Orally administrable hydrogel was prepared by crosslinking chitosan (CS) with ?-poly(glutamic acid) (?-PGA) for an excellent pH-responsive colon-targeted drug delivery system. The stable crosslinked amide bond appeared in the shifted region of FTIR spectroscopy, and the tensile strength and elastic modulus were also reduced by crosslinking of CS and ?-PGA. The surfaces of crosslinked hydrogel have a homogeneous pore array with pore size corresponding to the varied blending ratio. The swelling ratio was dramatically changed by increasing the pH from 3 to 6, and the responsiveness of swelling ratio to the reversible pH changes between 3 and 10 was reliable for 72 h. The drug diffusion rate was mainly dependent on the pH, and a water-soluble tetrazolium (WST-1) assay indicated that cytocompatibility of the hydrogel was in an acceptable range. (C) 2012 Wiley Periodicals, Inc. J Appl Polym Sci. 2012