自噬抑制剂和化疗药物协同纳米给药体系诱导肿瘤细胞凋亡作用的研究

The autophagy activity changes are closely associated with the genesis and development of human tumors and chemotherapy drug resistance. Enhanced autophagy activity can promote tumor cells autophagy to adapt to the lack of nutrition environment and survival via self-digestion, which enable tumor cells escape from apoptosis induced by chemotherapeutic drugs. Therefore, regulating autophagy activity in the treatment of tumors would become a new cancer treatment strategy. This project takes advantage of hyperbranched polymer nano-micelles as drug loading platform, co-loading autophagy inhibitor with conventional chemotherapy drug, and to form a collaborative nano-drug delivery system by autophagy inhibitor and chemotherapeutic agent. For this purpose,we design and synthesis amphiphilic hyperbranched polymer with hydrazone bond (pH sensitive) in molecular skeleton, and use it as a drug carrier. By using the molecular structure of the cavity and ligand reaction, both autophagy inhibitor (such as 3-Methyladenine etc.) and chemotherapy drug (such as doxorubicin etc.) are effective loaded. The drug release speed modulation, biofilm permeable increase, bioavailability improvement, and so on can be achieved through adjusting the functional molecule structure of the hyperbranched polymer carrier. Meanwhile, autophagy inhibitors can block the PI3K/Akt signaling pathway or inhibit destruction of the structure and function from lysosomal autophagic degradation, which will reduce the sensitivity of tumor cells to chemotherapeutic agents. So as to achieve the purpose of effectively induce apoptosis and to improve the therapeutic effect. Furthermore, the possible mechanism of the apoptosis of tumor cell induced by the collaborative nano-drug delivery system of autophagy inhibitor and chemotherapy drug is explored. This project aims to provide theoretical and experimental basis for effective cancer therapy.

自噬活性的变化与人类肿瘤的发生发展及肿瘤对化疗药物耐药密切相关，自噬活性增强可促使肿瘤细胞自噬适应缺养分环境，逃逸化疗药物诱导的凋亡。因此，调节自噬活性抑制肿瘤可能成为癌症治疗一个新策略。本课题利用超支化聚合物纳米胶束为载体，将自噬抑制剂与常规的化疗药物联合装载，形成自噬抑制剂和化疗药物协同纳米给药体系。为此，我们设计合成了分子骨架含有酰腙键（pH响应）的两亲性超支化聚合物作为药物载体，利用分子的空腔结构和配位反应实现自噬抑制剂（如3-甲基腺嘌呤等）与化疗药物（如阿霉素等）的有效装载。通过调节聚合物载体功能分子结构来调节释药的速度、增加生物膜的透过性、提高生物利用度等；通过自噬抑制剂抑制PI3K/Akt信号通路或破坏溶酶体的结构和功能阻止自噬降解，提高肿瘤细胞对化疗药物的敏感性，从而达到促进诱导细胞凋亡和提高疗效的目的。同时，探究其诱导肿瘤细胞凋亡的机理，为肿瘤有效治疗提供理论和实验依据。

本课题利用pH响应超支化聚酰腙为载体，将自噬抑制剂与常规的化疗药物联合装载，形成自噬抑制剂和化疗药物协同纳米给药体系。为此，我们设计合成了分子骨架含有酰腙键（pH响应）的两亲性超支化聚合物作为药物载体，利用分子的空腔结构和配位反应实现自噬抑制剂与化疗药物素等的有效装载。通过自噬抑制剂抑制PI3K/Akt信号通路阻止自噬降解，提高肿瘤细胞对化疗药物的敏感性，从而达到促进诱导细胞凋亡和提高疗效的目的。同时，探究其诱导肿瘤细胞凋亡的机理，为肿瘤有效治疗提供理论和实验依据。实验研究结果也充分证明了我们研究设想和方案的可行性和研究价值。进一步地，利用紫杉醇与多聚糖高分子（壳聚糖和葡聚糖）共组装构建微纳米纤维载药体系，探究其形成机制和在生物医药领域（如：药物洗脱支架、药物纳米悬液）中的潜在应用。