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Mol Pharm. 2013 Oct 7;10(10):3789-800. doi: 10.1021/mp4004892. Epub 2013 Sep 18.

Mitochondria-specific pro-apoptotic activity of genistein lipidic nanocarriers.

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Arizona College of Osteopathic Medicine and ┬žDepartment of Pharmaceutical Sciences, College of Pharmacy-Glendale, Midwestern University , 19555 North 59th Avenue, Glendale, Arizona 85308, United States.


Genistein (Gen) soy isoflavone produces extensive pro-apoptotic anticancer effects, mediated predominantly via induction of mitochondrial damages. Rationalization of the native mitochondrial selectivity of Gen, utilizing biophysical model assumptions, led to our design of cationic lipid-based nanocarriers (NC) of Gen. Prototype nanoformulations, lipidic micelles (Mic) and nanoemulsions (NEs) incorporated Gen to serve as both therapeutic and targeting moieties, specific for mitochondria. Both Gen-NCs, showing superior physicochemical properties, produced significant cytotoxicity (5-10-fold lower EC50), compared to all drug controls, in hepatic and colon carcinomas. Owing to the mitochondria-specific accumulation of Gen-NCs, their mitochondrial depolarization effect was most evident, leading to marked activation of intrinsic apoptotic pathway markers--cytosolic cytochrme c and specific caspase-9--thus, confirming the direct mitochondrial action of Gen-NCs. This mechanistic evidence of the mitochondria specificity of our Gen-NE and Gen-Mic strongly indicates their potential as targeted delivery nanosystems to augment anticancer efficacy of many lipophilic chemotherapeutics.

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