Mechanism Of Enhanced Drug Accumulation In Multidrug Resistance Cells Mediated By Poly (L-γ-glutamylglutamine)

Cancer cells employ various different defense mechanisms to become resistant to one or more chemotherapeutic agents which predominantly mediated by ATP-binding cassette (ABC) transporter superfamily, especially by P-glycoprotein (P-gp).Thus, the human non-small lung cancer A549cell line and human breast cancer MDA-MB-231cell line were induced by paclitaxel and doxorubicin to be multidrug resistant.Drug delivery systems have been intensively investigated for their use in tumor therapy to reduce drug toxicity, to achieve improved drug targeting to the tumor and to overcome the mechanisms of multidrug resistance. Polymer-based therapeutic drug delivery systems have been developed that were rationally designed to overcome drug resistance by neutralizing, evading or exploiting various drug efflux pumps.Previously, our group has developed poly-(L-γ-glutamylglutamine)-paclitaxel nanoconjugate, which demonstrated effective antitumor activity in vivo and outperformed albumin-bound Ptx nanoparticle in murine models. Studies of Pharmacokinetics and tissue distribution of PGG-Ptx showed prolonged half-life of total taxanes, extractable taxanes, and active free Ptx in both the plasma and tumor compartments compared with the Cremophor EL-ethanol formulation of Ptx in BABL/c nude mice bearing lung cancer xenografts.This work investigated antitumor efficacy of poly (L-y-glutamylglutamine) drug delivery system based prodrug in multidrug resistant cancer cells and the possible mechanisms. Multidrug resistant cell lines and wild type cell lines were applied to evaluate the effect of PGG-Dox on intracellular accumulation and retention of Dox. According to the results, PGG can significantly enhance the cell accumulation and retention of antitumor drugs. Endocytosis inhibition studies and transmission electron microscope assay were used to investigate the mechanisms of cellular PGG-Dox uptake. Confocal laser scanning microscopy was performed to confirm the drug accumulation. Treatment of MDR cells with PGG-Dox resulted in significantly enhanced drug accumulation and retention after the end of treatment compared with free Dox. Endocytosis inhibition studies showed pinocytosis is the mainly pathway in the elevated membrane permeability of the PGG-Dox.These demonstrated that Dox conjugate with PGG NPs effectively bypass the multidrug resistance. Our PGG based DDS may be considered as an attractive and promising delivery system to overcome multidrug resistance.