State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Mol Pharm. 2011 Feb 7;8(1):162-75. doi: 10.1021/mp100249x. Epub 2010 Dec 10.
Intrinsic resistance of cancers is a major cause of failure in chemotherapy. We proposed here a strategy to overcome intrinsic resistance by constructing cancer cell mitochondria-specifically targeting drug-loaded liposomes, namely, mitosomal daunorubicin plus amlodipine. Anticancer agent daunorubicin and apoptotic inducer amlodipine were loaded together into the mitosomes, and targeting molecule dequalinium was modified on the surface. Evaluations were performed on the breast cancer MCF-7 and resistant MCF-7/adr cells and in animals. Mitosomal daunorubicin plus amlodipine were about 97 nm, selectively accumulated in mitochondria, induced the swelling and disruption of mitochondria, dissipated the mitochondrial membrane potential, released a large amount of cytochrome C by translocation, cleaved Bid, and initiated a cascade of caspase 8 and 3 reactions. A robust anticancer effect was evidenced in vivo. Mitochondria-specifically targeting drug-loaded liposomes would provide a new strategy for treating resistant cancers.
癌症的内在抗性是化疗失败的主要原因。在这里，我们提出了一种通过构建专门针对癌细胞线粒体的载药脂质体来克服内在抗性的策略，即米托蒽醌联合氨氯地平的载药脂质体。将抗癌药物米托蒽醌和凋亡诱导剂氨氯地平一起装载到米托体中，并在表面修饰靶向分子地喹氯铵。在乳腺癌 MCF-7 和耐药 MCF-7/adr 细胞及动物中进行了评估。米托蒽醌联合氨氯地平的载药脂质体约为 97nm，选择性地积聚在线粒体中，诱导线粒体肿胀和破坏，线粒体膜电位耗散，通过易位释放大量细胞色素 C，裂解 Bid，并启动 caspase 8 和 3 反应级联。体内也证明了强大的抗癌作用。线粒体特异性靶向载药脂质体为治疗耐药癌症提供了一种新策略。
