Radiation Protection with SOD Mimetics

该项目的目标是最终确定一个有效的，实用的，广泛使用的 使用金属卟啉抗氧化剂化合物MnTnHex-2-PyP 5+减轻和/或治疗辐射引起的肺损伤的医疗对策。金属卟啉模拟物作为医学对策的基本原理来自于充分表征的病理生理学途径，其依赖于氧化还原信号传导，其是辐射诱导的肺损伤发展的基础。在上一个资助期间，当以相对低的剂量（0.05 mg/kg）给药时，在啮齿动物和非人灵长类动物模型中证明了MnTnHex-2-PyP 5+有效减轻辐射诱导的肺损伤的能力。基于这些研究，我们现在建议与灵长类动物中心合作，进行剂量递增研究，以确定MnTnHex-2-PyP 5+的最佳皮下剂量，以改善NHP模型中全胸照射后的肺功能和存活率（具体目标1）。与此同时，我们认识到需要改进交付技术。因此，具体目标2专注于开发MnTnHex-2-PyP 5+口服制剂，在我们的NHP模型中进行疗效研究之前，将首先在我们的啮齿动物模型中进行测试（最佳剂量，持续时间和治疗开始的机会窗口），这将在新资助期的最后一年进行。最后，将进行平行研究以确定MnTnHex-2-PyP 5+的作用机制。如果成功，该项目将提供一种安全有效的可交付物，可以储存并广泛提供，以在发生意外或蓄意辐射紧急情况后的大规模伤亡情况下使用。

The goal of this project is to finalize the development of an effective, practical, and widely available medical countermeasure to mitigate and/or treat radiation-induced lung injury using a metalloporphyrin antioxidant compound, MnTnHex-2-PyP5+ developed during the last funding period. The rationale for metalloporphyrin mimetics as medical countermeasures arises from well-characterized pathophysiological pathways, which rely on redox signaling, that underiy the development of radiation-induced lung injury. In the previous funding period the ability of MnTnHex-2-PyP5+ to effectively mitigate radiation-induced lung injury was demonstrated in both rodent and in non-human primate models when given at relatively low doses (0.05 mg/kg). Based on these studies, we now propose in collaboration with the Primate Core, to perform dose escalation studies to determine the optimum subcutaneous dose of MnTnHex-2-PyP5+ to improve lung function and survival after whole thorax irradiation in a NHP model (Specific Aim 1). At the same time we recognize the need for improved delivery techniques. Therefore, Specific Aim 2 is focused on development of an oral formulation of MnTnHex-2-PyP5+ which will be first tested in our rodent model (optimum dose, duration, and window of opportunity for treatment initiation) prior to efficacy studies in our NHP model, which will occur in the last year of the new funding period. Lastly, parallel studies will be conducted to determine the mechanism of action of MnTnHex-2-PyP5+ . If successful, this project will provide a safe and effective deliverable that can be stockpiled and made widely available for use in mass casualty settings after an accidental or deliberate radiation emergency.