Multifunctional Hyaluronic Acid-Decorated Redox-Responsive Magnetic Complex Micelle for Targeted Drug Delivery with Enhanced Antitumor Efficiency and Anti-Cell-Migration Activity.

Abstract

A novel multifunctional hyaluronic acid-decorated redox-responsive magnetic complex micelle (HA/CSO-SS-Hex/Fe3O4/PTX) based on a reducible hexadecanol-modified chitosan oligosaccharide polymer micelle (CSO-SS-Hex) coated with hyaluronic acid (HA) and loaded with paclitaxel (PTX) Fe3O4 nanoparticles is developed. HA is coated onto the surface of micelles via electrostatic absorption and acts as a targeting ligand for CD44 over expression in many tumor cells. A CSO-SS-Hex polymer micelle was used for PTX incorporation and GSH-triggered intracellular release. The PTX in micelles was used to provide chemotherapy. Fe3O4 nanoparticles were used for magnetic targeting. The complex micelle showed enhanced antitumor efficiency and anti-cell-migration activity. The HA/CSO-SS-Hex/Fe3O4/PTX micelle was stable under physiological conditions, while it was sensitive to release the loaded drug in the presence of 10 mM glutathione (GSH). The complex micelle showed enhanced cellular uptake and fast drug release due to the combined effect of magnet targeting, CD44 receptor-mediated internalization and redox-response drug release in tumor cells. Cell viability tests revealed that HA/CSO-SS-Hex/Fe3O4/PTX micelle displayed enhanced cytotoxicity against A549, B16F10 and HepG2 cell lines compared to non-targeted formulations of PTX. An anti-cell migration assay was also performed. The result showed that although there was no significant difference in the anti-cell migration activities between the HA/CSO-SS-Hex/Fe3O4/PTX micelle and free PTX, the activities of HA/CSO-SS-Hex/Fe3O4/PTX were stronger than non-targeted CSO-SS-Hex/Fe3O4/PTX micelles. Thus, the novel HA/CSO-SS-Hex/Fe3O4/PTX micelle is highly effective for targeted drug delivery and might have potential implications for the chemotherapy of primary tumors and their metastases.