A diselenide/disulfide unit was introduced into camptothecin (CPT), and two selenoprodrugs (e.g., CPT–Se3 and CPT–Se4) were identified to show improved potency in killing cancer cells and inhibiting tumor growth in vivo. Interestingly, the intrinsic fluorescence of CPT was severely quenched by the diselenide bond. Both the selenoprodrugs were activated by glutathione with a nearly complete recovery of CPT’s fluorescence. The activation of prodrugs was accompanied by the production of selenol intermediates, which catalyzed the constant conversion of glutathione and oxygen to oxidized glutathione and superoxides. The diselenide unit is widely employed in constructing thiol-responsive materials. However, the selenol intermediates were largely ignored in the activation process prior to this study. Our work verified that integration of the diselenide unit may further enhance the parent drug’s efficacy. Also, the discovery of the fluorescence quenching property of the diselenide/disulfide bond further shed light on constructing novel theranostic agents.

中文翻译：

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二硒化物单元的整合产生具有改善的对癌细胞的细胞毒性的荧光喜树碱前药

将二硒化物/二硫化物单元引入喜树碱 (CPT)，并鉴定出两种硒前药（例如，CPT-Se3 和 CPT-Se4）在体内杀死癌细胞和抑制肿瘤生长方面显示出更高的效力. 有趣的是，CPT 的固有荧光被二硒键严重淬灭。两种硒前药都被谷胱甘肽激活，CPT 的荧光几乎完全恢复。前药的活化伴随着硒醇中间体的产生，它催化谷胱甘肽和氧气不断转化为氧化型谷胱甘肽和超氧化物。二硒化物单元广泛用于构建硫醇响应材料。然而，硒醇中间体在本研究之前的活化过程中很大程度上被忽略了。我们的工作证实了二硒化物单元的整合可以进一步增强母体药物的疗效。此外，二硒/二硫键荧光猝灭特性的发现进一步为构建新型治疗诊断剂提供了启示。