Tumor-targeted glutathione oxidation catalysis with ruthenium nanoreactors against hypoxic osteosarcoma

Hanchen Zhang, Nicolás Montesdeoca, Dongsheng Tang, Ganghao Liang, Minhui Cui, Chun Xu, Lisa-Marie Servos, Tiejun Bing, Zisis Papadopoulos, Meifang Shen, Haihua Xiao (), Yingjie Yu () and Johannes Karges ()
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Hanchen Zhang: Chinese Academy of Sciences
Nicolás Montesdeoca: Ruhr-University Bochum
Dongsheng Tang: Chinese Academy of Sciences
Ganghao Liang: Chinese Academy of Sciences
Minhui Cui: Chinese Academy of Sciences
Chun Xu: The University of Queensland
Lisa-Marie Servos: Ruhr-University Bochum
Tiejun Bing: ICE Bioscience
Zisis Papadopoulos: Ruhr-University Bochum
Meifang Shen: Beijing University of Chemical Technology
Haihua Xiao: Chinese Academy of Sciences
Yingjie Yu: Beijing University of Chemical Technology
Johannes Karges: Ruhr-University Bochum

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract The majority of anticancer agents have a reduced or even complete loss of a therapeutic effect within hypoxic tumors. To overcome this limitation, research efforts have been devoted to the development of therapeutic agents with biological mechanisms of action that are independent of the oxygen concentration. Here we show the design, synthesis, and biological evaluation of the incorporation of a ruthenium (Ru) catalyst into polymeric nanoreactors for hypoxic anticancer therapy. The nanoreactors can catalyze the oxidation of glutathione (GSH) to glutathione disulfide (GSSG) in hypoxic cancer cells. This initiates the buildup of reactive oxygen species (ROS) and lipid peroxides, leading to the demise of cancer cells. It also stimulates the overexpression of the transient receptor potential melastatin 2 (TRPM2) ion channels, triggering macrophage activation, leading to a systemic immune response. Upon intravenous injection, the nanoreactors can systemically activate the immune system, and nearly fully eradicate an aggressive osteosarcoma tumor inside a mouse model.

Date: 2024
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DOI: 10.1038/s41467-024-53646-y

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