Signature-Directed Combination Mitigator Therapy Based on GS-Nitroxides

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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.