Methods in Molecular Biology, 2015, 1265:85-101.

Mitochondriotropic Nanoemulsified Genistein-Loaded Vehicles for Cancer Therapy

Jimmy Pham, Oliver Grundmann, Tamer Elbayoumi

Arizona College of Osteopathic Medicine, Midwestern University, 19555N. 59th Avenue, Glendale, AZ, 85308, USA.

Genistein (Gen), a major soy isoflavone, produces extensive pro-apoptotic anticancer effects, mediated predominantly via induction of mitochondrial damage. Based on several biophysical model criteria, our rational assumptions for the native mitochondrial selectivity of Gen allowed its design as a cationic lipid-based nanocarrier (NC) system. Proof-of-concept nano-formulations, lipidic micelles (Mic), and nanoemulsions (NEs) incorporated Gen, which serves as therapeutic and targeting moieties, specific for mitochondria. Our in vitro experimental data demonstrated superior physicochemical properties and significant cytotoxicity of Gen-NCs (five- to tenfolds lower EC50) compared to all drug controls, in hepatic and colon carcinomas. The established mitochondria-specific accumulation of the various Gen-NCs positively correlated with marked mitochondrial depolarization effects. Within first 24 h, Gen-NC treatments ultimately lead to distinct activation of intrinsic apoptotic pathway markers, such as cytosolic cytochrome c and specific caspase-9 vs. nonspecific caspases-3, 7, and 8. Such mechanistic evidence of the mitochondriotropic activity of our Gen-NC platforms favors their prospective as intracellularly targeted delivery nano-vehicles, to enhance anticancer efficacy of different co-formulated chemotherapeutic agents.

美国《分子生物学方法》，2015年

线粒体纳米乳化的金雀异黄素负载物用于治疗癌症

吉米范、 奥利弗 格伦德曼、 塔梅尔 奥拜尤米

美国西部大学亚利桑那骨科医学院

金雀异黄素 （Gen），一种主要的大豆异黄酮，产生了广泛的促凋亡抗癌效果，主要通过诱导线粒体损伤调节。基于几种生物模型标准，我们理性的假设，原生的线粒体对Gen 的选择性允许其被设计为阳离子基脂质纳米载体 (NC) 体系。概念证明纳米剂型，油脂胶束 (Mic)，和纳米乳液 (NEs) 封装Gen，可作为治疗和靶向性基团，特定的线粒体。我们在体外的实验数据证明与所有药物相比，Gen-NCs在肝癌及大肠癌中具有优异的理化性能和显著的细胞毒性（低于 EC50 5-10倍）。不同的Gen-NCs已获得的特定线粒体累积物与标记线粒体的去极化效应呈正相关。第一个 24 小时内，Gen-NC治疗最终导致了内在凋亡通路标记物的明显活化，如游离细胞色素 c 和特异性半胱氨酸蛋白酶-9与 非特异性半胱氨酸蛋白酶-3，7 和 8。Gen-NC的线粒体活性的机械证据有利于他们将来成为细胞内靶向性纳米载体，以增强不同组成化疗药物的抗癌疗效。