Biodegradable copper-metformin nanoscale coordination polymers for enhanced chemo/chemodynamic synergistic therapy by reducing oxygen consumption to promote H2O2 accumulation.

Abstract

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 (O2) consumption to promote H2O2 accumulation in the tumor. Inside tumor cells, Met can inhibit the consumption of O2 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.

• Authors: Xiangyu Meng, Xuezhong Zhang, Yunfeng Lei, Dongwei Cao, Zhifei Wang
• Journal: Journal of materials chemistry. B (J Mater Chem B) Vol. 9 Issue 8 Pg. 1988-2000 (03 04 2021) ISSN: 2050-7518 [Electronic] England
• PMID: 33511387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Carriers
• Polymers
• Copper
• Doxorubicin
• Metformin
• Hydrogen Peroxide
• Superoxide Dismutase
• NADPH Oxidases

Topics

• Cell Line, Tumor
• Copper (chemistry)
• Doxorubicin (chemistry, pharmacology)
• Drug Carriers (chemistry)
• Drug Synergism
• Energy Metabolism (drug effects)
• Humans
• Hydrogen Peroxide (metabolism)
• MCF-7 Cells
• Metformin (chemistry)
• NADPH Oxidases (metabolism)
• Nanostructures (chemistry)
• Oxygen Consumption (drug effects)
• Polymers (chemistry)
• Superoxide Dismutase (metabolism)
• Tumor Hypoxia (drug effects)