Novel Cutaneous Radiation Injury Countermeasures

描述(申请人提供)：电离辐射引起的皮肤损伤是裂变炸弹/脏弹扩散的主要组成部分，贝塔和伽马辐射发射的同位素。放射性弥散装置(RDD)“脏弹”事件与爆炸地区受害者的热烧伤和辐射烧伤有关。特别是，同位素尘埃辐射产生的β-a粒子辐射会造成严重的皮肤损伤。目前用于治疗电离辐射/热烧伤的常见措施主要集中在可用的局部制剂和主要基于热烧伤经验的策略。迫切需要开发新的局部给药药物来预防或减轻电离辐射引起的皮肤损伤，特别是因为人们担心辐射到远离热烧伤相关区域的人群。我们已经证明，线粒体靶向于半谷氨酸菌素连接的氮氧化物，以及其他稳定线粒体膜和心磷脂/细胞色素C相互作用的小分子药物，可以改善器官特异性、全身照射C57BL/6J小鼠模型中电离辐射引起的损伤。通过这个项目，我们将开发和表征局部应用的小分子线粒体靶向抗氧化剂预防或减轻皮肤辐射损伤的能力。为了实现这一目标，我们组建了一个多学科的研究团队，他们在辐射生物学、化学、药理学和皮肤生物学方面拥有成熟的专业知识。我们将利用这个研究团队的综合经验和技能提供的独特协同效应来开发线粒体靶向小分子辐射防护剂/缓释剂，以及旨在将这些药物的治疗水平输送到皮肤中的局部配方。我们将在小鼠模型上评估这些化合物在预防和/或减轻辐射引起的皮肤损伤方面的传递和功能有效性。重要的是，在临床前的转化研究中，我们将使用我们的新型活体人体皮肤移植系统来评估药物释放和这些化合物在预防或减轻辐射引起的活体皮肤损伤方面的功能有效性。这些体外活体人体皮肤研究被设计为体内临床测试和最终临床应用这些预防或减轻辐射引起的皮肤损伤的新策略的直接前奏。

DESCRIPTION (provided by applicant): Ionizing irradiation-induced cutaneous injury is a major component of fission bomb/dirty bomb dispersal of beta and gamma irradiation emitting isotopes. Radiological dispersion device (RDD) "dirty bomb" events are associated with both thermal burn and radiation burn of victims in the blast area. In particular, beta-a particle radiation from isotopic fallout irradiation produces significant cutaneous injury. Common measures currently utilized to treat ionizing irradiation/thermal burns focus on available topical agents and strategies based primarily on experience with thermal burn injury. Development of new topically administered agents to prevent or mitigate ionizing irradiation- induced skin damage is desperately needed, particularly because of the concern for fallout irradiation to populations distant from the area associated with thermal burns. We have demonstrated that mitochondrial targeting of hemigramacidin-linked nitroxides, and other small molecule agents that stabilize mitochondrial membranes and cardiolipin/cytochrome C interaction, can ameliorate ionizing irradiation-induced damage in the organ specific, total body irradiation C57BL/6J mouse model. Through this project, we will develop and characterize the capacity of topically applied small molecule mitochondrial targeted antioxidants to prevent or mitigate radiation induced damage in skin. To accomplish this we have assembled a multidisciplinary team of investigators with well established expertise in radiation biology, chemistry, pharmacology, and skin biology. We will utilize the unique synergies that the combined experience and skills of this investigative team affords to develop mitochondrial targeted small molecule radioprotectants/mitigators, and topical formulations designed to deliver therapeutic levels of these drugs into the skin. We will evaluate delivery and the functional effectiveness of these compounds in preventing and/or mitigating radiation induced skin damage in murine models. Importantly, in pre-clinical translational studies we will use our novel living human skin explant system to evaluate drug delivery and the functional effectiveness of these compounds in preventing or mitigating radiation induced skin damage in living human skin. These in vitro living human skin studies are designed as a direct prelude to in vivo clinical testing and eventual clinical application of these novel strategies to prevent or mitigate radiation induced skin damage.