酶响应性纳米介孔硅药物控释系统及生物学评价研究

针对肝肿瘤治疗中药物利用效率低及毒副作用大的问题，本研究设计了基于肿瘤细胞及其细胞外微环境触发的2类酶响应性纳米介孔硅药物控释系统：金属基质蛋白酶响应性及谷胱甘肽还原酶响应性系统。拟采用天然大分子(羧甲基化壳聚糖、明胶、透明质酸等)及天然蛋白分子(牛血清蛋白、纤维原蛋白等)作为纳米介孔硅封堵剂，提高该系统的生物相容性及降低炎症响应。通过引入靶向分子(叶酸、半乳糖等)及细胞穿膜肽，赋予该系统靶向给药性能及提高细胞吞噬效率。研究酶响应性药物释放性能及规律。从细胞和分子水平系统地探究纳米介孔硅药物控释系统的细胞相容性、细胞内分布、细胞内吞途径(网格蛋白通路等)及机理、炎症响应及机制、抗肿瘤药物（多霉素盐酸盐、阿霉素等）细胞内释放诱导细胞凋亡及机制。以小鼠肿瘤模型探究该系统在肝、肾、脾等器官及肿瘤组织中的分布及靶向性聚集，对肿瘤治疗的抑制作用及机理。为此类药物控释系统的研究提供重要的理论依据。

Considering the issues of low drug efficiency and high toxic side effect during liver tumor therapy, the project designs two types of enzyme responsive controlled drug release systems based on meseoporous silica nanoparticles (MSNs): matrix metalloproteinase responsive and glutathione reductase responsive systems. Those systems would be triggered by enzymes within tumor cells and extracellular microenvironment. Natural polymers (carboxymethyl chitosan, gelatin, hyaluronic acid, etc.) and natural proteins (bovine serum albumin, fibrinogen, etc) would be employed to seal the MSNs as capping agents, which are expected to improve the biocompatibility and reduce the inflammatory responses of the systems. The introduction of targeting molecules (folic acid, galactose, etc.) and cell-penetrating peptides (CPPs) would provide the systems with targeted drug delivery and improve cellular endocytosis efficiency. The study will investigate the enzyme responsive drug release property and its rules. Then, the study will systematically investigate at cellular and molecular levels on the cytocompatibility, intracellular distribution, cellular endocytosis pathways (i. g. clathrin pathway) and its mechanism, inflammatory reaction and its mechanism, intracellular delivery of anti-tumor drug (daunorubicin hydrochloride, doxorubicin etc.) and its induced cell apoptosis as well as mechanism of the MSNs controlled drug release systems. Finally, the study will investigate the distribution and targeted aggregation of the MSNs system within organs (liver, kidney and spleen etc.) and tumor tissue, and their inhibition effects on tumor therapy and the potential mechanism, by employing a naked mouse model. The study would provide important theory reference for the development of the similar controlled drug release system.