A recombinant melanin-associated molecule as a novel and efficacious biologic countermeasure for acute radiation syndrome

Abstract

Abstract Currently, there are no United States Food and Drug Administration (US FDA)-approved radioprotectors for prophylaxis. It is of national importance that a radioprotector is developed as an addition to the Strategic National Stockpile (SNS), because these types of medications can help protect warfighters and first responders prepare for and complete tasks in areas of high radiation contamination. Among the agents under investigation that have natural radioprotective capability, melanins are of interest due to their ability to protect cells against ionizing radiation, acting as both a physical shield blocking the high energy waves from damaging DNA molecules and by scavenging free radicals. In this study, we present preliminary data surrounding the radioprotective efficacy of THL-FM3021, a bio-melanin–related compound recombinantly expressed in Escherichia coli . Using CD2F1 mice, we investigated its toxicity, optimized its dose and administration schedule, tested its protective ability against various modes of radiation, and explored its ability to protect hematopoietic cells and induce cytokines. We found the no-observed-adverse-effect level (NOAEL) of THL-FM3021 as 100 mg/kg for both single and repeated doses, and the dose reduction factor to be 1.107. THL-FM3021 was found to be most effective at a dose of 50 mg/kg when administered 24 h prior to irradiation against either a cobalt-60 gamma source or a mixed-field (65% neutron 35% gamma) source from a nuclear reactor. Also, THL-FM3021 was found to induce several cytokines and improve the recovery of red blood cells, platelets, and neutrophils. Our studies indicate that this drug is a promising candidate for further development as a radioprotector.