Paclitaxel delivered by CD44 receptor-targeting and endosomal pH sensitive dual functionalized hyaluronic acid micelles for multidrug resistance reversion

• Published in: Colloids and surfaces, B, Biointerfaces Vol. 170; pp. 330 - 340
• Main Authors: Liu, Yanhua, Zhou, Chengming, Wei, Shijie, Yang, Tong, Lan, Yang, Cao, Aichen, Yang, Jianhong, Hou, Yanhui
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2018
• Subjects: CD44 receptor-targeting; Endosomal pH sensitive hyaluronic acid micelles; Multidrug resistance reversion; Paclitaxel; CD44 receptor-targeting; Endosomal pH sensitive hyaluronic acid micelles; Multidrug resistance reversion; Paclitaxel
• ISSN: 0927-7765; 1873-4367
• DOI: 10.1016/j.colsurfb.2018.06.024

Schematic illustration on proposed multidrug resistance (MDR) reversion mechanisms of paclitaxel/hyaluronic acid-deoxycholic acid-histidine (PTX/HA-DOCA-His) micelles in MCF-7/Adr cells. [Display omitted] •CD44 receptor and endosome pH sensitive dual-targeted HA-DOCA-His micelles were developed.•Intracellular uptake and cytotoxicity study confirmed the multidrug resistance reversion efficacy of HA-DOCA-His micelles.•HA-DOCA-His micelles exhibited longer circulation time and larger AUC.•HA-DOCA-His micelles demonstrated excellent therapeutic efficacy on MDR tumors. The drug efflux mediated by P-glycoprotein (P-gp) transporter is a major factor responsible for multidrug resistance (MDR) of paclitaxel (PTX). The efficient intracellular PTX delivery is a promising strategy for overcoming the MDR of tumor cells. A CD44 receptor targeting and endosome-pH sensitive dual functionalized hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar formulation was developed to overcome MDR, and a CD44 receptor targeting hyaluronic acid-deoxycholic acid (HA-DOCA) micelles was used as a comparison. Compared with Taxol solution and HA-DOCA micelles, the cytotoxicity of PTX loaded in HA-DOCA-His micelles against drug-resistant tumor cells was improved significantly and possessed superior MDR-overcoming performance; this phenomenon is due to the increased intracellular PTX delivery by CD44 receptor-mediated endocytosis pathway and endosome-pH sensitivity-mediated PTX triggering release. Upon pharmacokinetic study, PTX/HA-DOCA-His micelles demonstrated longer blood circulation time, larger AUC, decreased Vd and CL than the Taxol solution. More importantly, PTX/HA-DOCA-His micelles were more effective in tumor growth inhibition in MCF-7/Adr tumor-bearing mice compared with PTX/HA-DOCA micelles and Taxol solution. Dual targeting strategy-functionalized HA-DOCA-His micelles demonstrated excellent MDR-reversing ability for therapeutic efficacy and improvement on MDR tumors, thereby providing an effective targeting strategy for PTX delivery of nano-drug delivery system in MDR cancer chemotherapy.