环糊精功能化无机纳米材料的构建及其介导的肿瘤多靶点治疗研究

Due to the special properties in optics, thermology, magnetics and excellent chemical stability, surface modified inorganic nano-materials can be applied as drug carriers to solve some key problems in tumor therapy and mechanism study in drug delivery. And inorganic nano-material has become the hot spot in cross-cutting areas of inorganic chemistry and life science research. This project is planned to assemble quantum dots and gold nanoparticles exhibiting unique optical and thermal properties with a series of 2-hydroxypropyl-cyclodextrin (2-HP-CD) coupled to positively charged linker and targeting ligands by mixed cordination. In-depth study would be conducted in the law of controlled assembly, biocompatibility in vitro and in vivo, drug encapsulation and release process and silence efficiency of target gene by anti-sense nucleotides including siRNA, miRNA and shRNA. New visible drug delivery systems with high targeting and delivery efficiency, especially clinically translatable gold nanoparticles drug delivery systems, would be obtained. Besides, combination therapy mediated by the above mentioned delivery systems, specifically co-delivery of different RNAi anti-sense nucleotides with chemotherapeutics, such as carboplatin, histone heacetylase inhibitor SAHA and paclitaxel, would be studied in vitro and in vivo. Through analyzing the results, we expect to establish laws and methods in sequential assembly of organic and inorganic hybrid medical nano-materials, summarize the impact of morphology and surface functionalization groups on the delivery efficiency and mechanism of drugs and genes, in order to lay the theoretical foundation for developing multifunctional drug co-delivery platforms in theranostic.

经过特定修饰的无机纳米材料作为药物载体，具有脂质体和高分子类药物载体所无法比拟的光、热、磁学特性和化学稳定性，可望解决药物输送机制研究和治疗的关键性难题，已成为无机化学与生命科学交叉领域的研究热点。本项目拟将不同空腔大小的环糊精和肿瘤细胞靶向修饰的电性偶联分子"混配"到具有光、热特性的量子点或纳米金等无机纳米材料上，研究其组装规律、生物相容性、药物包裹与缓释以及RNA干扰反义核酸（如siRNA、miRNA、shRNA等）对靶向基因的沉默效率，获得高靶向性、高输送效率的无机纳米载药系统，特别是具有临床价值的纳米金载药系统，在细胞和动物层次上开展联合运载RNA和化疗药物（如卡铂、伏立诺他、紫杉醇等）对肿瘤的多靶点治疗研究，拟发现和建立有机-无机医学材料多级组装和混配的规律和方法，总结材料尺寸形貌及表面功能化基团对药物输送效率及作用机制的影响，为构建肿瘤治疗多功能的联合载药平台奠定理论基础。

癌症治疗中药物疗法仍然是主要手段，包括化学与基因药物，但长时间使用产生耐药性、脱靶效应和各种毒性。如何提高药物靶向性及有效利用率并降低其毒副作用成为了科学家及医学工作者们最为关注的重要科学问题。由于顺铂类配合物占临床实际化疗药物的一半，因此发展靶向性好的新型抗肿瘤金属配合物和生物相容性好、基因转染效率高的新型药物输运材料是解决上述科学问题的重要方向之一。因此，本项目自2013年1月执行以来，取得了如下预期的研究成果：（1）发展了药物输运纳米材料构建新策略。通过优化设计、系统合成环糊精修饰量子点/介空二氧化硅无机有机杂化纳米材料，以及配合物与脂质体杂化组装，通过对siRNA及化学药物联合输运，开展基于纳米材料的协同及靶向治疗研究，揭示了联合治疗的协同机制，总结了纳米材料杂化修饰的可控组装规律。（2）发展和丰富了环糊精化学，从环糊精与无机纳米粒子组装到与环糊精修饰配合物自组装，大幅提升配合物的细胞摄取能力和靶向可控性，首次实现了配合物通过环糊精超分子自组装成纳米体系的药物自输送即“零载体”设计策略。（3）以G4-DNA、组蛋白去乙酰化酶等为分子靶点，设计合成一系列具备成像和联合治疗等功能的金属抗肿瘤配合物，进一步使用EPR自旋标记和NMR结构分析技术，确定了部分铂配合物与端粒核酸G-四连体的复合物的精确结构，为阐明化合物抗肿瘤的构效关系提供了化学生物学的结构基础。（4）以溶酶体、线粒体等细胞器为靶向，分别针对自噬、凋亡及能量代谢设计合成一系列荧光抗肿瘤过渡金属配合物，并作为光动力试剂，部分总结了配合物靶向定位规律与细胞死亡的关系，首次利用铱配合物诱导细胞自噬并用成像技术观察到活细胞内自噬过程。