Disulfiram (DS), in the presence of copper (Cu), exhibited potent broad anticancer activity. However, its clinical application is limited due to the poor solubility and stability. Hence, a novel nanocombination of DS with bacterially synthesized copper oxide nanoparticles (CuO NPs) was prepared herein to improve the anticancer efficacy of the typical DS–Cu complex. Our design utilized the nanocharacterization and prooxidant effect-mediated anticancer activity of CuO NPs which may lead to enhanced cellular uptake and thus improved anticancer efficacy of this unique nanocomplex. The characterized DS–CuO NPs exhibited high stability in serum and the strongest selective anticancer activity, with the lowest half-maximum inhibitory concentration (IC50 < 15 nM), against human breast, lung and liver cancer cells, by >10-fold, compared to DS–Cu, CuO NPs and Cu. Importantly, DS–CuO NPs revealed better synergistic anticancer effect and higher cellular uptake than DS–Cu. Moreover, this novel nanocomplex showed higher prooxidant effect-mediated apoptosis and anti-metastatic potential. This was accomplished by elevating cellular reactive species content with inhibiting the antioxidant defenders (functional marker of cancer stem cells (aldehyde dehydrogenase) and nuclear factor erythroid 2-related factor2), matrix metallopeptidase 9 and NF-κB as well as enhancing p53 expression. All of the aforementioned findings verified that this novel nanocomplex was capable of improving the therapeutic index of the conventional DS–Cu complex. The potent selective anticancer activity of this promising nanomedicine merits further investigation, as a separate future study, using animal models as preliminary step before its clinical application.

中文翻译：

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双硫仑与细菌合成氧化铜纳米颗粒的新型纳米制剂用于增强抗癌活性：一项体外研究

双硫仑 (DS) 在铜 (Cu) 存在下表现出强大的广泛抗癌活性。但其溶解性和稳定性较差，限制了其临床应用。因此，本文制备了 DS 与细菌合成的氧化铜纳米粒子 (CuO NPs) 的新型纳米组合，以提高典型 DS-Cu 复合物的抗癌功效。我们的设计利用了 CuO NPs 的纳米表征和促氧化作用介导的抗癌活性，这可能会导致细胞摄取增强，从而提高这种独特纳米复合物的抗癌功效。表征的 DS-CuO NPs 在血清中表现出高稳定性和最强的选择性抗癌活性，对人乳腺癌、肺癌和肝癌细胞的半数最大抑制浓度 (IC50 < 15 nM) 最低，相比之下提高了 >10 倍到 DS-Cu，CuO NPs 和 Cu。重要的是，DS-CuO NPs 显示出比 DS-Cu 更好的协同抗癌作用和更高的细胞摄取。此外，这种新型纳米复合物显示出更高的促氧化作用介导的细胞凋亡和抗转移潜力。这是通过通过抑制抗氧化防御者（癌症干细胞的功能标志物（醛脱氢酶）和核因子红细胞 2 相关因子 2）、基质金属肽酶 9 和 NF-κB 以及增强 p53 表达来提高细胞活性物质含量来实现的。上述所有发现都证实这种新型纳米复合物能够提高传统 DS-Cu 复合物的治疗指数。这种有前途的纳米药物的有效选择性抗癌活性值得进一步研究，作为一项单独的未来研究，