The enzymatic degradation mechanism of semi-interpenetrating network (semi-IPN) hydrogel of poly (acrylic acid-acrylamide-methacrylate) crosslinked by azo-compound and amylose in vitro was investigated in the presence of Fungamyl 800L (alpha-amylase) and rat cecum content (cecum bacteria). The degradation mechanism involves degradable competition, i.e., reduction of azo crosslinkage is dominant in the earlier period of degradation. Subsequently, the degradation of gels is continued by combination of reduction of azo crosslinkage and hydrolysis of amylose. The cumulative release ratios of Bovine serum albumin (BSA, as a model drug) loaded semi-IPN gels are 25% in pH 2.2 buffer solutions and 74% in pH 7.4 buffer solutions within 48 h. Moreover, the release behavior of BSA from the semi-IPN gels indicates that it follows Fickian diffusion mechanism in pH 2.2 media and non-Fickian diffusion and polymer chains relaxation mechanism in pH 7.4 media. The results indicate that the release of BSA from the semi-IPN gels was controlled via a combined mechanism of pH dependent swelling and specificity to enzymatic degradation. (C) 2007 Wiley Periodicals, Inc.