Self-assembly of pH-responsive dextran-g-poly(lactide-co-glycolide)-g-histidine copolymer micelles for intracellular delivery of paclitaxel and its antitumor activity

Abstract

pH-Sensitive copolymers have been widely used in drug delivery systems to selectively enhance drug release at tumor sites. Herein, dextran (DX) was conjugated with poly(lactide-co-glycolide) (PLGA) and histidine (His) to prepare a pH-responsive nanocarrier, dextran-g-poly(lactide-co-glycolide)-g-histidine (HDP) micelles, for the delivery of antitumor drugs. Different grafting ratio HDP micelles were synthesized and prepared successfully and confirmed by the critical micelle concentration (CMC) and particle size distribution (PSD). In vitro drug release showed that the release behaviour of paclitaxel (PTX) loaded HDP micelles was pH-dependent. All blank micelles were nontoxic in the in vitro cytotoxicity assay. In an MTT assay, PTX-loaded HDP micelles with medium grafting ratios (MHDP) showed the highest cytotoxicity against MCF-7 cells. Cellular uptake experiments revealed that these pH-sensitive micelles could be taken up effectively and PTX could be delivered into the cytoplasm to reach the antitumor effect. NIR fluorescence imaging experiments demonstrated that HDP micelles could specifically accumulate in tumor sites via enhancing the permeability and retention (EPR) effect to reduce their systematic toxicity. In vivo antitumor activities showed that HDP micelles could effectively inhibit tumor growth and prolong survival time compared with free PTX solution. These results confirm that the biocompatible pH-responsive HDP micelles are a novel nanocarrier for the intracellular delivery of PTX.