Abstract Body: Despite modern radiation therapy (RT) advancements, radiation-induced cardiovascular (CV) disease still 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, which play a key role in promoting radiation-induced cell injury. Endothelial cells (ECs) injured by RT contribute to the development and progression of CV disease. Reducing ROS injury can be a promising strategy to alleviate the harmful effects of RT.
Fullerenes and their derivatives are potent antioxidants, often referred to 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 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 establish proof-of-principle that C₆₀-ser is non-toxic and can protect non-malignant normal endothelial but not cancer cells, from RT-mediated damage. This radioprotection is exerted by scavenging RT-induced free radicals, amplifying 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. Furthermore, inhibition of endothelial oxidative stress could have salutary effects across multiple endotheliopathies such that C₆₀-ser may be a turn-key unified class solution to cardiovascular injury caused by various insults.