Reversing the pathological microenvironment by radiocatalytic sensitizer for local orthotopic osteosarcoma radiotherapy enhancement. (February 2023)

• Record Type: Journal Article
• 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
• Is Part Of: Nano today. Volume 48(2023)
• Publication Date: 2023-02
• Subjects: Radiotherapy -- Polyoxotungstate nanocluster -- Osteosarcoma -- Local control -- Osteolysis; Nanotechnology -- Periodicals; Nanosciences -- Périodiques; 620.505
• DOI: 10.1016/j.nantod.2022.101739
• Languages: English
• ISSNs: 1748-0132

Abstract

Abstract: 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 (Fe4 Se2 W18, 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 H2 O2 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. Graphical Abstract: Radiation therapy (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 controllable strategy for selectively killing in the tumor lessions. Herein, a sandwich-type polyoxotungstate nanoclusters (Fe4 Se2 W18, SWF) with multiple high-Z elements for radiation attenuation and unique electronic structure for catalytic reaction were designed as a smart nanoradiosensitizer to realize a X-ray-triggered Fenton/Fenton-like reaction for enhanced local control of orthotopic OS. The radiosensitizer exhibits tumor microenvironment-responsiveness selectively kill OS cells through consuming GSH to convert Fe(III)-SWF to Fe(II)-SWF, resulting in the transform of endogenous H2 O2 into highly toxic·OH through enhanced Fenton catalytic reaction. Apart from tumor-killing effect, the radiosensitizer presents potent anti-osteolytic activity by specifically killing OCs in response to their low pH (∼4.5) microenvironment. Following the radiosensitizer treatment and X-ray irradiation, orthotopic OS is effectively controlled, OS cells were eliminated and reducing osteolysis was reduced, eventually leading to the restoration of motor function. This work demonstrates the feasibility of OS microenvironment-responsive radiosensitizer in specific killing OS cells and OCs for potent orthotopic OS local control, and provides a novel paradigm for design of radiosensitizer. ga1 Highlights: 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.