Doxironide Magnetic Nanoparticles for Selective Drug Delivery to Human Acute Myeloid Leukemia

We report the development of a chemotherapeutic formulation made of polymeric-stabilized multifunctional magnetic metal oxide nanoparticles (M(3)NPs) of ferrites loaded with the anticancer drug Doxorubicin (Dox) as a promising drug carrier to AML. Loading efficiencies and release rates of the prepared NPs were thoroughly investigated. Using M(3)NPdrug conjugates (denoted as Doxironide), nanoparticulate uptake and cell death were evaluated in four different types of human AML target cells: ML-2, HL-60, Mono-Mac-1, and TF1-vRaf, as well as on normal human SVG-p12 cells. While the unloaded NPs were not toxic to any of the cells, Doxironide was found to be highly potent to the four AML cell lines, albeit at different inhibition concentrations (IC50 ranging from 0.48 to 4.8 mu M Dox). Interestingly, and superior to free Dox, Doxironide was found to be more effective in killing the AML cells compared to the human normal cells (similar to 40x fold), suggesting huge potentials as selective AML anticancer agents. Electron, flow, and live confocal microscopy imaging mechanistically confirmed that the NPs were successfully uptaken, endocytosed and packaged into vesicles inside the cytoplasm, where Dox is released and then translocated to the nucleus exerting its cytotoxic action and causing apoptotic cell death. Importantly, this selective payload may potentially enhance the efficacy of drugs in AML patients and may further allow physicians to image leukemic cells exposed to Doxironide, opening new opportunities for in vivo AML theranostics.