Targeted anticancer prodrugs that can be controllably activated are highly desired for personalized precision medicine of cancer therapy. Such prodrugs with unique action modes are also promising to overcome drug resistance. Herein, we report coumaplatin, an oxaliplatin-based and photocaged Pt(IV) prodrug, to realize nuclear accumulation along with "on-demand" activation. This prodrug is based on a Pt(IV) complex that can be efficiently photoactivated via water oxidation without the requirement of a reducing agent. Coumaplatin accumulates very efficiently in the nucleoli and upon photoactivation, this prodrug exhibits a level of photocytotoxicity up to two orders of magnitude higher than that of oxaliplatin. Unexpectedly, this prodrug presents strikingly enhanced tumor penetration ability and utilizes a distinct action mode to overcome drug resistance, i.e., coumaplatin but not oxaliplatin induces cell senescence, p53-independent cell death, and immunogenic cell death along with T cell activation. Our findings not only provide a novel strategy for the rational design of controllably-activated and nucleolus-targeted Pt(IV) anticancer prodrugs but also demonstrate that accumu-lating conventional platinum drugs to the nucleus is a practical way to change its canonical mechanism of action and to achieve re-duced resistance.

中文翻译：

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具有独特抗癌机制的光笼罩、水氧化和核仁靶向 Pt(IV) 复合物

可以可控激活的靶向抗癌前药对于癌症治疗的个性化精准医疗非常需要。这种具有独特作用模式的前药也有望克服耐药性。在此，我们报告了香马铂，一种基于奥沙利铂的光笼化 Pt(IV) 前药，可实现核积累以及“按需”激活。该前药基于 Pt(IV) 复合物，可通过水氧化有效地光活化，而无需还原剂。香马铂在核仁中非常有效地积累，并且在光活化后，该前药表现出比奥沙利铂高两个数量级的光细胞毒性水平。不料，这种前药具有显着增强的肿瘤穿透能力，并利用独特的作用模式来克服耐药性，即香马铂而非奥沙利铂诱导细胞衰老、p53 非依赖性细胞死亡和免疫原性细胞死亡以及 T 细胞活化。我们的研究结果不仅为合理设计可控活化和核仁靶向 Pt(IV) 抗癌前药提供了一种新策略，而且还表明将常规铂类药物积累到细胞核是改变其典型作用机制的实用方法。并达到降低阻力的目的。