线粒体靶向性铂类配合物干预肿瘤代谢机制的研究

Cancer therapy has gained much attention in recent years. The substance and energy metabolisms of some cancer cells keep increasing after chemotherapy, which is supposed to be a major risk of cancer recurrence. Mitochondria play central roles in cell energy conversion, metabolism, and apoptosis. Particularly, energy metabolism is important for balancing the energy requirements of cell maintenance. The bioenergetic alterations associated with cancer cells could be key factors to inhibit cancer growth. Therefore, targeting mitochondria and intervening cellular metabolism could be a feasible and effective strategy for tumor therapy. Platinum-based drugs are major chemotherapeutic agents used to treat various cancers. However, the side effects and drug resistance are huge barriers for improving the clinical efficacy. Thus, the design of new functional platinum-based complexes is important for understanding distinct anticancer mechanisms. In this study, some mitochondrion-targeted Pt complexes will be designed and prepared, in which platinum pharmacophore will be linked to delocalized lipophilic cations. The complexes are designed to target mitochondria and interrupt cancer cell metabolisms. The interaction between the complexes and DNA will be studied; the cellular uptake, in vitro and vivo anticancer activity, and pharmacokinetics will be evaluated. The mitochondrial accumulation, abnormality in mitochondria of cancer cells after drugs treatment will be investigated, including depolarized mitochondrial membrane potential, respiration injury and related-enzymes activities. This study will provide a new insight into the mechanism of action of platinum-based anticancer complexes towards cancer cells.

癌症治疗的严峻形势使抗癌药物研究受到广泛关注。癌细胞化疗后，其物质代谢和能量代谢增强，易引起癌症复发。线粒体是细胞能量产生的重要场所，诱导线粒体结构和功能障碍是抑制癌细胞增殖的重要手段，因此，靶向线粒体从而干预癌细胞能量代谢途径，是治疗癌症的新策略。传统铂类抗癌药物在临床应用时存在严重的毒副作用和耐药性，新型铂类配合物有望完善抗癌机制，改善治疗效果。本项目拟设计一系列线粒体靶向性铂类配合物，它们同时具有铂药效中心和线粒体靶向基团，可影响线粒体结构和功能，干预癌细胞代谢方式，从而发挥多重抗癌机制。该项目除了研究配合物与DNA的相互作用，细胞摄取能力以及体内体外抗肿瘤效果外，重点研究配合物靶向线粒体的能力，对线粒体结构和功能的影响以及对癌细胞能量代谢的影响，为金属抗癌药物的设计和研发探索新方向。

癌细胞与正常细胞相比，其能量代谢能力更强，即使化疗，也易引起癌症复发。因此，干预癌细胞能量代谢成为治疗癌症的新策略。线粒体作为能量代谢和凋亡机制的关键场所，成为本项目的研究重点靶标。本项目从改进铂类药物的结构入手，成功设计合成了七种新型线粒体靶向性铂类配合物。第一类铂（II）配合物，可使细胞核DNA构象改变、线粒体DNA基因损伤、破坏线粒体的结构和功能，这种同时干预DNA复制和能量代谢途径的作用机制与现有铂类药物的作用机理不同。第二类前药型铂（IV）配合物，铂中心轴向配体为羟基和三苯基鏻衍生物，铂（IV）配合物在体内被生物含硫分子还原后，可引起线粒体功能障碍，影响肿瘤代谢，促进细胞凋亡。同时，阐明了铂中心轴向配体修饰功能化基团的个数与细胞毒活性之间的关系。第三类前药型铂（IV）配合物，铂中心轴向配体为生物素（biotin）和二氯乙酸，可抑制biotin受体高表达的癌细胞，下调PDK2蛋白，损伤癌细胞线粒体内糖酵解和氧化磷酸化过程，通过线粒体介导的凋亡蛋白诱导癌细胞死亡。此研究不仅确定了线粒体为铂类抗肿瘤药物新的作用靶点，还拓宽抗癌药物设计方向——癌细胞能量代谢，有效规避了细胞核DNA的自我修复机制，在克服铂类药物毒副作用及癌细胞耐药性问题上取得了原创性成果。