Biodegradable copper-metformin nanoscale coordination polymers for enhanced chemo/chemodynamic synergistic therapy by reducing oxygen consumption to promote H2O2 accumulation
Biodegradable copper-metformin nanoscale coordination polymers for enhanced chemo/chemodynamic synergistic therapy by reducing oxygen consumption to promote H2O2 accumulation
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可生物降解的铜-二甲双胍纳米级配位聚合物，通过减少耗氧量促进 H2O2 积累，增强化学/化学动力学协同治疗
DOI：
10.1039/d0tb02476g
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发表时间：
2021-02-28
影响因子：
7
通讯作者：
Wang, Zhifei
中科院分区：
文献类型：
--
作者：
Meng, Xiangyu;Zhang, Xuezhong;Wang, Zhifei
化学/化学动力学协同治疗是提高肿瘤疗效的有效策略。然而，肿瘤微环境（TME）中的缺氧和有限量的过氧化氢（H2 O2）严重限制了这种联合治疗的疗效。在此，我们报告了可生物降解的多柔比星（Dox）负载的铜-二甲双胍（Met）纳米配位聚合物（Dox@Cu-Met NPs），其通过减少氧（O-2）消耗以促进H2 O2在肿瘤中的积累来发挥化学/化学动力学协同治疗作用。在肿瘤细胞内，Met可以通过抑制线粒体呼吸来抑制O-2的消耗以缓解肿瘤缺氧。肿瘤缺氧不仅可以通过Dox激活的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOXs）和超氧化物歧化酶（SOD）的级联反应提高H2 O2含量，而且可以提高Dox的疗效。更重要的是，谷胱甘肽（GSH）的消耗伴随着整个治疗过程，可以实现Cu 2+向Cu+的转化，促进活性氧（ROS）的积累，以提高化学动力学治疗（CDT）的疗效。同时，Met有望通过抑制呼吸来切断能量供应，从而导致饥饿疗法。体内研究表明，通过增强的化学/化学动力学协同治疗，肿瘤生长被显著抑制。这项工作提供了一个新的范例，癌症治疗使用一个经济和简单的方法来构建一个协同纳米医学平台。
Chemo/chemodynamic synergistic therapy is a promising strategy to improve the antitumor effect. However, hypoxia and a limited amount of hydrogen peroxide (H2O2) in the tumor microenvironment (TME) severely restrict the therapeutic efficacy of this combined treatment. Herein, we report biodegradable doxorubicin (Dox)-loaded copper-metformin (Met) nanoscale coordination polymers (Dox@Cu-Met NPs), which exert a chemo/chemodynamic synergistic therapeutic effect by reducing oxygen (O-2) consumption to promote H2O2 accumulation in the tumor. Inside tumor cells, Met can inhibit the consumption of O-2 to relieve tumor hypoxia by suppressing mitochondrial respiration. The alleviated-tumor hypoxia can not only elevate H2O2 content via the Dox-activated cascade reaction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and superoxide dismutase (SOD), but also improve the efficacy of Dox. More importantly, the depletion of glutathione (GSH) accompanies the whole treatment process, which can realize the conversion of Cu2+ to Cu+ and boost reactive oxygen species (ROS) accumulation to improve chemodynamic therapy (CDT) efficacy. Meanwhile, Met is expected to cut off the energy supply by inhibiting respiration, leading to starvation therapy. In vivo investigations demonstrate that tumor growth is significantly inhibited through the enhanced chemo/chemodynamic synergistic treatment. This work provides a new paradigm for cancer therapy using an economical and straightforward method to construct a synergistic nanomedicine platform.