Mitochondrial Targeted Small Molecule Radiation Mitigators

线粒体靶向抗氧化剂转基因产物MnSOD质粒脂质体的研究表明 是有效的电离辐射损伤保护剂和缓释剂，但体内基因产品需要数小时 制作。一种小分子线粒体靶向去氧核苷(GS)-氮氧化物，JP4-039是一种快速的 代理全身照射(TBI)损伤缓解剂，是贝塔辐射的有效局部治疗方法 C57BL/6HNsd小鼠烧伤及复合伤(照射/骨伤)的实验研究第一个具体目标是测试 线粒体靶向GS-氮氧化物增强辐射缓解的假说可以通过以下方式改善 碳纳米囊结合和内皮或上皮靶向脂质体递送。第二个具体问题 目的验证线粒体靶向小分子(GS-NOS-1、XJB-5-133和MCF-201)的假说。 89将是有效的辐射损伤缓释剂，碳纳米胶囊和脂质体也会增强 定向投放。第三个特定目的是检验小分子p53/mdm2/mdm4 抑制剂BEB55和BEB59是有效的脑损伤缓释剂，可被碳纳米胶囊和脂质体增强 瞄准目标。成年男性和女性、21日龄青春期前各药物最佳辐射缓解效果 然后，小鼠、E13只怀孕雌性小鼠及其后代将被组合在一种多药物方案中。正性 急性和晚期效应的对照药物为小环状MnSOD-质粒脂质体和双转基因MnSOD， MT-CAT-质粒脂质体。方法包括定时释放可降解碳纳米胶囊结合小分子 分子，内皮细胞p-CAM靶向或，上皮I-CAM，靶向脂质体，器官特异性肠道， 骨髓和肺线粒体药物摄取的ESR定量，药代动力学研究，全身 辐射和器官组织病理学。一个长远的目标是发展一个实用的 局部/经皮给药，在创伤性脑损伤后24小时或更晚给予时有效。这些研究 应建立和优化新型多药线粒体靶向治疗辐射损伤 适用于辐射反恐。

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.