TRAIL介导基于无机材料的层次化双重靶向肿瘤联合治疗给药系统构建及机制研究

Although traditional tumor treatment methods including chemotherapy, radiotherapy and surgery can achieve a good effect at present, the shortcomings such as side effect and potential risk cannot be ignored. In addition， traditional method can't control the recurrence and transfer of tumor, so the urgent call of a new treatment method is necessary. Selective inducing tumor tissues apoptosis and autophagy becomes a new research direction. The composite system based on inorganic materials which we intend to construct in this project could target to cell membrane and mitochondrial under the combined impact of TRAIL and triphenylphosphine（TPP）. Then the graphene quantum dots（GQDs） under the impact of near-infrared light and the targeting antibody for death receptor 4 can induce cell apoptosis and autophagy through different cell signalling pathways. In the meantime adriamycin inside of polydiethylaminoethylmethacrylate（PDEAEMA）with a combination of physical absorption can induce DNA damage through chemotherapy, so a combination of measures makes cancer therapy come true. The composite system has the following characteristics: long circulation, double targeting and combined therapy, etc. So it can breakthrough layer upon layer barriers , induce tumor tissues apoptosis and autophagy with a strong selectivity and have scarcely any effect on normal tissues. In addition, polymer dots conjugated on the graphene quantum dots can realize real time monitoring of composite system's distribution in vivo. Based on the composite system, we can study its intake mechanism、apoptosis and autophagy mechanism、mitochondrial function、immunogenicity、distribution in vivo and pharmacodynamic evaluation and provide reference for the application of it in both theory and practice significantly.

目前传统化疗、放疗和手术等手段虽可以对原位肿瘤进行较好治疗但存在毒副作用大、风险创伤大等缺陷，因此，迫切需要新型且更智能型的多重靶向治疗方法的出现。选择性诱导肿瘤细胞凋亡和自噬成为我们的构思。本课题拟构建的基于无机材料新型载药UGBT-PPA复合体系可在TRAIL靶向细胞膜和TPP靶向线粒体的双重靶向作用下，分别由石墨烯量子点受光激发和TRAIL通过不同信号通路诱导细胞凋亡和自噬，同时物理吸附于PDEAEMA中的DOX通过化疗造成DNA损伤，达到多管齐下联合治疗肿瘤的目的。该体系具有长循环、层次化双重靶向和联合治疗等特点，因此能突破层层障碍最终针对性较强的导致肿瘤凋亡自噬与坏死而对正常组织不产生损伤。同时共价连接的荧光聚合物点可通过荧光实时监测复合体系的体内分布情况。在此基础上，考察复合体系性质、摄取机制、凋亡自噬机制及体内分布、免疫原性、靶向性能和药效，为该体系的应用提供理论与实践基础。