College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China.
J Mater Chem B. 2021 Sep 15;9(35):7172-7181. doi: 10.1039/d1tb00742d.
A comprehensive understanding of ferroptosis signaling pathways significantly contributes to the advances in cancer ferrotherapy. Herein, we constructed a self-assembled prodrug nanosystem targeting system x, a key regulator for ferroptosis, to amplify the therapeutic efficacy of cancer ferrotherapy. The prodrug nanosystem is assembled between sulfasalazine (SSZ, a ferroptosis resistance inhibitor) and disulfide-bridged levodopa (DSSD) that can chelate Fe ions to form SSZ-Fe@DSSD, and the resulting nanoassembly can not only inhibit ferroptosis resistance, but also generate ROS in the tumor microenvironment. Whereas the prodrug nanosystem is stable in the physiological environment, it becomes unstable in the tumoral and intracellular reductive microenvironment, where the disulfide linkers are disrupted by high levels of glutathione (GSH), triggering the release of active Fe and SSZ. Under the Fenton reaction, the released Fe thus can induce ferroptosis, which is amplified by SSZ-mediated inhibition of ferroptosis resistance to synergistically improve the therapeutic efficacy of ferroptosis. Our study thus provides an innovative prodrug strategy to advance anticancer ferroptosis.
全面了解铁死亡信号通路显著有助于癌症铁疗的进展。在此，我们构建了一种针对系统 x 的自组装前药纳米系统，系统 x 是铁死亡的关键调节因子，用于放大癌症铁疗的治疗效果。该前药纳米系统由柳氮磺胺吡啶（SSZ，铁死亡抵抗抑制剂）和二硫键桥连左旋多巴（DSSD）组装而成，可螯合 Fe 离子形成 SSZ-Fe@DSSD，所得纳米组装体不仅可以抑制铁死亡抵抗，还可以在肿瘤微环境中产生 ROS。虽然前药纳米系统在生理环境中稳定，但在肿瘤内和细胞内还原微环境中不稳定，其中二硫键连接物被高浓度谷胱甘肽（GSH）破坏，触发活性 Fe 和 SSZ 的释放。在芬顿反应下，释放的 Fe 因此可以诱导铁死亡，SSZ 介导的铁死亡抵抗抑制作用增强了这一作用，从而协同提高铁死亡的治疗效果。我们的研究因此提供了一种创新的前药策略，以推进抗癌铁死亡。
