线粒体靶向性铂配合物的设计合成及其抗肿瘤活性研究

How to overcome severe side effects and drug resistance is the most compelling problem in the current development of platinum-based antitumor drugs. In this proposal, a class of mitochondria-targeted platinum-based antitumor drugs is designed to induce mitochondrial damage, directly leading to cell death. Considering the characteristics of the relative high polarity and negative potential of mitochondrial membrane in tumor cell, lipophilic cationic platinum complexes are synthesized for targeting mitochondria in this proposal. The bulky ligands are utilized to coordinate platinum, evading the attacks of glutathione and other thiol-functionalized bioactive substances and resultant drug resistance. The antitumor activities of mitochondria-targeted platinum complexes and their interactions with extra-/intracellular bioactive substances will be systematically studied using multiple analysis technics. This work is to pave a way for the development of next-generation platinum-based antitumor drugs with high efficiency, low toxicity, specific targets and clear mechanism.

如何有效克服毒副作用和耐药性是当前铂类抗肿瘤药物研究亟待解决的问题。本项目希望将铂类抗肿瘤药物靶向性导向肿瘤细胞线粒体，诱发线粒体损伤直接杀死肿瘤细胞。基于肿瘤细胞线粒体膜较高的极性和负电势这一特征，本项目拟设计一类亲脂性阳离子型铂配合物作为线粒体靶向性药物，同时引入空间位阻较大的配体螯合铂金属中心避免谷胱甘肽和其他巯基活性物质对铂原子进攻而产生耐药性。本研究将通过多种分析测试手段系统地研究线粒体靶向性铂配合物的抗肿瘤活性及其与细胞内外活性物质的相互作用，为设计新一代高效低毒、靶点明确及作用机制清楚的铂类抗肿瘤药物奠定基础。

如何对肿瘤进行精确治疗是当前肿瘤治疗领域的关键问题。本研究主要包括以下两个方面：1）基于肿瘤细胞线粒体膜较高的极性和负电势，设计合成了线粒体靶向性铂化合物PIP-platin，并研究了其抗肿瘤活性。研究发现线粒体靶向性铂类化合物PIP-platin在细胞和动物水平表现出优越的抗肿瘤活性，并且对细胞粘附和迁移能力具有很大影响。研究结果表明此类线粒体靶向性铂类化合物不但具有很好的抗肿瘤活性，而且能够有效抑制肿瘤迁移，有望开发成为一种具有双功能的新型靶向药物；2）近年来，光治疗作为肿瘤治疗新型手段，具有诸多优势。研究利用“铂基化”的策略成功构建出光敏剂自组装胶束Bodiplatin-NPs。该胶束具有均一的纳米尺寸，表现出良好的肿瘤靶向性。研究发现铂基化纳米药物在近红外光激发下，表现出优越的光动力/光热协同肿瘤治疗效果。上述工作已发表于Adv Mater（2篇），Metallomics（1篇），并申请国家发明专利2项。