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Abstract
Therapeutics that are activated in situ by radiation to enhance the efficacy of RT are highly desirable. Here, we investigated 7-dehydrocholesterol (7DHC), a biosynthetic precursor of cholesterol, as a radiosensitizer by exploiting its ability to propagate free radical chain reactions. Radiation-induced radicals effectively abstract hydrogen atoms from 7DHC, initiating radical chain reactions and accelerating 7DHC-mediated lipid damage in cancer cells. This interaction leads to direct lipid peroxidation, culminating in cell death via ferroptosis. Outside the radiation field, 7DHC is safely metabolized to cholesterol by 7-dehydrocholesterol reductase (DHCR7), ensuring minimal toxicity to normal tissues.In this dissertation, we investigated different nanoparticles as vehicles to deliver 7DHC to tumor sites. First, PLGA nanoparticles were used as carriers. Results showed that these 7DHC-loaded nanoparticles were minimally toxic but significantly enhanced the efficacy of radiation. Subsequently, a liposome with a neurotensin (NTS) peptide targeting ligand on its surface (N-7DHC-LNPs) was developed using 7DHC to replace cholesterol, a traditional component of lipid-based nanoparticles. The results showed that N-7DHC-LNPs exhibited high loading capacity and strong tumor targeting ability. When combined with irradiation, cancer cell death was efficiently induced by ferroptosis.
Finally, the formulation was further developed into synthetic low-density lipoproteins (sLDLs) that mimic the natural LDL responsible for cholesterol transport in the body. This design significantly enhanced 7DHC tumor accumulation, demonstrated the ability to transcytosis through endothelial cell layers, and reached hypoxic tumor regions. In addition, our results showed that the ferroptosis induced by our treatment can further induce immunogenic cell death (ICD) in both highly and poorly immunogenic tumor models, making them ideal for combination with immunotherapy to induce systemic immunity.
Overall, we have developed nanoparticles that act as radiation-activatable sensitizers. They enhance radiation-induced lipid peroxidation and ferroptosis without systemic toxicity. Given their potential in antitumor immune responses, we believe these nanoparticles hold promise for clinical translation.