基于中药活性成分的金属抗肿瘤药物对线粒体靶向作用机制的研究

Mitochondria play a role in regulation of cell apoptosis and necrosis; it is involved with a lot of diseases, such as cancer. Therefore, it is a frontier of the current drug research that to choose mitochondria as the targets. Meanwhile, it is a new approach on innovating drugs that by making use of the dual functions of the traditional Chinese medicine active ingredients (TCMAIs) and metal ions in the metal-based drug design field. The aim of this project is to investigate the targeting mechanism of the new metal complex anticancer agents what are designed by our key laboratory to the mitochondria comprehensively. A series of metal-based anticancer agents which are with different ligands and metal ions will be choused. The effects of these compounds on the functiones and conditiones of mitochondria will be investigated by using a serious experimental methods, such as microscope analysis, fluorescence anisotropy, Clark Oxygen Electrode, and micro-calorimetry, et al. The changes of the physiological functions of mitochondria such as the structure of mitochondria, permeability of H+ and K+, membrane potential, opening of the permeability transition pores and membrane fluidity will be systematically investigated, and the possible mechanisms will be discussed. Base on the above researches, several new metal-based TCMAI complexes with the better targeting activity to mitochondria will be designed and synthesized. The results will provide the basic information and experimental proofs for improving the new metal-based anticancer agents. It will also play an important guiding role in understanding the anticancer mechanisms of these drugs more comprehensively, and in improving the theory of designing the mitochondria targeted anticancer agents.

由于线粒体具有调控细胞凋亡和坏死的功能，它与癌症等疾病的发生密切相关，因此以线粒体为靶点的药物设计成为前沿科学领域。同时，在金属药物设计中发挥中药活性成分和金属离子的双重功能是创新药物的一条途径。本项目拟以线粒体为靶点，研究本重点实验室近年来合成的系列基于中药活性物质的新型金属抗肿瘤药物对线粒体的靶向作用机制。本项目将综合利用显微分析、荧光偏振、呼吸耗氧、微量热等多种手段和方法，系统的研究以不同中药活性物质为配体、不同金属离子为中心原子的配合物，对于线粒体的结构、钾、氢离子的渗透性、膜电势、渗透转换孔开放、膜流动性等生理参数的影响，并探讨其机理。在此基础上进一步设计和合成对线粒体靶向性更好的中药活性成分金属药物。研究结果将为设计更好的金属抗肿瘤药物提供基础信息和理论依据；也将对我们更全面地认识该类药物的抗癌机理、完善线粒体靶向的药物设计理论具有重要的指导意义。

线粒体是重要的细胞器，它与癌症等疾病的发生密切相关，因此以线粒体为靶点的药物设计成为前沿科学领域。许多中药活性成分具有抗肿瘤的活性，在金属药物设计中发挥中药活性成分和金属离子的双重功能是创新药物的一条途径。本项目主要研究了中药活性成分及其金属配合物、金属离子、有机溶剂等在体外对线粒体的结构、钾、氢离子的渗透性、膜电势、渗透转换孔开放、膜流动性等生理活性参数的影响，并探讨其机理。这些物质包括1-氮杂苯并蒽酮及其Pt配合物、芦丁、桑色素、白皮杉醇、山柰酚、氧化白藜芦醇、三乙酰基间苯三酚、有机胂(PDT-BIPA)、棕矢车菊素、Hg2+、Pb2+、CH3HgCl、DMSO、DMF和EtOH等。研究发现各种物质对线粒体的作用效果和机制有自己的特点：当助溶用有机溶剂在研究体系中的浓度小于1%体积分数时，其影响可以忽略，较高浓度时对线粒体结构和功能有损害；Hg2+、Pb2+、CH3HgCl等对线粒体结构和功能有强烈的损伤作用；药物对线粒体结构和功能的影响存在浓度依赖效应，多数物质是损伤效果，少数物质具有保护的效果。为了提高此类研究的效率，研制了线粒体生理活性指标同步分析仪器和方法。这些研究结果将对更全面地认识该类药物的抗癌机理、完善线粒体靶向的药物设计理论具有重要的指导意义。