诱导细胞涨亡的铱(III)配合物研究

Overcoming tumor drug resistance is challenge in chemotherapy drug design. In recent years, the exploration of new mechanisms for drug-induced cell death has attracted great interest. Oncosis is a kind of atypical cell death, and may offer a new effective way for overcoming the tumor resistance. This project is constructing cyclometalated iridium(III) complexes that target the cell mitochondria; Combined with the spectroscopy, biochemistry, biophysics and molecular biology, we will study the specific form and acting way of mitochondria damage caused by iridium complexes. From the cell level, the mitochondria damage of signal transduction, and the relationship between the activation of cancer cells signal regulating oncosis kinase and downstream events will be investigated, the relationship between the iridium complexes damage mitochondria and induce the oncosis will be discussed, and the chemical small molecular probe with specific regulation function to the action of relevant signal molecules will be looked for. For those iridium complexes with obvious tumor proliferation inhibitory activity in naked mice animal model experiment, we will evaluate their drug effectiveness from living level. We hope the results to be of value in further setting up the new metal complexes drug design thought, as well as looking for high efficiency, low toxicity of a new generation of inorganic cancer drugs.

克服肿瘤耐药是化疗药物设计的难题。近年来探寻化疗药物诱导癌细胞死亡的新机制，引起了人们的极大兴趣。细胞涨亡是一种非典型性细胞死亡，可为克服肿瘤耐药性提供一种新的有效途径。本项目拟通过环金属化结构修饰，构建靶向富集线粒体的铱(III)配合物。结合波谱学、生物化学、生物物理和分子生物学方法，研究铱(III)配合物引起线粒体损伤的具体作用机制和构效关系；从细胞水平上研究线粒体损伤信号的转导、对肿瘤细胞中涨亡相关蛋白的激活及下游事件的关系，探讨铱(III)配合物损伤线粒体诱导细胞涨亡的作用机制，寻找对相关信号分子有特异性调控作用的化学小分子探针；对有明显抑制肿瘤增殖作用的铱(III)配合物开展裸鼠动物模型实验，从活体水平上评价其药物有效性。这方面的研究对建立新的金属配合物药物设计思想，寻找高效、低毒的新一代无机抗癌药物有着重要意义。

克服肿瘤耐药是化疗药物设计的难题。近年来探寻化疗药物诱导癌细胞死亡的新机制，引起了人们的极大兴趣。本项目基于铱(III)配合物，通过金属配合物的构建和结构修饰，实现了对肿瘤细胞内细胞器的靶向富集和特异性杀伤，发现多个能有效诱导肿瘤细胞涨亡或诱导免疫原性细胞死亡的金属配合物；通过金属配合物的超分子组装和光物理性质调控，发展了具有双光子荧光示踪和乏氧光动力疗的分子诊疗试剂，实现了对癌细胞内关键蛋白的氧化损伤，揭示了乏氧条件下可引起细胞内氧化还原失衡而导致细胞死亡的新机制。在Nat. Chem., Nat. Commun., Angew. Chem. Int. Ed., Proc. Natl, Acad. Sci. USA, Biomaterials, Chem. Sci.等国际期刊发表SCI论文46篇，所有论文均为通讯作者。培养博士研究生12人、硕士研究生2人。先后在国内外20多个学术会议做大会报告、主题报告和邀请报告。