Novel biodegradable and pH-sensitive hydrogels composed of four types of pH-sensitive polyacrylic acid derivatives (PAAD) and a biodegradable poly(L-glutamic acid) (PGA) crosslinker were synthesized and characterized for oral delivery of proteins or peptides. The swelling ratios of hydrogels in buffer solutions showed a pH-dependent profile at different pH values. Insulin was loaded into the hydrogels as a model protein. The in vitro drug release experiment was carried out at different pH values and the release data suggested that both the pH and the type of the AAD unit played important roles in the drug release behaviors of the hydrogels. In vitro MU assay indicated that the hydrogels displayed good cyto-compatibility. After oral administration of insulin-loaded hydrogel particles to streptozotocin-induced diabetic rats at 60 IU/kg, the fasting plasma glucose level was reduced continuously to 67.4% within 7 h. These results indicated that the hydrogels are potential new vehicles for oral delivery of drugs. (c) 2013 Elsevier Ltd. All rights reserved.