Synthesis of hydrophilic microsphereswith LCST close to body temperature for controlled dual-sensitive drug release

Novel stimuli-responsive hydrophilic microspheres were prepared by free radical polymerization of hydroxyethyl methacrylate (HEMA) and methacrylic acid (MA), as hydrophilic monomers, and N-isopropylacrylamide (NIPAAm) and N,N'-ethylenebisacrylamide (EBA), as thermo-sensitive monomer and crosslinker, respectively. Hydrophilic comonomers were introduced in the macromolecular network to synthesize materials with tunable thermal behavior. In addition, by introducing in the polymerization feed both a hydrophilic and a pH-sensitive monomer, such as MA, dual stimuli-responsive (pH and temperature) hydrogels were synthesized. The incorporation of monomers in the network was confirmed by infrared spectroscopy, while the network density and the shape of hydrogels was found to strictly depend on the concentration of monomers in the polymerization feed. Thermal analyses showed negative thermo-responsive behavior with pronounced water affinity of microspheres at a temperature lower than lower critical solution temperature (LCST). In our experiment, the LCST values of the hydrogels were in the range 34.6-37.5 degrees C, close to the body temperature, and the amount of hydrophilic moieties in the polymeric network allows to collect shrinking/swelling transition temperatures higher than the LCST of NIPAAm homopolymers. In order to test the preformed materials as drug carriers, diclofenac diethylammonium salt (DDA) was chosen and drug entrapment percent was determined. Drug release profiles, in media at different temperature and pH, depend on hydrogels crosslinking degree and drug-bead interactions. By using semi-empirical equations, the release mechanism was extensively studied and the diffusional contribute was evaluated.