Qian Junmin, Aldai Abdalrheem Jarelnaby Musa, Xu Weijun, Wang Taibing, Zhao Kunkun, Wang Yaping, Fan Jingjing, Suo Aili
State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
Carbohydr Polym. 2025 Mar 15;352:123201. doi: 10.1016/j.carbpol.2024.123201. Epub 2024 Dec 30.
Cuproptosis shows great prospects in cancer treatments. However, insufficient intracellular copper amount, low-level redox homeostasis, and hypoxic tumor microenvironment severely restrict cuproptosis efficacy. Herein, hydrazided hyaluronan-templated decorated CuO-doxorubicin (CuDT) nanodot clusters (NCs) are developed for efficient doxorubicin (DOX)-sensitized cuproptosis therapy in breast cancer via a three-pronged strategy. The CuDT NCs with an average size of 56.2 nm are fabricated from 3,3'-dithiobis(propionohydrazide)-conjugated hyaluronan, Cu, and DOX through a one-pot mineralization process. The CuDT nanoparticles exhibit pH-responsive HO, Cu, and DOX release profiles and catalytic activity. Upon entrance into tumor cells, CuO-based exogenous HO supply and DOX-augmented endogenous HO generation jointly elevate intracellular HO level, which can further be transformed into hydroxyl radicals and O through Fenton-like reaction to achieve oxidative stress amplification and hypoxia relief, respectively. Moreover, the CuDT NCs can efficiently deplete intracellular overexpressed glutathione via Cu/Cu cycle and abundant disulfide bonds, further enhancing cellular oxidative stress. These results demonstrate that the novel CuDT NCs achieve DOX-sensitized cuproptosis in breast cancer cells through elevating copper level, amplifying oxidative stress and alleviating hypoxia, thus displaying prominent in vivo antitumor efficacy. Such a three-pronged strategy of targetedly boosting cuproptosis in cancer cells represents a novel approach for antitumor treatments.
铜死亡在癌症治疗中展现出巨大前景。然而，细胞内铜含量不足、低水平的氧化还原稳态以及缺氧的肿瘤微环境严重限制了铜死亡的疗效。在此，通过一种三管齐下的策略，开发了酰肼化透明质酸模板修饰的氧化铜-阿霉素（CuDT）纳米点簇（NCs），用于在乳腺癌中进行高效的阿霉素（DOX）致敏铜死亡治疗。平均尺寸为56.2纳米的CuDT NCs是由3,3'-二硫代双（丙酰肼）共轭透明质酸、铜和阿霉素通过一锅矿化过程制备而成。CuDT纳米颗粒呈现出pH响应性的羟基、铜和阿霉素释放曲线以及催化活性。进入肿瘤细胞后，基于氧化铜的外源性羟基供应和阿霉素增强的内源性羟基生成共同提高细胞内羟基水平，其可通过类芬顿反应进一步分别转化为羟基自由基和氧气，以实现氧化应激放大和缺氧缓解。此外，CuDT NCs可通过铜/铜循环和丰富的二硫键有效消耗细胞内过度表达的谷胱甘肽，进一步增强细胞氧化应激。这些结果表明，新型CuDT NCs通过提高铜水平、放大氧化应激和缓解缺氧，在乳腺癌细胞中实现了DOX致敏铜死亡，从而在体内显示出显著的抗肿瘤疗效。这种在癌细胞中靶向增强铜死亡的三管齐下策略代表了一种新型的抗肿瘤治疗方法。
