Department of Chemistry, City University of Hong Kong, Hong Kong, SAR, P. R. China.
City University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, P. R. China.
J Am Chem Soc. 2020 Apr 29;142(17):7803-7812. doi: 10.1021/jacs.0c00221. Epub 2020 Apr 7.
Targeted anticancer prodrugs that can be controllably activated are highly desired for personalized precision medicine in 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 2 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 accumulating conventional platinum drugs to the nucleus is a practical way to change its canonical mechanism of action and to achieve reduced resistance.
用于癌症治疗的个性化精准医学中，人们非常需要可被控制激活的靶向抗癌前药。具有独特作用模式的此类前药也有望克服耐药性。在此，我们报告了一种基于奥沙利铂的光笼 Pt(IV)前药——考马铂，以实现核积累和“按需”激活。该前药基于一种 Pt(IV)配合物，可通过水氧化高效光激活，而无需还原剂。考马铂非常有效地在核仁中积累，并且在光激活后，该前药表现出高达 2 个数量级的比奥沙利铂更高的光细胞毒性。出乎意料的是，该前药表现出显著增强的肿瘤穿透能力，并利用独特的作用模式克服耐药性；即，考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 细胞激活。我们的研究结果不仅为设计可控制激活和靶向核仁的 Pt(IV)抗癌前药提供了一种新策略，还表明将常规铂类药物积累到细胞核中是改变其典型作用机制并降低耐药性的一种实用方法。
