Intestinal Peptide and Protein Delivery: Novel Bioadhesive Drug-Carrier Matrix Shielding from Enzymatic Attack

Abstract

□ We have been developing a novel bioadhesive drug-carrier matrix that protects embedded therapeutic peptides and proteins from degradation by the most abundant intestinal proteases. Increasing amounts of the Bowman−Birk inhibitor (BBI) were thereby covalently linked to chitosan−EDTA. The bioadhesive properties of the resulting polymer—BBI conjugates and their inhibitory effect toward trypsin (EC 3.4.21.4), chymotrypsin (EC 3.4.21.1), elastase (3.4.21.36), carboxypeptidase A (EC 3.4.17.1), and aminopeptidase N (EC 3.4.11.2) were evaluated in vitro. Whereas unmodified chitosan−EDTA exhibited under our experimental conditions an adhesive strength of 54.4±7.7 mN, it was determined to be 21.0±3.8 mN for the comparably most adhesive polymer—BBI conjugate (mean±SD; n=5). All polymer—BBI conjugates showed a strong inhibitory activity toward the serine proteases trypsin and chymotrypsin. However, the protective effect toward elastase was markedly lower. Due to the high binding affinity of chitosan−EDTA toward zinc, which represents an essential cofactor for carboxypeptidase A and aminopeptidase N, all polymer−BBI conjugates displayed additionally a strong protective effect toward these exopeptidases. The novel bioadhesive polymer−BBI conjugates described in this study seem to be very useful drug-carrier matrixes in overcoming the enzymatic barrier to orally administered peptide and protein drugs.