NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 21 Lower Kent Ridge Road, 119077, Singapore, Singapoare.
Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore.
Angew Chem Int Ed Engl. 2020 Oct 19;59(43):19070-19078. doi: 10.1002/anie.202008604. Epub 2020 Sep 17.
Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can improve the clinical outcomes of chemo-immunotherapeutic combination regimens through the establishment of a long-term cancer immunity. None of the clinically used DNA-binding Pt complexes is considered a Type II ICD inducer. We generated a series of Pt -carbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt-NHC and compared their efficiency in triggering ICD-related cellular responses and phagocytosis. We successfully identified PlatinER, a novel highly potent Pt candidate with superior ICD properties. Crucially, the magnitude of ICD-associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER-localized reactive oxygen species (ROS) generation, which underpins their mechanisms of action and provides a feasible approach for the design of more effective Type II ICD inducers.
免疫原性细胞死亡（ICD）是一种罕见的免疫刺激性细胞死亡形式，通过建立长期的癌症免疫，可以改善化疗免疫联合治疗方案的临床效果。目前临床使用的 DNA 结合型铂配合物都不被认为是 II 型 ICD 诱导剂。我们通过对 II 型 ICD 诱导剂 Pt-NHC 支架进行微小结构改变，生成了一系列 Pt-卡宾配合物，并比较了它们触发 ICD 相关细胞反应和吞噬作用的效率。我们成功地鉴定出 PlatinER，这是一种新型高效的 Pt 候选物，具有优越的 ICD 特性。至关重要的是，癌细胞暴露于铂配合物后诱导的 ICD 相关吞噬作用的程度取决于 ER 定位的活性氧（ROS）生成水平，这为它们的作用机制提供了依据，并为设计更有效的 II 型 ICD 诱导剂提供了一种可行的方法。
