Development of a mitochondria-targeted nano-complex of imidazole-substituted oleic acid as a radiomitigator.
Star-A; Kapralov-A; Amoscato-A; Tyurin-V; Seo-W; Epperly-M; Greenberger-J; Tyurina-Y; Kagan-V
Toxicologist 2013 Mar; 132(1):428
Increasing likelihood of intended or accidental exposure to ionizing radiation dictates the necessity to develop effective medical countermeasures of radiation injury as has been recognized as a high priority both in the US and worldwide. No effective medical radiation countermeasures of acute and delayed radiation injuries are currently known. Based on newly discovered mechanisms of radiation damage - oxidation of cardiolipin by cytochrome c in mitochondria as a required stage in radiation- induced apoptosis - we designed and synthesized mitochondria-targeted triphenylphosphonium-conjugated imidazole-substituted oleic (TPP-OA) which prevented/mitigated cell death induced by irradiation and protected C57BL6 mice against total body irradiation. To improve therapeutic efficiency of TPP-IOA we chose to employ branched polyethylene glycol (PEG) functionalized single walled carbon nanotubes (SWCNT) and use it as a carrier to deliver mitochondria-targeted TPP-IOA to tissues. We found that loading of PEG-SWCNT with TPP-IOA caused a marked extension of the life-span of TPP-IOA in circulation. Moreover we showed that TPP-IOA-nano-complex was more effective as radiomitigator than free TPP-IOA. While the dose of TPP-IOA in TPP-IOA-nano-complexes was two times lower compared with free TPP-IOA the mitigating effect of TPP-IOA-nanocomplexes was higher than that of TPP-IOA alone. Importantly, we were able to detect TPP-IOA nano-complexes in radiosensitive tissue such as small intestine. These data warrant further studies aimed at the development of radioprotectors/radiomitigators with broad spectrum of applications in biomedicine and biodefense.
Toxicology; Nanotechnology; Laboratory-animals; Cellular-function; Cellular-reactions; Ionizing-radiation; Radiation; Radiation-injury; Cell-damage; Ethylenes; Glycols; Therapeutic-agents; Radiation-therapy; Radiobiology; Tissue-culture; Intestinal-tissue; Dose-response; Radiation-protection
The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, March 10-14, 2013, San Antonio, Texas
University of Pittsburgh at Pittsburgh