Zwitterionic PH-Responsive Hyaluronic Acid Polymer Micelles For Delivery Of Doxorubicin

The stimuli-responsive drug carrier utilizes the special microenvironment of the tumor tissue to achieve rapid release of the antitumor drug,and exhibits a good application prospect in the antitumor drug delivery system.Zwitterionic materials are very suitable for preparing pH-sensitive drug carriers due to their excellent properties of anti-protein non-specific adsorption and charge reversal.To improve the uptake rate of antitumor drug carriers,control the drug release,and solve the problem that zwitterionic nanoparticles are difficult to degrade,biodegradable materials were used to construct zwitterionic polymers for preparing novel pH-sensitive antitumor drug carriers.In this paper,the zwitterionic polysaccharide was prepared by deacetylation of natural polysaccharide hyaluronic acid(HA),and then modified by grafting dodecylamine to construct pH-sensitive zwitterionic polymer dHAD,which was used as the nanocarrier for antitumor drugs.The polymer structure was characterized by FT-IR and ~1H NMR.The dHAD polymer self-assembled to form micelles,and its performance was characterized by a nanometer particle size analyzer.It was found that the particle size of dHAD micelles was about 180 nm and has a narrow particle size distribution.The dHAD micelles were negative charge at pH 7.4 and were approximately spherical.In addition,the micelles had good stability in the solution containing fetal bovine serum(FBS),indicating that the micelles could avoid the adsorption of proteins in the blood,thereby prolonging the blood circulation time of the dHAD micelles.The dHAD-DOX micelles would cause charge reversal with the pH decrease and promote drug release under acidic conditions in a pH-sensitive manner.At pH 5.0,the cumulative release of DOX from the dHAD-DOX micelles has exceeded 70%,greatly improving the bioavailability of the antitumor drug.In vitro experiments demonstrated that dHAD blank micelles had very low cytotoxicity against MCF-7 cells.Compared to free DOX,the dHAD-DOX micelles showed higher cytotoxicity,meaning that the dHAD-DOX micelles could effectively inhibit MCF-7 cells growth.In addition,the results of qualitative observation by laser confocal microscopy and qualitative analysis by flow cytometry have revealed that dHAD-DOX micelles could be uptaken by MCF-7 cells more rapidly,indicating that the endocytosis mediated by CD44+receptor and the electrostatic interaction of the positive charge micelles with the cell membrane promoted rapid internalization of the micelles in tumor cells.The in vivo results of tumor-bearing mice clearly demonstrated that dHAD-DOX micelles could deliver DOX to tumor cells in a targeted manner,greatly inhibiting the increase in tumor volume and reducing the systemic toxicity of DOX by decreasing the toxicity of DOX to normal organs and tissues.Comprehensive analysis of these results indicated that the novel pH-responsive zwitterionic nanomaterials formed by dHAD polymers have broad prospects as nanocarriers for the delivery of hydrophobic antitumor drugs.