Chemical vs Physical Radioenhancement from TiO₂ and Au Nanoparticles to Overcome Hypoxic Radioresistance in X-ray Therapy

Hypoxia, a common feature in solid tumors, induces cellular radioresistance and reduces radiotherapy efficacy. Nanoparticles present a promising radiosensitizing approach providing localized dose enhancement through physical or chemical mechanisms. While many preclinical studies have shown nanoparticle radiosensitization, most have focused on normoxic conditions, leaving the impact of hypoxia on nanoparticle-mediated dose enhancement unclear. Here, we report on physical and chemical dose enhancement of Au and TiO₂ nanoparticles, along with their efficacy in sensitizing normoxic and hypoxic fibrosarcoma cells. Photo- and radiocatalytic activities improved in hypoxia, while electron paramagnetic resonance spin traps confirmed hydroxyl radicals. Radiotherapy efficacy and DNA damage in HT1080 cells were evaluated under varying oxygen concentrations using preclinical and clinical X-ray sources. Our findings indicate a slight reduction in the physical dose enhancement of Au nanoparticles and an increase in the chemical dose enhancement of TiO₂ in hypoxia, suggesting a critical role of ROS in overcoming hypoxic radioresistance.