The University of Pittsburgh CMCR proposes a paradigm-shifting approach to administer a series of new highly effective small molecule radiation mitigators, each with a different mechanism of action, and each delivered by novel topical biodegradable microneedle arrays. Based on the multiple successes of the past two funding cycles, the University of Pittsburgh CMCR has discovered many new small molecule radiation mitigators by targeting the oxidative lipidomics effects of ionizing irradiation. Four projects and 6 service cores will establish the time course for administration of each of 6 new drugs (as well as our established mitochondrial targeted GS-nitroxide small molecule radiation mitigator) with times of each drug release sequenced to its respective mechanism-based target in the radiation response. Project 1, Joel S. Greenberger, M.D., P.I. will utilize the mitochondria targeted anti-apoptotic drug GS-nitroxide, JP4-039, as the initial mitigator, and then using plasma and tissue signatures and pharmacokinetics (PK), administer each new radiation mitigator, by I.V. compared to topical biodegradable microneedle arrays (MNAs) that facilitate timed delivery. Project 2, Valerian Kagan, Ph.D., P.I. will discover new radiation mitigators based on cardiolipin-derived biosynthetic pathways for lipid mediators. Project 3, Hulya Bayir, M.D., P.I. will develop new small molecule radiation mitigators based on targeting necroptosis and ferroptosis. Project 4, Jian Yu, Ph.D., P.I. will discover new radiation mitigators targeted to acute compared to delayed intestinal stem cell irradiation induced damage. The Administrative Core A will oversee the programs. Core B Innovative Medicinal Chemistry, Peter Wipf, Ph.D./Detcho Stoyanovsky, Ph.D., Co-PIs, will deliver modifications of each of the new mitigators to optimize PK and sequenced delivery. Core C Radiobiological Standardization, Michael Epperly, Ph.D., P.I. will provide appropriate in vitro and mouse models representing standard and vulnerable populations. Core D Biostatistics, Hong Wang, Ph.D., P.I. will oversee calculations for efficient yet robust data generation. Core E Computational Systems Pharmacology, Ivet Bahar, Ph.D., P.I. will determine efficient sequenced times of delivery of radiation mitigators based on each mechanistic step in the total body irradiation response. Core F Lipidomics and Bioanalytical Core, Yulia Tyurina, Ph.D., P.I. will determine the optimal timing for drug delivery based on plasma and tissue signatures of oxidized phospholipid changes that follow radiation injury. Core G Imaging Radiation Pathology, Simon Watkins, Ph.D., P.I. will guide the discovery of new radiation mitigators at the level of inflammatory cell to epithelial cel interfaces during the radiation response in intestine, lung, and other organs. This CMCR will carry radiation mitigation to the next level using multiple drugs and mechanism-based timed delivery.
The University of Pittsburgh CMCR will capitalize on its discovery of the critical role of oxidative lipidomics in the total body irradiation response to establish the timing of delivery of multiple small molecule radiation mitigators. Several new mitigators will be sequenced for delivery over 24 - 96 hrs. after total body irradiation, administered by one time applied, but sequentially released topical biodegradable microneedle arrays that deliver each drug at a different mechanism-based time. This program will decrease the toxicity of irradiation and increase the number of survivors in both general and vulnerable populations. Project 1: Signature-Directed Combination Mitigator Therapy Based on GS-Nitroxides Project Leader (PL): Greenberger, J. DESCRIPTION (provided by applicant): 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 - 9 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.
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