Files
Abstract
Radiation therapy remains a mainstay treatment modality for cancer, but its dose and efficacy are limited by normal tissue toxicity. Pro-drugs that can be selectively activated under radiation to enhance radiotherapy are desirable. Even more desirable is the ability to deliver these pro-drugs directly to the site of disease. Upon delivery, the ideal drug would become activated, thus only enhancing radiation therapy in the desired tissues, and potentially eliminating off-target effects and normal tissue toxicity. Herein, we investigate the potential of 7-dehydrocholesterol (7-DHC), a cholesterol analog and precursor, as a pro-drug for radiosensitization. 7-DHC is highly susceptible to radical oxidization, and has the highest propagation rate for free radical chain oxidation among known lipid molecules. As reviewed in chapter 1, 7-DHC can react with free radicals generated during radiation, undergoing autoxidation and catalyzing the oxidation of other biomolecules, in turn amplifying radiation-induced cell damage. Chapter 2 describes, in length, in vitro studies with CT26 cells confirming this postulation, finding significantly elevated oxidative stress, lipid peroxidation, DNA damage, and mitochondrial depolarization in treated cancer cells. This results in increased cancer cell viability drop and reduced clonogenicity, indicating effective radiosensitization. For efficient delivery, 7-DHC was encapsulated into poly(lactide-co-glycolic)-block-poly(ethylene glycol) nanoparticles or 7-DHC@PLGA NPs. When tested in vivo, chapter 3 shows that 7-DHC@PLGA NPs significantly enhanced radiotherapy, resulting in 40% eradication of the tumors after one round of treatment. Importantly, the nanoparticles caused no detectable tissue or hematological toxicities, nor hypercalcemia. Our studies suggest the promise of 7-DHC as an efficient, safe, and activatable radiosensitizer.