基于胸苷酸合成酶靶标和半乳糖凝集素受体介导的多重结肠肿瘤靶向给药系统的构建及评价

针对临床结肠癌化疗中存在的问题，根据结肠的生理特点和药物的作用机理,本项目拟构建一类基于胸苷酸合成酶靶标和半乳糖凝集素受体介导的多重结肠肿瘤靶向给药系统。该给药系统利用结肠存在大量多糖降解酶的生理特点，以半乳糖化壳聚糖（GC）和海藻酸钠复合膜降解实现结肠定位释放；同时利用GC具有粘膜粘附性和可能增强所载药物通过粘膜上皮细胞的性质，延长给药系统作用时间，增强药物粘膜吸收；然后利用半乳糖凝集素受体(galectin-3)介导的内吞作用实现结肠肿瘤细胞靶向，并高效入胞到达胞浆；最后利用5-Fu及其增效剂甲酰四氢叶酸（LV）的代谢产物与胸苷酸合成酶形成三联复合物，抑制DNA合成。本项目拟构建的给药系统将集结肠靶向、结肠癌细胞靶向和胸苷酸合成酶靶向三级靶向，同时兼具粘膜粘附性，可为新型高效、低毒的结肠靶向肿瘤治疗的设计、发现和成药性提供理论和实验基础。

Considering the issues existing in the clinical chemotherapy for colon cancer, we intend to develop a class of oral multi-targeted drug delivery system in our project, which is mediated by galectin receptor and then targets at thymidylate synthase (TS).This idea is proposed according to the physiological characteristics of colon and the function mechanism of drugs. The composite film made up by galactosylated chitosan(GC) and sodium alginate(Alg) is degraded in the colon due to a mass of polysaccharide degrading enzymes in this place , thus realizing the positioning release of drug; Simultaneously, this system also take advantage of the properties,including prolonging the duration of this drug delivery system in colon and enhancing the drug uptake by the mucosa cells, which play a role by characteristics of mucoadhesion and promoting the loading-drug through epithelial cells possessed by galactosylated chitosan(GC); Afterwards, the endocytosis mediated by galectin-3 will be utilized to achieve cell targeting for colon cancer, furthermore, the drug enters into the cytoplasm with high efficiency; Ultimately, the metabolites of 5-fluorouracil(5-Fu) and leucovorin(LV) that acts as a synergist for 5-FU will form a triple complex together with TS, contributing to the inhibition of DNA synthesis. The drug delivery system constructed by our project is a three-level target involving colon targeting, colon cancer cell targeting, and TS targeting, and is provided with the characteristics of adhesion to mucosa, consequently shedding light on the design, discovery and druggability of a novel colon cancer targeting therapy with high efficiency and low toxicity.