以胆酸介导的肝靶向Pt(II)抗癌配合物的设计、合成、靶向性和抗癌作用研究

Platinum-based drugs represented by cisplatin, carboplatin and oxaliplatin are among a few chemotherapeutic agents effective against the liver cancer. However, the efficacy and applicability of platinum drugs are heavily restricted by severe systemic toxicities and drug resistance, due to their poor tumor-specificity. Nowadays, Drug targeting is a highly active field of research for anticancer drugs, for it can deliver the drugs directly to tumour sites, resulting in the decrease of drug-related toxicity as well as the increase of chemotherapy efficiency. Cholic acid, as a fundamental component for synthesis of bolic acid in liver organ, is up-taken and used mainly by hepatocytes, leading to the suggestion that this steroid could be used as carrier molecules to shuttle drugs to the liver.. With a view to using cholic acid as shuttles for delivering platinum anti-drugs to the liver tumor site, the present research program is to adopt a new coupling way for attaching cholic acid to the pharmacophores of clinically approved platinum drugs via cyclobutane-1,1-dicarboxylate as the linker, and to develop new cholic acid-mediated platinum anticancer complexes for targeting the liver tumor. The work of the present program mainly involves synthesis, liver targeting profile and anticancer activity of the designed platinum complexes. In addition, possible structure-activity relationship will also be explored.

铂类抗癌药物是少数几种对肝癌有效的药物之一，用于肝动脉灌注化疗和肝动脉介入栓塞化疗。然而，它们的临床应用还存在着两大缺陷，即毒副反应和耐药性，主要原因是药物对癌细胞/组织缺乏选择性。靶向给药是降低药物毒性和提高疗效的最有效方法之一，是抗癌药物发展的重要方向。胆酸为肝细胞合成胆汁酸的基本原料，主要被肝细胞摄取和利用，对肝组织具有很高的选择性，体内给药后大部分聚集在肝内，是一个理想的药物靶向肝的载体。. 本项目拟采用胆酸作为铂类药物的肝靶向载体，通过一种新的偶联方式和技术，将胆酸通过稳定的酰胺键连接在1,1-环丁二羧酸根的3位碳上，再与已批准上市的铂类药物的药效基团配位，合成出一类以胆酸为运转分子的肝靶向Pt(II)抗癌配合物，以期获得一种治疗肝癌的新型候选药物。项目的主要研究内容包括：目标铂配合物的合成、结构表征、靶向性研究、体内外抗肝癌的疗效评价和构效关系探讨。

肝癌是我国最常见的恶性肿瘤之一，全球50%以上的肝癌患者在中国。对于晚期患者，基于奥沙利铂Oxaliplatin 的FOLFOX4化疗，与索拉非Sorafenib分子靶向药物治疗和纳武单抗免疫疗法一起，成为被我国SFDA批准一线系统治疗的3个主要方案。尽管奥沙利铂化疗方案在延长中晚期肝癌患者生存期、控制病情，改善预后发挥着重要作用，然而它的临床应用还存在着两大缺陷（毒副反应和耐药性），主要原因是药物对癌细胞/组织缺乏选择性。靶向给药是降低药物毒性和提高疗效的最有效方法之一，是抗癌药物发展的重要方向。胆酸为肝细胞合成胆汁酸的基本原料，主要被肝细胞摄取和利用，对肝组织具有很高的选择性。胆酸在体内给药后大部分聚集在肝内，是一个理想的药物靶向肝的载体。. 通过研究和试验，已成功将胆酸通过酰胺键和1,1-环丁二羧酸根作linker，连接在治疗肝癌的一线药物奥沙利铂的药效基团上，研制出了一个具有自主知识产权的肝靶向性奥沙利铂前药LLC-202。通过药学学、药代动力学和初步毒性评价，LLC-202对动物模型的自发性原位肝癌的疗效优于奥沙利铂，显示出靶向治疗肝癌的前景。