Astronauts on long term space missions incur multiple space radiation risks including cancer, late and early central nervous system effects, cardiovascular diseases, and accelerated aging. A common mechanistic pathway in these events is unchecked oxidative stress. We have developed a countermeasure that protects mice from whole body x-ray radiation-induced death when given systemically 4 hours after lethal radiation exposure. At this time point, a lot of the immediate free radical generation from ionizing radiation exposure has already occurred and yet, we were able to protect these mice. This is largely due to the extremely potent free radical scavenging ability of our C60 fullerene derivative we term C60-ser that (i) has been made biocompatible by decorating it with a serinol malonamide to dramatically increase its water solubility (>250 mg/ml) and (ii) readily traverses physical barriers within tissues and cells to achieve excellent concentrations in all tissues within the body. C60-ser exists in a dynamic equilibrium state seamlessly flipping between the conjugate monomers (~3nm) and aggregates (100-2000 nm). Such duality enables the conjugates to use passive diffusion and active transport (e.g. endocytosis, transcytosis) for efficient and seamless shuttling from the vasculature to tissues including the brain. The sub-5nm size also allows a long circulation time by evading opsonization and reticuloendothelial capture and facilitating renal elimination. C60-ser can be reliably and reproducibly created in our facilities by facile and scalable techniques that we have pioneered. The studies proposed in this submission are extensions of this exciting preliminary work that will now explore the ability of C60-ser to protect multiple cell types from charged particle radiotherapy injuries. Collectively these studies will set the stage for testing C60-ser in animal models in phase II of this NASA SBIR program. Potential NASA Applications (Limit 1500 characters, approximately 150 words) We have developed a radiation countermeasure, C60-ser, that protects mice from whole body x-ray radiation-induced death when given systemically 4 hours after lethal radiation exposure. If these properties hold true with space exposure-relevant radiation types, energies, and doses, we expect C60-ser could be used by astronauts during space missions (prophylactically before take-off or therapeutically after documented high-risk exposure such as a solar flare event). Potential Non-NASA Applications (Limit 1500 characters, approximately 150 words) Our radiation countermeasure, C60-ser, protects mice from whole body x-ray radiation-induced death when given systemically 4 hours after radiation via extremely potent free radical scavenging. This ability could make it valuable as a radiation protector during cancer radiotherapy and/or as a radiation mitigator following incidental radiation exposure from nuclear accidents or bioterrorism.
