Redox-Activatable ATP-Depleting Micelles with Dual Modulation Characteristics for Multidrug-Resistant Cancer Therapy

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.