Wang Yingjie, Chen Fangmin, Zhou Huiling, Huang Lujia, Ye Jiayi, Liu Xiaoying, Sheng Weizhong, Gao Weidong, Yu Haijun, Wang Feng
Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, P. R. China.
Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, P. R. China.
Small Methods. 2023 May;7(5):e2200888. doi: 10.1002/smtd.202200888. Epub 2022 Nov 29.
Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to conventional therapies, including chemo-, radio-, and immunotherapy. In this study, it is first determined that a combination of dihydroartemisinin (DHA) and RSL-3 (a glutathione peroxidase 4 (GPX4) inhibitor) markedly induced ferroptosis of PDAC tumor cells. A mechanistic study revealed that DHA can react with iron ions to generate carbon radicals and deplete intracellular glutathione, thereby cumulatively triggering the lipid peroxidation of tumor cells with RSL-3-mediated GPX4 inhibition. A DHA-conjugated amphiphilic copolymer is subsequently synthesized, and intracellular acidity and oxidation dual-responsive DHA nanoparticles are further engineered for the tumor-specific co-delivery of DHA and RSL-3. The resultant nanoparticles (PDBA@RSL-3) efficiently induce ferroptosis of tumor cells in the Panc02 tumor-bearing immune-deficient mouse model, and elicit T-cell-based antitumor immunity in the immune-competent mouse model. The combination of PDBA@RSL-3 nanoparticles and programmed death ligand 1 blockade therapy efficiently inhibits PDAC tumor growth in the immune-competent mouse models. This study may provide novel insights for treatment of PDAC with ferroptosis-based immunotherapy.
胰腺导管腺癌（PDAC）具有高度致死性，并且对包括化疗、放疗和免疫疗法在内的传统疗法具有抗性。在本研究中，首次确定双氢青蒿素（DHA）与RSL-3（一种谷胱甘肽过氧化物酶4（GPX4）抑制剂）联合使用可显著诱导PDAC肿瘤细胞发生铁死亡。机理研究表明，DHA可与铁离子反应生成碳自由基并消耗细胞内谷胱甘肽，从而在RSL-3介导的GPX4抑制作用下，累积触发肿瘤细胞的脂质过氧化。随后合成了一种DHA共轭两亲共聚物，并进一步设计了对细胞内酸度和氧化双重响应的DHA纳米颗粒，用于肿瘤特异性共递送DHA和RSL-3。所得纳米颗粒（PDBA@RSL-3）在携带Panc02肿瘤的免疫缺陷小鼠模型中有效诱导肿瘤细胞发生铁死亡，并在免疫健全小鼠模型中引发基于T细胞的抗肿瘤免疫。PDBA@RSL-3纳米颗粒与程序性死亡配体1阻断疗法联合使用可有效抑制免疫健全小鼠模型中的PDAC肿瘤生长。本研究可能为基于铁死亡的免疫疗法治疗PDAC提供新的见解。
