Self-Assembled Copper Amino Acid Nanoparticles for in Situ Glutathione "AND" H2O2 Sequentially Triggered Chemodynamic Therapy
Self-Assembled Copper Amino Acid Nanoparticles for in Situ Glutathione "AND" H2O2 Sequentially Triggered Chemodynamic Therapy
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用于原位谷胱甘肽和 H2O2 顺序触发化学动力学疗法的自组装铜氨基酸纳米颗粒
DOI：
10.1021/jacs.8b08714
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发表时间：
2019-01-16
影响因子：
15
通讯作者：
Li, Linlin
中科院分区：
文献类型：
--
作者：
Ma, Baojin;Wang, Shu;Li, Linlin
纳米制剂可以响应特定的肿瘤微环境（TME），如弱酸性pH值，低氧和高谷胱甘肽（GSH），显示出以最小侵入性和高特异性杀死癌细胞的前景。在这项研究中，我们展示了自组装铜-氨基酸硫醇纳米颗粒（Cu-Cys NPs）用于原位谷胱甘肽激活和H2 O2增强的耐药乳腺癌的化学动力学治疗。内吞进入肿瘤细胞后，Cu-Cys NPs可首先与局部GSH反应，诱导GSH耗尽，并将Cu 2+还原为Cu+。随后，产生的Cu+将与局部H2 O2反应，通过类芬顿反应产生毒性羟基自由基（中心点OH），其在弱酸性TME中具有快速反应速率，这是肿瘤细胞凋亡的原因。由于肿瘤细胞中的高GSH和H2 O2浓度，其依次触发氧化还原反应，Cu-Cys NPs对癌细胞表现出相对高的细胞毒性，而正常细胞存活。体内实验结果也证明了Cu-Cys纳米粒对耐药乳腺癌的有效抑制作用，且没有明显的全身毒性。作为一种新型的硫醇铜纳米制剂响应TME，这些Cu-Cys纳米颗粒可能有很大的潜力，在化学动力学癌症治疗。
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 (center dot 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.