口服给药、直盲肠靶向的新型手性铂-环糊精键接物前药研究

Oxaliplatin is the first chiral platinum-based anticancer drug and now is the preferred drug in treating advanced colorectal cancer. For the drug metabolism in stomach and small intestine, oxaliplatin has not the oral activity like other clinical platinum-based drugs, and for this reason, the cancer patients showed lower psychological acceptance, and oxaliplatin also showed serious side effects for being unable to target drug delivery. Cyclodextrin-drug conjugates exhibit favorable ideas of prodrug design for colon-specific delivery: after oral administration, there are very little conjugated prodrugs metabolized in stomach and small intestine, and most of them are metabolized by the specific enzymes in colon and release the parent drugs, and showed good targeting character. We will conjugate the important pharmacophore of oxaliplatin (chiral DACH or its derivatives) to the cyclodextrins by multistep reactions and afford new chiral ligands of amine-cyclodextrin conjugates, and further get the objective chiral platinum-cyclodextrin conjugated prodrugs via coordination chemistry reactions. We will also evaluate the biological characteristics of the prodrugs though in vitro anticancer activity tests, in vitro simulative drug release tests and tests of bioavailability after oral administration. Summarize the structure-activity relationship and lay a good foundation for finding a kind of platinum-cyclodextrin conjugated prodrugs which show favorable anticancer activity, oral administration activity and colon-specific delivery character.

奥沙利铂是第一个手性铂类药物，也是目前治疗晚期结直肠癌的首选药。由于在胃及小肠等处的代谢，奥沙利铂像其它已上市铂药一样无口服活性，病人心理接受度低；并且因不能实现靶向给药，毒副作用较为严重。环糊精键接药物体系作为一种直盲肠靶向药物载体，体现了良好的前药设计理念：键接物前药经口服给药后，在胃、小肠处的代谢极少，大部分为直盲肠处特定的酶代谢，释放出原药，具有很好的靶向性。我们采用独有的专利技术，通过多步反应将奥沙利铂重要的药效基团手性环己二胺(DACH)或其衍生物键接到环糊精边壁上，得到一类新型手性胺-环糊精键接物配体，进而通过配位化学反应得到目标手性铂-环糊精键接物前药。通过体外抗肿瘤活性实验、体外模拟释药实验以及大鼠口服给药生物利用度实验测试目标前药的生物学特征。总结构效关系，为发现一类具有良好抗肿瘤活性且可以实现口服给药、直盲肠靶向的新型手性铂-环糊精键接物前药先导配合物奠定良好的基础。

奥沙利铂是第一个手性铂类抗肿瘤药物，也是目前治疗晚期结直肠癌的首选药。由于在胃及小肠等处的代谢，奥沙利铂像其它已经上市的经典顺铂类药物一样没有口服活性，需要通过静脉滴注给药，病人心理接受度低；并且因不能实现靶向给药，毒副作用较为严重。环糊精键接药物给药体系作为一种直盲肠靶向的药物载体，体现了良好的前药设计理念：键接物前药经口服给药后，在胃、小肠处的代谢极少，大部分为直盲肠处特定的酶代谢，释放出原药，具有很好的靶向性。本项目实施过程中采用团队的专利合成技术，通过多步反应将奥沙利铂重要的药效基团手性环己二胺(DACH)或其衍生物键接到环糊精边壁上，得到一类新型手性胺-环糊精键接物配体，进而通过配位化学反应得到约70个新型的手性铂-环糊精键接物前药。通过核磁、质谱等一系列表征方法确证了它们的结构，并进行了基本的理化测试和稳定性测定。采用MTT法测试了其中理化性质较为稳定的60个键接物前药的体外抗肿瘤活性。结果表明，其中有3个键接物前药表现了良好的体外抗肿瘤活性，达到或接近阳性对照奥沙利铂，为下一步进行更加深入的作用机制研究指明了方向，同时也探索了铂类抗肿瘤药物靶向给药体系构建的一条新思路。总结本项目新制备化合物的构效关系，为发现一类具有良好抗肿瘤活性且可以实现口服给药、直盲肠靶向的新型手性铂-环糊精键接物前药先导配合物奠定了良好的基础。