Synthesis and Characterization of Covalently Crosslinked pH-Responsive Hyaluronic Acid Nanogels: Effect of Synthesis Parameters

Stable hyaluronic acid nanogels were obtained following the water-in-oil microemulsion method by covalent crosslinking with three biocompatible crosslinking agents: Divinyl sulfone, 1,4-butanediol diglycidyl ether (BDDE), and poly(ethylene glycol) bis(amine). All nanoparticles showed a pH-sensitive swelling behavior, according to the pKa value of hyaluronic acid, as a consequence of the ionization of the carboxylic moieties, as it was corroborated by zeta potential measurements. QELS studies were carried out to study the influence of the chemical structure of the crosslinking agents on the particle size of the obtained nanogels. In addition, the effect of the molecular weight of the biopolymer and the degree of crosslinking on the nanogels dimensions was also evaluated for BDDE crosslinked nanoparticles, which showed the highest pH-responsive response.