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Self-Assembled Copper–Amino Acid Nanoparticles for in Situ Glutathione “AND” H₂O₂ Sequentially Triggered Chemodynamic Therapy
- Ma, Baojin, Wang, Shu, Liu, Feng, Zhang, Shan, Duan, Jiazhi, Li, Zhao, Kong, Ying, Sang, Yuanhua, Liu, Hong, Bu, Wenbo, Li, Linlin
- Journal of the American Chemical Society 2018 v.141 no.2 pp. 849-857
- amino acids, apoptosis, breast neoplasms, copper, copper nanoparticles, cytotoxicity, drug resistance, endocytosis, glutathione, hydrogen peroxide, hydroxyl radicals, neoplasm cells, oxygen, pH, redox reactions, therapeutics
- Nanoformulations that can respond to the specific tumor microenvironment (TME), such as a weakly acidic pH, low oxygen, and high glutathione (GSH), show promise for killing cancer cells with minimal invasiveness and high specificity. In this study, we demonstrate self-assembled copper–amino acid mercaptide nanoparticles (Cu-Cys NPs) for in situ glutathione-activated and H₂O₂-reinforced chemodynamic therapy for drug-resistant breast cancer. After endocytosis into tumor cells, the Cu-Cys NPs could first react with local GSH, induce GSH depletion, and reduce Cu²⁺ to Cu⁺. Subsequently, the generated Cu⁺ would react with local H₂O₂ to generate toxic hydroxyl radicals (·OH) via a Fenton-like reaction, which has a fast reaction rate in the weakly acidic TME, that are responsible for tumor-cell apoptosis. Due to the high GSH and H₂O₂ concentration in tumor cells, which sequentially triggers the redox reactions, Cu-Cys NPs exhibited relatively high cytotoxicity to cancer cells, whereas normal cells were left alive. The in vivo results also proved that Cu-Cys NPs efficiently inhibited drug-resistant breast cancer without causing obvious systemic toxicity. As a novel copper mercaptide nanoformulation responsive to the TME, these Cu-Cys NPs may have great potential in chemodynamic cancer therapy.