Beijing National Laboratory for Molecular Sciences, Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Nat Commun. 2024 Oct 31;15(1):9405. doi: 10.1038/s41467-024-53646-y.
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.
大多数抗癌药物在缺氧肿瘤内的治疗效果降低甚至完全丧失。为了克服这一限制，研究人员致力于开发具有独立于氧浓度的作用机制的治疗剂。在这里，我们展示了将钌（Ru）催化剂纳入用于缺氧抗癌治疗的聚合物纳米反应器的设计、合成和生物学评价。纳米反应器可以在缺氧癌细胞中催化谷胱甘肽（GSH）氧化为谷胱甘肽二硫化物（GSSG）。这会引发活性氧（ROS）和脂质过氧化物的积累，导致癌细胞死亡。它还刺激瞬时受体电位 melastatin 2（TRPM2）离子通道的过表达，触发巨噬细胞激活，导致全身免疫反应。静脉注射后，纳米反应器可以系统地激活免疫系统，并几乎完全消除小鼠模型中侵袭性骨肉瘤肿瘤。
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