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Dual‐Targeting Dual‐Action Platinum(IV) Platform for Enhanced Anticancer Activity and Reduced Nephrotoxicity
Author(s) -
Babak Maria V.,
Zhi Yang,
Czarny Bertrand,
Toh Tan Boon,
Hooi Lissa,
Chow Edward KaiHua,
Ang Wee Han,
Gibson Dan,
Pastorin Giorgia
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201903112
Subject(s) - prodrug , in vivo , cytotoxicity , nephrotoxicity , chemistry , liposome , in vitro , pharmacology , drug delivery , biochemistry , toxicity , medicine , biology , microbiology and biotechnology , organic chemistry
Abstract 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.