CD44 Receptor Targeting and Endosomal pH-Sensitive Dual Functional Hyaluronic Acid Micelles for Intracellular Paclitaxel Delivery

A novel CD44 receptor targeting and endosome pH-sensitive dual functional hyaluronic acid deoxycholic acid histidine (HA-DOCA-His) micellar system was designed for intracellular paclitaxel (PTX) delivery. The HA-DOCA-His micelles exhibited desirable endosome pH (5.0-6.0)-induced aggregation and deformation behavior verified by size distribution, critical micellar concentration, and zeta potential changes. The HA-DOCA-His micelles presented excellent encapsulation efficiency and loading capacity of 90.0% and 18.9% for PTX, respectively. The PTX release from HA-DOCA-His micelles was pH-dependent, with more rapid PTX release at pH 6.0 and 5.0 than those at pH 7.4 and 6.5. The cellular uptake performance of HA-DOCA-His micelles was enhanced comparing with pH-insensitive HA-DOCA micelles by qualitative and quantitative measurements. HA-DOCA-His micelles could be taken up via CD44-receptor mediated endocytosis, transported into endosomes, and triggered drug release to cytoplasm. In vitro cytotoxicity study exhibited PTX-loaded HA-DOCA-His micelles were more active in tumor cell growth inhibition in MCF-7 cells at pH 5.8 than those at pH 6.8 and pH 7.4. A superior antitumor efficacy was demonstrated with HA-DOCA-His micelles in a MCF-7 breast tumor model. These indicated that the dual functional HA-DOCA-His micelles combined targeted intracellular delivery and endosomal release strategies could be developed as a promising nanocarrier for anticancer efficacy improvement of PTX.