Dual‐Targeting Dual‐Action Platinum(IV) Platform for Enhanced Anticancer Activity and Reduced Nephrotoxicity

A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action Pt^IV prodrugs. The dual targeting was established by liposomal encapsulation of Pt^IV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug‐loaded liposomes in the tumor. After the release of the Pt^IV prodrug inside cancer cells, a second stage of targeting directed a portion of the Pt^IV prodrugs to the mitochondria. Upon intracellular reduction, these Pt^IV prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our Pt^IV system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual‐targeting dual‐action platform.