Abstract Body (Do not enter title and authors here): Despite modern radiation therapy (RT) advancements, radiation-induced cardiovascular (CV) disease remains a significant cause of morbidity and mortality among cancer patients. Reactive oxygen species (ROS) cause oxidative damage to biomolecules such as DNA, lipids, and proteins within endothelial cells (ECs), which play a key role in promoting radiation-induced cell injury. Reducing ROS injury can be a promising strategy to alleviate the harmful effects of RT.
Fullerenes and their derivatives are potent antioxidants, serving as "free radical scavengers" because of their electron-deficient structure and their ability to readily interact with and neutralize free radicals. Despite promising reports of the antioxidant and anti-inflammatory activity of C60 fullerenes in recent years, the greatest challenge for translating them to the clinic is their inherent lipophilicity and insolubility in aqueous media. We have developed a novel chemistry for the custom-synthesis of C60 fullerene derivatized with serinol (C₆₀-ser) to make it amphiphilic in nature, creating a compound that is neutral and exquisitely soluble in water. Our data confirm that C₆₀-ser is non-toxic and can protect non-malignant normal endothelial cells but not cancer cells from RT-mediated damage. This radioprotection is exerted by scavenging RT-induced free radicals, amplifying multiple anti-oxidant response pathways, and mitochondrial metabolic reprogramming. By reducing RT-induced ROS levels, C₆₀-ser also inhibits DNA damage, apoptosis, senescence, and inflammatory responses within ECs.
Successful translation of this clinically relevant radioprotective role for C₆₀-ser could reduce RT-induced CV morbidity and mortality in cancer patients. By inhibiting endothelial oxidative stress, C₆₀-ser could be a turn-key solution to endotheliopathies from multiple etiologies.