Signature-Directed Combination Mitigator Therapy Based on GS-Nitroxides

摘要：项目1 包括JP 4 -039在内的抗细胞凋亡GS-氮氧化物药物的线粒体靶向， 证明了高度有效的全身辐射缓解。改进的辐射缓解可以 通过补充其他新的小分子辐射缓解剂， TBI后24 - 96小时内有效作用的靶点和次数。我们发现6 新的小分子TBI缓解剂，其作用机制与GS-氮氧化物不同。 具体目标1检验全身照射的等离子体和组织特征， 以及在TBI后24小时递送的JP 4 -039对其的调节，可以用于指导TBI后24小时的时间。 施用6种新的小分子辐射缓解剂中的每一种，以提供添加剂或 协同缓解成果。 第二个具体目的检验了在24 ℃下施用GS-氮氧化物JP 4 -039的假设， 在TBI后30小时，改变了第二缓解药物的药代动力学（PK），需要进一步的 修改顺序交付的时间。 第三个具体目标检验了以下假设： 一系列的辐射缓解药物，将是非常有效和安全的传统以及 弱势群体。 所有具体的目标将利用一种新的局部可生物降解的微针阵列递送系统， 使用不同种类的药物的多药物顺序释放药物的单次应用 每个微针具有不同的药物释放特性。 这个翻译项目将采取发现和交付多种辐射缓解， 更进一步

Abstract: Project 1 Mitochondrial targeting of anti-apoptotic GS-nitroxide drugs, including JP4-039, has demonstrated highly effective total body irradiation mitigation. Improved radiation mitigation can be achieved by supplementing other new small molecule radiation mitigators with distinct targets and times of effective action during the 24 – 96 hrs after TBI. We have discovered 6 new small molecule TBI mitigators with mechanisms of action distinct from GS-nitroxides. Specific Aim 1 tests the hypothesis that plasma and tissue signatures of total body irradiation, and their modulation by JP4-039 delivered at 24 hrs after TBI, can be used to direct the time for administration of each of 6 new small molecule radiation mitigators to provide additive or synergistic mitigation outcomes. The second specific aim tests the hypothesis that administration of GS-nitroxide, JP4-039, at 24 hrs after TBI, modifies the pharmacokinetics (PK) of the second mitigator drug, requiring further modification of time of sequential delivery. The third specific aim tests the hypothesis that signature directed and PK modified delivery of a sequence of radiation mitigator drugs, will be highly effective and safe in conventional as well as vulnerable populations. All specific aims will utilize a novel topical biodegradable microneedle array delivery system for single application of multi-drug sequentially released drugs using different categories of microneedles each with different drug release characteristics. This translational project will take discovery and delivery of multiple radiation mitigators to the next level.