Mineralized hyaluronic acid nanoparticles as a robust drug carrier

Hyaluronic acid nanoparticles (HA-NPs), mineralized by calcium phosphate, were synthesized as a robust carrier of the anticancer drug, doxorubicin (DOX). The HA-NPs were readily mineralized in the presence of calcium nitrate and ammonium phosphate, which was confirmed by various instruments such as FT-IR, thermogravimetric analysis, transmission electron microscopy, and energy-dispersive X-ray photoelectron spectroscopy. Mineralization reduced the particle size of the HA-NPs in PBS (pH 7.4) from 263 nm to 142 nm, indicating the formation of compact nanoparticles. Mineralized HA-NPs were highly stable at pH 7.4, whereas their particle size rapidly increased in a mildly acidic solution, which was due to the dissolution of calcium phosphate. When DOX-loaded bare HA-NPs were exposed to buffer solutions of various pH, most of the DOX (>80%) was released within 48 h, and the release behavior was not dependent upon the pH of the solution. Notably, the mineralized HA-NPs released DOX in a sustained manner at pH 7.4, whereas a rapid release of DOX was observed in the acidic solution. The release rate of DOX from the mineralized HA-NPs was higher in the solution with a lower pH. These results indicate that mineralized HA-NPs have potential as robust nanoparticles that can release DOX at specific sites under mildly acidic conditions, such as in the extracellular matrix of tumor tissue and in intracellular compartments (e.g., endosome and lysosome) of the cell.