Novel Cutaneous Radiation Injury Countermeasures

描述（由申请方提供）：电离辐射引起的皮肤损伤是裂变弹/脏弹散布β和γ辐射放射性同位素的主要组成部分。放射性弥散装置（RDD）“脏弹”事件与爆炸区域内的人体热烧伤和辐射烧伤有关。特别是，β-a粒子放射同位素沉降物照射产生显着的皮肤损伤。目前用于治疗电离辐射/热烧伤的常见措施主要集中在现有的局部药物和主要基于热烧伤经验的策略。迫切需要开发新的局部施用的药剂来预防或减轻电离辐射诱导的皮肤损伤，特别是因为担心落尘辐射到远离与热烧伤相关的区域的人群。我们已经证明，线粒体靶向的hemigramacidin连接的氮氧化物，和其他小分子药物，稳定线粒体膜和心磷脂/细胞色素C的相互作用，可以改善电离辐射诱导的损伤的器官特异性，全身照射C57 BL/6 J小鼠模型。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的能力，以预防或减轻辐射引起的皮肤损伤。为了实现这一目标，我们组建了一个多学科的研究团队，他们在放射生物学、化学、药理学和皮肤生物学方面具有良好的专业知识。我们将利用该研究团队的经验和技能提供的独特协同作用来开发线粒体靶向小分子辐射防护剂/缓解剂，以及旨在将这些药物的治疗水平递送到皮肤中的局部制剂。我们将在鼠模型中评价这些化合物在预防和/或减轻辐射诱导的皮肤损伤中的递送和功能有效性。重要的是，在临床前转化研究中，我们将使用我们的新型活体人类皮肤外植体系统来评估药物递送和这些化合物在预防或减轻活体人类皮肤中辐射诱导的皮肤损伤方面的功能有效性。这些体外活体人类皮肤研究被设计为这些新策略的体内临床试验和最终临床应用的直接前奏，以预防或减轻辐射诱导的皮肤损伤。

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.