Doxorubicin-loaded hydrogen peroxide self-providing copper nanodots for combination of chemotherapy and acid-induced chemodynamic therapy against breast cancer.
Doxorubicin-loaded hydrogen peroxide self-providing copper nanodots for combination of chemotherapy and acid-induced chemodynamic therapy against breast cancer.
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DOI：
10.1016/j.jcis.2021.02.085
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发表时间：
2021-03
影响因子：
9.9
通讯作者：
Jie-xia Li;Lingmin Zhang;Cheng-cheng Liu;Qian-ni Wu;Songpei Li;Xue-ping Lei;Yu-gang Huang;
中科院分区：
文献类型：
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作者：
Jie-xia Li;Lingmin Zhang;Cheng-cheng Liu;Qian-ni Wu;Songpei Li;Xue-ping Lei;Yu-gang Huang;
近年来，化学动力疗法(CDT)在肿瘤治疗中受到越来越多的关注。与光动力疗法和声动力疗法相比，CDT不需要激光或超声等外部刺激。因此，CDT的性能不受外部刺激的渗透深度的限制。然而，CDT在很大程度上依赖于肿瘤微环境中的过氧化氢(H_2O_2)。TME中H_2O_2的不足限制了CDT的性能，而已报道的在TME中产生H_2O_2的方法大多依赖于氧气供应，而氧气供应受到低氧TME的限制。本研究提出了过氧化氢自提供铜纳米点，并成功地负载了药物阿霉素(DOX)来构建DOX纳米点。我们的结果表明，在弱酸性的TME中，由于过氧基团的作用，纳米点生成了过氧化氢，进而通过类Fenton反应生成了最活跃的羟基自由基(DotOH)。这一过程依赖于pH，在中性环境中不发生。除了氧自由基，这些纳米点还能在癌细胞中产生单线态氧(1O2)和超氧阴离子(O2-)。铜纳米点在体内外对乳腺癌具有良好的抗癌效果，具有促进细胞凋亡、抑制细胞增殖的作用。化疗和使用DOX纳米点的CDT的结合进一步提高了治疗效果。这些处理显示出良好的生物相容性，在主要组织中没有明显的毒性，可能是由于在弱酸性TME中产生了特异的自由基dotOH。综上所述，双氧水自提供的铜纳米点与DOX的结合显示了良好的癌症治疗效果，这是由于氧非依赖性和肿瘤特异性产生的活性氧物种以及化疗的配合。
In recent years, chemodynamic therapy (CDT) has gained increasing interest in cancer treatment. In contrast to photodynamic therapy and sonodynamic therapy, extrinsic excitations such as laser or ultrasound are not required in CDT. As a result, the CDT performance is not limited by the penetration depth of the external irritation. However, CDT relies heavily on hydrogen peroxide (H2O2) in the tumour microenvironment (TME). Insufficient H2O2in the TME limits the CDT performance, and the most reported methods to produce H2O2in the TME are dependent on oxygen supply, which is restricted by the hypoxic TME. In this study, H2O2self-providing copper nanodots were proposed, and the drug doxorubicin (DOX) was successfully loaded to construct DOX-nanodots. Our results showed that the nanodots produced H2O2in the weakly acidic TME due to the peroxo group and further generated the most active hydroxyl radical (radical dotOH) through the Fenton-like reaction. This process was pH-dependent and did not occur in a neutral environment. In addition toradical dotOH, the nanodots also produced singlet oxygen (1O2) and superoxide anions (O2–) in the cancer cells. The copper nanodots performed promising CDT against breast cancer in vitro and in vivo, with enhanced cell apoptosis and decreased cell proliferation. The combination of chemotherapy and CDT using DOX-nanodots further improved the therapeutic effects. The treatments showed good biocompatibility with no obvious toxicity in major tissues, possibly due to the specificradical dotOH generation in the weakly acidic TME. In summary, the H2O2self-providing copper nanodots in combination with DOX showed promising cancer-curing effects due to the oxygen-independent and tumour-specific production of reactive oxygen species and the cooperation of chemotherapy.