原响应性的二硫键，控制纳米胶束的夹层交联，以减少载药胶束在血流循环中的释放损失；把上述功能集成起来，构筑光敏性、靶向性、还原响应性、夹层交联的聚氨基酸共聚物纳米医学系统。研究主要包括：糖端基化光敏性聚氨基酸-嵌段-聚乙二醇共聚物的设计合成、物化性能、及其自组装性能；纳米胶束的功能集成、在抗肿瘤作用中的协同效应、生物学评价。

如何实现抗癌药在癌症部位及其细胞内的高效富集与快速释放是高分子生物材料及其纳米医学的关键科学问题之一。因此，制备与组装刺激响应性（特别是近红外光响应性）、靶向性、高载药量的聚肽纳米药物体系为癌症等疑难疾病的高效治疗提供了切实可行的途径。本研究首次设计合成了紫外光敏性S-邻硝基苄基-L-半胱氨酸-N-羧酸酐单体，发展了基于氨基酸新单体的光敏性聚肽共聚物及其乳糖端基化共聚物的控制合成方法学，发现其具有光响应性和多重刺激响应性的自组装性能，进而提出了构筑乳糖靶向性和近红外光响应性的聚肽复合纳米药物的新途径。主要进展与成果包括：合成了精致结构的紫外光敏性聚（S-邻硝基苄-L-半胱氨酸）-嵌段-聚乙二醇共聚物及其乳糖端基化共聚物，建立了共聚物二级结构、组成与物化性能、光响应性组装性能的关系规律；阐明了多重刺激响应性（紫外光响应性、氧化或还原响应性）聚肽囊泡的自组装、再组装及其多响应性调控的抗癌药物控释性能和细胞毒性的关系；构建了乳糖靶向性、近红外光响应性、以及具有“开-关”药物释放模式的聚肽复合纳米药物，在细胞层次上揭示了“乳糖靶向性和近红外光响应性”在抗肿瘤作用中的协同效应。已发表SCI论文16篇，其中IF>5的论文11篇。