Radiation Protection with SOD Mimetics

本项目的目标是最终开发出一种有效的、实用的、广泛可用的 减轻和/或治疗辐射引起的肺损伤的医学对策，使用在上一次供资期间开发的金属卟啉抗氧化剂化合物MnTnHex-2-PyP5+。金属卟啉类似物作为医学对策的理论基础来自于充分描述的病理生理途径，这些途径依赖于氧化还原信号，而氧化还原信号是放射性肺损伤发生的基础。在之前的资助期间，在相对较低的剂量(0.05 mg/kg)下，在啮齿动物和非人类灵长类动物模型中都证明了MnTnHex-2-PyP5+能够有效地减轻放射性肺损伤。基于这些研究，我们现在建议与Primate Core合作进行剂量递增研究，以确定在NHP模型中，MnTnHex-2-PyP5+用于改善全胸照射后的肺功能和存活率的最佳皮下剂量(特定目标1)。同时，我们认识到需要改进交付技术。因此，具体目标2集中在开发一种口服配方的MnTnHex-2-PyP5+，它将首先在我们的啮齿动物模型中进行测试(最佳剂量、持续时间和开始治疗的机会窗口)，然后在我们的NHP模型中进行疗效研究，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-PyP5+的作用机理。如果成功，该项目将提供一种安全有效的交付成果，可以储存起来，广泛用于意外或故意辐射紧急情况下的大规模伤亡环境。

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.