Platinum(IV) Prodrug-Coupled TAT Nuclear-Targeting Peptide for Drug Delivery and High Antitumor Efficacy with Low Toxicity

The occurrence of serious toxic side effects caused by the low selectivity of first-line platinum drugs is the main limitation of their clinical application. To address this issue, this work fully utilizes the designable, targetable, and easily modifiable characteristics of peptides to successfully prepare a nuclear targeted peptide-coupled Pt(IV) prodrug, named Pt(IV)-TAT. In vitro experiments showed that at the same concentration, the Pt(IV)-TAT prodrug accumulates more in the tumor cell nucleus than cisplatin and induces genomic DNA damage, activating apoptotic pathways. Notably, at concentrations effective in inhibiting tumor cell growth, the Pt(IV)-TAT prodrug exhibits higher biological safety toward normal cells. Additionally, the Pt(IV)-TAT prodrug demonstrates excellent antitumor activity in mice with low systemic toxicity. Therefore, the peptide-targeted Pt(IV)-TAT prodrug developed in this study provides a strategy for delivering and activating platinum-based drugs within cancer cells and offers an approach to improving platinum drug delivery while avoiding systemic toxicity.