Mitochondrial targeted antioxidant transgene product MnSOD delivered by plasmid liposomes has shown to be an effective ionizing irradiation damage protector and mitigator but requires hours for in vivo gene product production. A small molecule mitochondrial targeted hemlgramacidin (GS)-nitroxide, JP4-039, is a rapid acting total body irradiation (TBI) damage mitigator, and is an effective topical therapeutic for beta irradiation burns and combined injury (irradiation/bone wound) in C57BL/6HNsd mice. The First Specific Aim tests the hypothesis that enhanced radiation mitigation by mitochondrial targeted GS-nitroxide can be improved by carbon nanocapsule binding and endothelial or epithelial targeted liposome delivery. The Second Specific Aim tests the hypothesis that mitochondrial targeted small molecules (GS-NOS-1) XJB-5-133 and MCF-201- 89 will be effective radiation damage mitigators, also enhanced by carbon nanocapsule, and liposome targeted delivery. The Third Specific Aim tests the hypothesis that the small molecule p53/mdm2/mdm4 inhibitors, BEB55 and BEB59 are effective TBI mitigators, enhanced by carbon nanocapsule, and liposome targeting. Optimized radiation mitigation by each drug in adult male and female, 21 day old prepubescent mice, E13 pregnant females and their progeny will then be combined in a multidrug regimen. Positive controls for acute and late effects will be mini circle MnSOD-plasmid liposomes, and dual transgene MnSOD, mt-CAT-plasmid liposomes. Methods include timed-release degradable carbon nanocapsule bound small molecules, endothelial p-CAM targeted or, epithelial i-CAM, targeted liposomes, organ specific intestinal, marrow, and lung mitochondrial drug uptake quantitation by ESR, phamnacokinetics studies, total body irradiation, and organ histopathology. A long term goal is the development of a practical topical/transdermally delivered mitigator that is effective when given 24 hrs or later after TBI. These studies should establish and optimize novel multidrug mitochondrial targeting for radiation damage mitigation applicable for use in radiation counter terrorism.
We propose to iprove both the pharmacokinetics and pharmacodynamics of GS-nitroxide as a radiation mitigator and determined additive/synergisitc effects for two other novel mitochondrial-targeted small molecule radiation mitigators: [GS (nitric oxide synthetase)-NOS] inhibitors (NOS-1) and p53/mdm2/mdm4 inhibitors through drug delivery via biodegradable carbon nanocapsules in endothelial or epithelial cell targeted liposomes
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