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Development of a mitochondria-targeted nano-complex of imidazole-substituted oleic acid as a radiomitigator.

Authors
Star-A; Kapralov-A; Amoscato-A; Tyurin-V; Seo-W; Epperly-M; Greenberger-J; Tyurina-Y; Kagan-V
Source
Toxicologist 2013 Mar; 132(1):428
NIOSHTIC No.
20042445
Abstract
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.
Keywords
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
CAS No.
25322-68-3; 7440-44-0
Publication Date
20130301
Document Type
Abstract
Funding Type
Grant
Fiscal Year
2013
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-008282; B20130502
Issue of Publication
1
ISSN
1096-6080
Source Name
The Toxicologist. Society of Toxicology 52nd Annual Meeting and ToxExpo, March 10-14, 2013, San Antonio, Texas
State
PA; TX
Performing Organization
University of Pittsburgh at Pittsburgh
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