Using photodynamic therapy (PDT) to trigger nonconventional cell death pathways has provided a new scheme for highly efficient and non-side effects to drug-resistant cancer therapies. Nonetheless, the unclear targets of available photosensitizers leave the manner of PDT-induced tumor cell death relatively unpredictable. Herein, we developed a novel Ru(II)-based photosensitizer, Ru-Poma. Possessing the E3 ubiquitin ligase CRBN-targeting moiety and high singlet oxygen yield of 0.96, Ru-Poma was demonstrated to specifically photodegrade endogenous CRBN, increase lipid peroxide, downregulate GPX4 and GAPDH expression, and consequently induce ferroptosis in cisplatin-resistant cancerous cells. Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT.

中文翻译：

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Ru(II) 复合物对 E3 泛素连接酶 Cereblon 的双光子光降解：诱导顺铂耐药肿瘤细胞铁死亡


利用光动力疗法（PDT）触发非常规细胞死亡途径，为耐药癌症治疗提供了高效、无副作用的新方案。尽管如此，现有光敏剂的靶点不明确，使得 PDT 诱导的肿瘤细胞死亡的方式相对难以预测。在此，我们开发了一种新型的基于 Ru(II) 的光敏剂 Ru-Poma。 Ru-Poma 具有 E3 泛素连接酶 CRBN 靶向部分和 0.96 的高单线态氧产率，被证明可以特异性光降解内源性 CRBN，增加脂质过氧化物，下调 GPX4 和 GAPDH 表达，从而诱导顺铂耐药癌细胞中的铁死亡。此外，随着双光子激发的深度渗透，Ru-Poma在3D肿瘤细胞模型中实现了耐药规避。因此，我们描述了在 PDT 中具有活性的 CRBN 靶向 Ru(II) 复合物的第一个样品。