Synthesis of stimuli-responsive copolymeric hydrogels for temperature, reduction and pH-controlled drug delivery

Stimuli-responsive copolymeric hydrogels (CH) are synthesized for controlled drug delivery. Oxidized glycyrrhizic acid is connected to acrylamide through Schiff base reaction, which is then copolymerized with N,N-bis (acryloyl) cystamine and N-isopropylacrylamide by free-radical polymerization for the loading of 5-fluorouracil with a loading efficiency of 96.7 %. The lower critical solution temperature of the CH is 39.14 °C. The N-isopropylacrylamide unit in the CH is sensitive to temperature, endowing the CH with temperature sensitivity. The carboxyl groups of oxidized glycyrrhizic acid can be deprotonated in alkaline solutions, and the electrostatic repulsions between the resultant carboxylate can cause swelling of the CH. The disulfide bond (S–S) of the N,N-bis (acryloyl) cystamine unit can be reduced to sulfhydryl (–SH) by glutathione, and thus the CH is also reduction-sensitive. Therefore, temperature, reduction and pH-controlled delivery of 5-fluorouracil from the CH is achieved. Cytotoxicity assay reveals that the drug-free hydrogels have good biocompatibility while the CH shows high cytotoxicity against human hepatoma SMMC-7721 cells, and the cell viability is only 25 % at the CH concentration of 1 mg mL −1 .