Analysis of the Metabolomic Profile in Serum of Mice Treated with RadioDefender, a Novel Radiation Medical Countermeasure.

Abstract

Ionizing radiation continues to be weaponized not only through the development of nuclear weapons, but also on a smaller scale through the development of radiological dispersal devices, or dirty bombs. Exposure to acute doses of ionizing radiation often leads to the development of acute radiation syndrome (ARS), for which treatment options are currently limited. Current treatment options include only post-exposure prophylaxes that are intended to restore bone marrow function and stimulate platelet production. To date, no pre-exposure prophylaxes are available to treat ARS, although many pharmaceuticals are currently under evaluation. Amifostine, for example, has been investigated as a radioprotector, but was found unsuitable due to its hypotensive effects, severe upper and lower gastrointestinal disturbances, and reduced efficacy at the doses required for effective radioprotection. RadioDefender, an amifostine-based drug, shows promise as a radioprotector due to its ability to shield bone marrow from the deleterious effects of ionizing radiation, offering protection at lower doses than those required for amifostine without the toxic effects. Two separate toxicity studies were performed: the first study investigated the effects of various doses of RadioDefender on blood and lymphoid tissue in unirradiated mice to establish the no-observed-adverse-effects-level (NOAEL), while the second study investigated the effects of various doses of RadioDefender on tissue and metabolomic profiles in irradiated mice (9.2 Gy total-body γ-irradiation). RadioDefender treatment significantly improved survival and provided substantial protection in the steroid hormone biosynthesis and arachidonic acid metabolism pathways, key pathways involved in inflammation and immune response that have been proven to be highly sensitive to ionizing radiation.