外界刺激调控的超支化聚肽的合成及其光热-化疗纳米医学系统

Organism exhibits efficient and precise controlled polymerization for the synthesis of biomacromelecules in a temporal and spatial manner, which provides theoretical guidance and new ideas for the design and synthesis of biodegradable polymers. Therefore, developing external trigger-regulated spatiotemporal controlled polymerization methodology is becoming an advanced and challenging topic of current polymer chemistry. From the viewpoint of controlling the architecture and size of biodegradable polypeptide and developing the combined therapy for anticancer, this project will develop a kind of external-trigger (acid and temperature) regulated ring-opening polymerization (ROP) methodology for the amino acid-N-carboxyandride based "inimer" (Inimer-NCA), prepare hyperbranched polypeptide and copolymer with controlled architecture; Based on the multiple coordination effect between the highly dense amine- or thiol-surfaced hyperbranched polypeptide micelles and gold, the hyperbranched polypeptide micelles@gold nanocomposites that have excellent NIR absorption and photothermal conversion properties will be prepared, and the combined "photothermal and chemotherpy" technology for anticancer will be developed. The main contents include: the synthesis of Inimer-NCA monomer and the effect of external trigger on the ROP of Inimer-NCA; the synthesis of hyperbranched polypeptide and copolymer, the relationship between the architecture and the physical-self-assembly properties; the preparation of the hyperbranched polypeptide micelles@gold nanocomposites, the synergistic effect of both photothermal therapy and chemotherapy for aniticancer, and the biological assay.

生物体在合成生物大分子时展示了高效而精准的时空控制聚合特征，这为设计合成生物降解高分子提供了理论指导和新思路。因此，发展外界刺激调控的时空控制聚合方法已成为当前高分子化学的前沿而挑战性的课题之一。以控制生物降解聚肽的结构尺寸功能和发展抗肿瘤的联合治疗技术为出发点，本研究通过"酸和温度"外界刺激的共调节，发展一类用于氨基酸的"引发单体"的控制开环聚合方法，制备结构可控的超支化聚肽及其共聚物；基于超支化聚肽胶束表面含有高密度的胺基或巯基与金的多价配位作用，制备对近红外光具有优异的光吸收和光热转化性能的超支化聚肽胶束/金纳米复合载体，发展用于抗肿瘤的"光热-化疗"联合治疗技术。研究包括：氨基酸的引发单体的合成、外界刺激对开环聚合的影响；超支化聚肽及其共聚物的合成、结构与物化性能和自组装性能的关系；超支化聚肽胶束/金纳米复合载体的制备、光热治疗和化疗在抗肿瘤作用中的协同效应、生物学评价。

生物体在合成生物大分子时展示了高效而精准的时空控制聚合特征，这为设计合成生物降解高分子提供了理论指导和新思路。因此，发展外界刺激调控的时空控制聚合方法已成为当前高分子化学的前沿而挑战性的课题之一。以控制生物降解聚肽的结构尺寸功能和发展抗肿瘤的联合治疗技术为出发点，基于酸-碱动态化学，设计合成了离子型氨基酸引发单体四氟硼酸盐-L-赖氨酸-N-羧酸酐，制备了一系列支化度可控的超支化聚赖氨酸，发展了温度驱动的氨基酸单体的开环聚合新方法；拓展了基于光驱动的点击化学法制备超支化聚赖氨酸衍生物及其嵌段共聚物；构建了近红外响应性、糖靶向性聚肽胶束/金复合纳米药物体系，发展了用于抗肿瘤的光热疗—化疗或鸡尾酒化疗的联合治疗技术。主要进展与成果包括：揭示了离子型氨基酸单体动态解离形成环状二聚体，作为二级活性种引发单体聚合，实现了温度驱动的氨基酸单体的开环聚合及其温度对支化度的调节，制备了分子量分布窄、支化度为0.34-0.53的超支化聚赖氨酸；基于光驱动的巯基-炔点击化学，高效而快速地制备了高度支化的超支化聚赖氨酸苄酯及其聚乙二醇嵌段共聚物。以高密度巯基化聚肽胶束为模板，基于Au-S多价配位作用，发展了自还原法高效制备聚肽胶束/金复合纳米粒子及其用于光热疗—化疗或鸡尾酒化疗一体化的纳米药物平台；光热疗和化疗之间以及光热疗和鸡尾酒化疗之间的协同因子分别为0.74和0.76，均展现了良好的抗肿瘤协同效应。已发表SCI论文18篇，其中IF>4的论文13篇。