诱导肿瘤细胞自噬的胞内信号感知纳米药物分级释放系统

Tumor drug resistance is the main reason leading to the decrease of chemotherapy effect. Autophagy inducer could increase the sensitivity of tumor cells to chemotherapeutic drugs and overcome drug resistance. The project aims to this problem to build a new nano-drug delivery system that induced autophagy in tumor cells with intracellular signal. The targeting molecule cRGD-modified hyaluronic acid (HA) as the main chain and the chrysin-modified polypeptide biodegradable polymer grafted modified HA which is able to sense intracellular stimulus signal, were loaded with autophagy inducer rapamycin and chemotherapy drug doxorubicin through the amphipathic polymeric self-assembly. High drug loading content is received via the π-π stacking interaction between chrysin and drugs. Drug released from the carriers in sequence after entering drug resistant SKOV3 tumor cells. Firstly released of rapamycin with intracellular enzyme-catalyzed, which could induce autophagy to enhance the sensitivity of SKOV3 tumor cells to doxorubicin and overcome resistance to doxorubicin. And then doxorubicin loaded nanoparticles enter the nucleus under the action of the transmembrane peptide TAT and improve the therapeutic effect on SKOV3 ovarian cancer cells. This project will acquire a new type of nano-drug delivery system, which will provide new ideas and methods for the treatment of drug-resistant tumors.

肿瘤耐药性是导致化疗效果降低的主要原因。利用自噬诱导剂可提高肿瘤细胞对化疗药物的敏感性，克服耐药性。本项目基于这一原理，构建能够诱导肿瘤细胞自噬，具有胞内信号感知功能的纳米药物分级释放系统。以靶向分子cRGD改性的透明质酸(HA)为主链，将能够感知胞内刺激信号并断裂的多肽将白杨素改性的生物降解高分子接枝到改性HA上，通过双亲性高分子的自组装分别负载细胞自噬诱导剂雷帕霉素和化疗药物阿霉素。利用白杨素与药物的π-π堆叠作用，提高载药量。进入SKOV3耐药肿瘤细胞后的载药纳米粒子分级释放出所负载的药物。先在胞内酶催化下释放雷帕霉素，诱导细胞自噬，加强SKOV3肿瘤细胞对阿霉素的敏感性，克服对阿霉素的耐药性。负载阿霉素的纳米粒子在穿膜肽TAT的作用下进入细胞核，提高对耐药SKOV3卵巢癌的治疗效果。本项目的实施，将获得一类新的纳米药物释放系统，为耐药肿瘤的治疗提供新的思路和方法。

肿瘤耐药性是导致化疗效果降低的主要原因。肿瘤细胞自噬可提高细胞对化疗药物的敏感性，克服耐药性。本项目设计合成了一系列能够诱导肿瘤细胞自噬，具有胞内信号感知功能的纳米载药释放系统，系统研究了载体材料的组成、结构、形貌与药物传输功能相关性，获得了多种高递送效率且具有胞内信号感知功能的药物载体材料；通过载药纳米粒子的跨膜入胞、溶酶体逃逸、自噬、核靶向递送药物等过程及途径，制备了能够诱导肿瘤细胞自噬，具有高递送效率的胞内多级感知响应型纳米载体材料；通过诱导肿瘤细胞自噬与化疗药物的协同作用对肿瘤耐药性作用机理研究，构建了可逆转肿瘤耐药性的高效自噬诱导活性纳米药物递送系统；建立了具有自噬诱导活性的纳米载药递送系统治疗肿瘤相关的检测技术；成功完成了具有胞内信号感知功能纳米载药释放系统的构建，载药纳米粒子在血液输送过程中的稳定性，体内组织器官的分布、代谢及生物安全性等体内外功能研究。本项目的实施，获得一系列新型功能型纳米载药系统，为临床上耐药肿瘤的治疗提供新的思路和方法。共发表SCI收录研究论文8篇，其中中科院分区一区的论文4篇，中科院分区二区的论文4篇；还有2篇内容均已完成投稿。项目团队成员与欧洲及美国的多所高校和研究所建立了合作关系，团队成员1人获得基金委面上项目。参加项目的硕士研究生共计4名，博士后合作1名。