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

• Published in: Nano today Vol. 48; p. 101739
• Main Authors: Chen, Kui, Zhou, Ruyi, Liang, Haojun, Liao, You, Zhu, Shuang, Dong, Xinghua, Wang, Yujiao, Liu, Sen, Hu, Fan, Li, Hao, Liu, Qiuyang, Lv, Linwen, Chang, Ya-nan, Li, Juan, Xing, Gengmei, Gu, Zhanjun
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.02.2023
• Subjects: Local control; Osteolysis; Osteosarcoma; Polyoxotungstate nanocluster; Radiotherapy; Polyoxotungstate nanocluster; Radiotherapy; Osteolysis; Osteosarcoma; Local control
• ISSN: 1748-0132; 1878-044X
• DOI: 10.1016/j.nantod.2022.101739

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. [Display omitted] •Polyoxotungstate nanoclusters with unique electronic structure were constructed as smart radiosensitizers for photons attenuation .•The radiosensitizer exhibits tumor microenvironment-selective killing of osteosarcoma cells and osteoclasts.•The radiosensitizer provides radiation therapy a potential for potent local control of orthotopic osteosarcoma.