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A self-assembled pH/enzyme dual-responsive prodrug with PEG deshielding for multidrug-resistant tumor therapy

Author:
Ni, Ronghua, Zhu, Jianhua, Xu, Zhiyuan, Chen, Yun
Source:
Journal of materials chemistry B 2020 v.8 no.6 pp. 1290-1301
ISSN:
2050-7518
Subject:
ABC transporters, chemical bonding, drugs, endocytosis, in vivo studies, mice, multiple drug resistance, nanoparticles, neoplasms, pH, polypeptides, therapeutics
Abstract:
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.
Agid:
6838973