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

Abstract

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.

Hyaluronic Acid-Modified and Doxorubicin-Loaded Gold Nanoparticles and Evaluation of Their Bioactivity

“…Hyaluronic acid (HA) is a macromolecule from a natural source, widely used in biomedical applications due to its good biocompatibility, biodegradability, and low toxicity, especially in cosmetics, treatments for arthritis, and drug delivery [ 19 , 20 , 21 , 22 , 23 , 24 ]. Recent studies have demonstrated that the surface of cancer cells over-express the CD44 receptors on their surface, to which HA strongly binds [ 25 , 26 , 27 , 28 , 29 , 30 ]. Therefore, HA can be utilized as a target ligand for tumor-targeted drug delivery [ 31 , 32 , 33 , 34 , 35 ].…”

Targeting Strategies for Enhancing Paclitaxel Specificity in Chemotherapy

“…Accompanied by PTX preloading, the NPs induced strong tumor apoptosis, cellular arrest, and cytotoxic activity (Ravar et al, 2016;Su et al, 2018;Zhao et al, 2018). After activation by the TME (pH, redox), HA-NPs exhibited great lysosomal release and antitumor efficacy (Yin et al, 2015;Liu et al, 2016Liu et al, , 2020Zhong et al, 2016;Han et al, 2019).…”

Carbohydrate‐based nanomaterials for biomedical applications

“…Similar systems based on GAG/DOCA were developed in recent years: ChS‐DOCA nanoparticles for DOX delivery (J.‐Y. Lee, Chung, Cho, & Kim, ), HA‐DOCA‐histidine micelles for intracellular paclitaxel (PTX) delivery (Yanhua Liu, Zhou, Wang, et al, ), phenylboronic acid‐decorated ChS‐DOCA system for DOX delivery (J. Y. Lee, Chung, Cho, & Kim, ), ChS‐DOCA/DOX nanoparticle for the therapy of CD44 receptor‐expressing ovarian cancers (J.‐Y. Lee et al, ), ChS‐DOCA conjugates for docetaxel delivery (M. Liu, Du, & Zhai, ).…”