A Photocaged, Water-Oxidizing, and Nucleolus-Targeted Pt(IV) Complex with a Distinct Anticancer Mechanism

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Detail(s)

Original languageEnglish
Pages (from-to)7803-7812
Journal / PublicationJournal of the American Chemical Society
Volume142
Issue number17
Online published27 Mar 2020
Publication statusPublished - 29 Apr 2020

Abstract

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.

Citation Format(s)

A Photocaged, Water-Oxidizing, and Nucleolus-Targeted Pt(IV) Complex with a Distinct Anticancer Mechanism. / Deng, Zhiqin; Wang, Na; Liu, Yingying; Xu, Zoufeng; Wang, Zhigang; Lau, Tai-Chu; Zhu, Guangyu.

In: Journal of the American Chemical Society, Vol. 142, No. 17, 29.04.2020, p. 7803-7812.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review