A Transformable Chimeric Peptide for Cell Encapsulation to Overcome Multidrug Resistance.

ABSTRACT

Multidrug resistance (MDR) remains one of the biggest obstacles in chemotherapy of tumor mainly due to P-glycoprotein (P-gp)-mediated drug efflux. Here, a transformable chimeric peptide is designed to target and self-assemble on cell membrane for encapsulating cells and overcoming tumor MDR. This chimeric peptide (C16 -K(TPE)-GGGH-GFLGK-PEG8 , denoted as CTGP) with cathepsin B-responsive and cell membrane-targeting abilities can self-assemble into nanomicelles and further encapsulate the therapeutic agent doxorubicin (termed as CTGP@DOX). After the cleavage of the Gly-Phe-Leu-Gly (GFLG) sequence by pericellular overexpressed cathepsin B, CTGP@DOX is dissociated and transformed from spherical nanoparticles to nanofibers due to the hydrophilic-hydrophobic conversion and hydrogen bonding interactions. Thus obtained nanofibers with cell membrane-targeting 16-carbon alkyl chains can adhere firmly to the cell membrane for cell encapsulation and restricting DOX efflux. In comparison to free DOX, 45-time higher drug retention and 49-fold greater anti-MDR ability of CTGP@DOX to drug-resistant MCF-7R cells are achieved. This novel strategy to encapsulate cells and reverse tumor MDR via morphology transformation would open a new avenue towards chemotherapy of tumor.