Reversing the pathological microenvironment by radiocatalytic sensitizer for local orthotopic osteosarcoma radiotherapy enhancement

Radiotherapy (RT) can be a means of local control that directly determines the outcome in many special cases of osteosarcoma (OS). Current strategies focus on radiation-dose amplification with nanosensitizers to increase the radiosensitivity and improve the outcome of OS, but still lack an effective local control strategy for selectively killing the tumor lesions. Herein, a sandwich-type polyoxotungstate nanocluster (Fe4Se2W18, SWF) with multiple high-Z elements for radiation attenuation and unique electronic structure for a catalytic reaction was designed as a smart nanoradiosensitizer to realize an X-ray-triggered Fenton reaction for enhanced local control of the orthotopic OS. The radiosensitizer exhibited tumor microenvironment-responsiveness selectively killing OS cells through consuming GSH to convert Fe(III)-SWF to Fe(II)-SWF, resulting in the transform of endogenous H2O2 into highly toxic·OH through enhanced Fenton catalytic reaction. Apart from the tumor-killing effect, the radiosensitizer presents potent anti-osteolytic activity by specifically killing osteoclasts (OCs) in response to their low pH (∼4.5) microenvironment. Following the radiosensitizer treatment and X-ray irradiation, orthotopic OS was effectively controlled, OS cells were eliminated and osteolysis was reduced, eventually restoring motor function. This work demonstrates the feasibility of pathological microenvironment-responsive radiosensitizer in specific killing OS cells and OCs for potent orthotopic OS local control and provides a novel paradigm for radiosensitizer design.