Mitochondrial Targeted Small Molecule Radiation Mitigators

通过质粒脂质体递送的线粒体靶向抗氧化转基因产物MnSOD已显示出， 是有效的电离辐射损伤保护剂和减轻剂，但体内基因产物需要数小时 生产一种小分子线粒体靶向的hemlgramacidin（GS）-氮氧化物，JP 4 -039，是一种快速的线粒体靶向化合物。 作用全身照射（TBI）损伤减轻剂，并且是β照射的有效局部治疗剂 烧伤和复合伤（辐射/骨创伤）。第一个具体目标测试 通过线粒体靶向GS-氮氧化物增强辐射缓解的假设可以通过以下方式得到改善： 碳纳米胶囊结合和内皮或上皮靶向脂质体递送。第二特定 目的检验线粒体靶向小分子（GS-NOS-1）XJB-5-133和MCF-201- 133的假设。 89将是有效的辐射损伤缓解剂，也被碳纳米胶囊和脂质体增强。 定向投放。第三个特定目的检验了小分子p53/mdm 2/mdm 4 抑制剂，BEB 55和BEB 59是有效的TBI缓解剂，通过碳纳米胶囊和脂质体增强 面向.每种药物在21日龄青春期前的成年雄性和雌性中的最佳辐射缓解作用 然后将小鼠、E13妊娠雌性和它们的后代组合在多药物方案中。积极 急性和晚期效应的对照是微环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，内皮p-CAM靶向或上皮i-CAM，靶向脂质体，器官特异性肠， 骨髓和肺线粒体药物摄取定量（ESR）、药理学研究、全身 照射和器官组织病理学。一个长期的目标是发展一个实用的 TBI后24小时或更晚给药时有效的局部/经皮递送缓解剂。这些研究 应该建立和优化新型多药线粒体靶向治疗以减轻辐射损伤 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.