中国药科大学孙敏捷团队报道了GSH耗竭诱导二聚体活化，增强“冷”肿瘤的铁下垂和免疫治疗。相关研究成果于2022年3月2日发表在国际顶尖学术期刊《德国应用化学》。

“冷”肿瘤中大量的谷胱甘肽（GSH）削弱了铁下垂的治疗和免疫反应。

该文中，受脂质的启发，研究人员将肉桂醛二聚体（CDC）制成类脂材料，形成能够消耗GSH的二聚体，并提供治疗药物，以增强乳腺癌的铁下垂和免疫治疗。二聚体在一年多的时间里表现出优异的储存稳定性。到达肿瘤后，由于亲水性GSH通过Michael加成结合到在CDC上，它们在细胞质中很快断裂，不仅触发药物释放和荧光开关“开启”，还导致细胞内GSH的耗竭。具体而言，与sorafenib（SRF）联合后，它显著增强了铁下垂，并通过促进树突状细胞成熟和CD8+T细胞启动，在体内引发了强大的免疫反应。因此CDC@SRF在四次给药后，二聚体治愈了所有小鼠的乳腺癌。

附：英文原文

Title: GSH Depletion-Induced Activation of Dimersomes for Potentiating the Ferroptosis and Immunotherapy of “Cold” Tumor

Author: Zhanwei Zhou, Huan Liang, Ruoxi Yang, Ying Yang, Jingwen Dong, Yongxiang Di, Minjie Sun

Issue&Volume: 2022-03-02

Abstract: The abundant glutathione (GSH) in “cold” tumors weakens the ferroptosis therapy and the immune response. Herein, inspired by lipids, we fabricated cinnamaldehyde dimers (CDC) into lipid-like materials to form dimersomes capable of depleting GSH and delivering therapeutics to potentiate the ferroptosis and immunotherapy of breast cancer. The dimersomes exhibited superior storage stability for over one year. After reaching the tumor, they quickly underwent breakage in the cytosol owing to the conjugation of hydrophilic GSH on CDC by Michael addition, which not only triggered the drug release and fluorescence switch “ON”, but also led to the depletion of intracellular GSH. Specifically, it significantly enhanced the ferroptosis after combination with sorafenib (SRF) and elicited a robust immune response in vivo by promoting the maturation of dendritic cells and the priming of CD8+ T cells. As a result, the CDC@SRF dimersomes cured breast cancer in all the mice after four doses of administration.

DOI: 10.1002/anie.202202843

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202202843