癌症已经成为威胁人类健康的第一杀手，但是目前主要基于靶受体和信号通路的化学药物治疗，虽然挽救了很多患者的生命，但是也给患者带来了很多副作用。虽然有时可以通过微粒给药系统来提高药物的靶向性，但并不都能行得通。肿瘤细胞上高度表达的膜转运蛋白，利用它们为靶点来提高药物的肿瘤靶向是非常有前途的，而且适合我国目前新药创制的条件。本课题以高度表达在结肠癌细胞上的氨基酸转运蛋白(ATB0, +)为靶点，选择氟尿苷（Floxuridine）为模型药物，在氟尿苷的羟基位引入氨基酸，从与ATB0, +亲和性和前药激活速率两方面对氟尿苷氨基酸酯前药进行考察和筛选；结合药物理化和结构参数，建立定量结构-亲和性/降解速率关系，指导前药的合理设计。选择适宜的前药进行小鼠药动学、组织分布和药效学研究，考察体内的活化机制、分布行为，并筛选出最佳候选前药。前期工作结果表明本项目可行性良好。

Cancer has become the first threat to the health of the people all over the world. Though the chemotherapy based on the target receptor and the signal channel saved many patients with cancer, it brought a lot of side effects to people. The particulate delivery system could increase the ability of anticancer drugs to target the tumor cell. But this strategy was not effective in some circumstance. The membrane transporters widely expressed in the tumor tissue have become promising targets for the drug delivery system. In the present study, some amino acid prodrugs of floxuridine targeted to amino acid transporter (ATB0, +, SLC6A14) highly expressed in the colon cancer were synthesized by attaching amino acid to the hydroxyl group. The prodrugs were evaluated by the affinity to ATB0, + and the activation rate. To help the rational design of successful prodrugs, the quantitative structure-affinity/hydrolysis rate relationships were constructed by analyzing the physiochemical and structural parameter of the prodrug. The pharmacokinetics, the tissue distribution and the pharmacodynamics of the candidate prodrug was studied in rat to delineate the hydrolysis mechanism, and the target efficiency. The preliminary result showed the present study was feasible.