新型骨癌靶向诊断治疗(theranostics)铂化合物研究

Because of the serious threat of bone tumors to human health and the special signance of chemotherapy . The anti-bone-cancer drugs of high activity and low toxicity is urgent . Combined with the new ideas, new methods of targeting prodrug, theranostics, multi-target and multi-mechanism studied modern anticancer drugs, we want to synthetize a group of prodrugs which are theranostics medicine and kill many birds with one stone, with the purpose that cisplatin, traditional chinese medicine active compounds and bisphosphonates would being synergistic anti-cancer effeciency of muti-targets and muti-mechanism when they are acting on tumors at the same times, and that the bisphosphonates is targeted-vector for bone tumor, 8-amino naphthalene acetamide is diagnosed-vector. Through the in vitro inhibition proliferation experiments of platinum complexes on bone-tumor and none-bone-tumor cell lines, One or two platinum complexes (candidates) with high antitumor activity and good selectivity are screened. At the same time, it,s tested that the reduction ability of candidates by enzymatic hydrolysis, and different anticancer mechanism with the bare drugs by molecular biology methods. It is expected that this project will provide new thought to obtain theranostics medicine which are targeted-bone tumors, with high activety, low toxicity, no-cross resistance.

由于恶性骨肿瘤严重威胁着人类健康及化疗对其治疗的特殊意义，寻求高效低毒性骨癌化疗药物具有迫切需求性。结合现代肿瘤药物研究中的靶向与前体药物、诊断治疗药物、多靶点多机制等新理念、新方法，利用多功能性双膦酸(N-BPs)作为骨肿瘤靶向载体和抗骨癌首选药—顺铂、特殊抗癌机制的中药活性成分(TCMAI)及抗骨转移类药—双膦酸在体内同时作用于肿瘤时会存在多靶点多机制协同抗癌效应的特点，同时利用8-氨基萘酰胺为时效诊断性分子，拟设计合成系列诊断治疗性化合物— “一石多鸟”型Pt(IV)类复合前体化合物。通过体内外实验对候选化合物的高效低毒性、耐药性、靶向性、时效诊断性等性质进行研究，同时利用分子生物学方法对前体化合物的酶解还原能力及与裸药(顺铂、TCMAI、N-BPs)抗癌机制的差异进行评价。期望为骨肿瘤特异靶向性、高效低毒性等诊断治疗性药物研究奠定一定理论基础。

针对临床药物选择性差，耐药性及毒副性大的缺点，以靶向策略设计合成了36个骨癌靶向性铂化合物，筛选出2个高细胞毒选择性、且具有诱导凋亡及免疫激活性能的候选化合物，这两个候选化合物具有较强的药用前景，为开发免疫活性铂类药物奠定了理论和实验基础。以前药的靶向策略合成了6个靶向缺氧癌细胞的顺铂前药化合物，这几个化合物在细胞水平表现出了较好的细胞毒选择性。同时利用前药的靶向性策略，合成了6个谷胱甘肽介导的喜树碱与其它不同抗癌机制的药效化合物形成的复合前体药物，这6个化合物在体内外体整体表现出较强的细胞毒选择性及抗耐药性，这几个复合前药也具有药用前景。结合金属有机化合物及异喹啉的生物活性特点，合成了8个类四氢异喹啉的金属有机化合物，筛选出了一个具有较强药用前景的双模式诱导细胞死亡的金属有机金化合物。本项目共发表SCI论文5篇，申请发明专利4项，授权1项。参加国际国内学术会议3次，培养硕士毕业生4名。