A self-assembled pH/enzyme dual-responsive prodrug with PEG deshielding for multidrug-resistant tumor therapy†
Multidrug resistance (MDR) is one of the major obstacles for tumor therapy. Intake by receptor-mediated endocytosis enables molecules to bypass ABC transporter efflux, which is the primary mechanism of MDR. Here, we developed a novel pH/enzyme dual-responsive polypeptide prodrug to reverse multidrug resistance. This drug is composed of pH/MMP2-sensitive nanoparticles (MSNPs) self-assembled from mPEG–peptide–DOX. MSNPs can overcome sequential physiological barriers of multidrug resistance by prolonging the circulation time through PEGylation, enhancing tumor accumulation through passive targeting, increasing tumor penetration by enzyme-sensitive PEG deshielding, bypassing ABC transporter efflux by undergoing receptor-mediated endocytosis, and inducing sufficient DOX release from nanoparticles triggered by lysosomal pH. The reversal of MDR by MSNPs was evaluated in MCF-7/ADR cells and nude mice bearing tumors consisting of MCF-7/ADR cells. Both in vitro and in vivo studies showed that the MSNPs can effectively reverse MDR. Thus, MSNPs may constitute a potentially promising strategy for overcoming MDR in clinical applications.