Multifunctional Nanoparticles as Radiosensitizers to Overcome Hypoxia-Associated Resistance in Cancer Radiotherapy

Hypoxia, a phenomenon that occurs when the oxygen level in tissues is lower than average, is commonly observed in human solid tumors. For oncological treatment, the hypoxic environment often results in radioresistance and chemoresistance. In this study, a new multifunctional oxygen carrier, carboxymethyl hexanoyl chitosan (CHC) nanodroplets decorated with perfluorohexane (PFH) and superparamagnetic iron oxide (SPIO) nanodroplets (SPIO@PFH-CHC), was developed and investigated. PFH-based oxygen carriers can augment oxygenation within tumor tissues, thereby mitigating radioresistance. Concurrently, oxygenation can cause deoxyribonucleic acid (DNA) damage via oxygen fixation and consequently suppress cancer cell proliferation. Moreover, these pH-sensitive nanodroplets allow higher cellular uptake with minimal cytotoxicity. Two distinctive mechanisms of SPIO@PFH-CHC nanodroplets were found in this study. The SPIO nanoparticles of the SPIO@PFH-CHC nanodroplets can generate hydroxyl radicals (HO^•) and other reactive oxygen species (ROS), which is vital to chemodynamic therapy (CDT) via the Fenton reaction. Meanwhile, the higher X-ray absorption among these nanodroplets leads to a local energy surge and causes more extensive deoxyribonucleic acid (DNA) damage via oxygen fixation. This study demonstrates that low cytotoxic SPIO@PFH-CHC nanodroplets can be an efficient radiosensitizer for radiation therapy.