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Redox‐Activatable ATP‐Depleting Micelles with Dual Modulation Characteristics for Multidrug‐Resistant Cancer Therapy
Author(s) -
Wang Hebin,
Li Yang,
Zhang Miaozun,
Wu Di,
Shen Youqing,
Tang Guping,
Ping Yuan
Publication year - 2017
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.201601293
Subject(s) - intracellular , cancer cell , micelle , chemistry , multiple drug resistance , biophysics , pharmacology , biochemistry , cancer , biology , aqueous solution , genetics , antibiotics
A fast adenosine triphosphate (ATP)‐depleting micellar system that is activated by intracellular redox for the codelivery of anticancer drug paclitaxel (PTX) and small interference RNA (siRNA) targeting polo‐like kinase1 (PLK1) is developed to address the key challenges of multidrug‐resistant (MDR) cancer therapy. The ATP‐depleting micelle is self‐assembled from a redox‐responsive amphiphilic polymer (termed as bPEG‐SS‐P123‐PEI (PSPP)) that is composed of biocompatible branched polyethylene glycol (PEG) with 8 arms (bPEG), ATP‐depleting Pluronic P123 (P123), and cationic low molecular weight polyethylenimine (PEI) blocks. Upon critical micelle concentration, the PSPP unimer self‐assembles into a well‐ordered multilayered nanostructure and is able to load PTX and siRNA targeting PLK1. The cleavage of disulfide linkages at intracellular glutathione‐rich reduction milieu not only promotes PTX and siRNA release, but also activates the fast ATP‐depletion action that is critical in preventing intracellular PTX efflux by multidrug‐resistant cancer cells. The combination of ATP depletion and siRNA inhibition by PSPP micelles is found to provide dual modulations for resensitizing multidrug‐resistant cancer cells for PTX treatment. As a result, the codelivery of PTX and PLK1 siRNA exerts a stronger combinational effect against tumor growth in MDR tumor models in vivo. The development of fast ATP‐depleting nanomicelle represents an original delivery strategy for the distinctive dual modulation of cancer MDR with spatial and temporal control.