Chitosan-pentaglycine-phenylboronic acid conjugate: a potential colon-specific platform for calcitonin.
Novel drug delivery vehicles based on the biodegradable, mucoadhesive polysaccharide chitosan covalently linked to a boronic acid protease inhibitor have been prepared and characterized. It was anticipated that these conjugates could protect a proteinaceous drug, such as salmon calcitonin, against proteolysis by serine proteases, an obstacle that prevents its oral administration. Specifically, 4-formylphenylboronic acid was linked to chitosan. Three types of conjugates were prepared. In the first, 4-formylphenylboronic acid was directly linked to chitosan. The other two conjugates employed glycylglycine and pentaglycine spacers. Enzyme-inhibition assays toward trypsin and elastase, in the presence of the enzyme chitosanase, demonstrated a strong inhibitory effect for the chitosan-pentaglycine-phenylboronic acid conjugates, while no inhibitory effect could be detected without chitosanase. The chitosan-pentaglycine-phenylboronic acid conjugate with the highest degree of substitution of 4-formylphenylboronic acid was able to decrease the salmon calcitonin degradation rate by trypsin. It is concluded that chitosan-pentaglycine-phenylboronic acid conjugates are a potential multifunctional, colon-specific vehicle for orally administered salmon calcitonin.
Smoum
Reem
R
Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
Rubinstein
Abraham
A
Srebnik
Morris
M
D001897:Boronic Acids / Q000737:chemistry*; D002116:Calcitonin / Q000737:chemistry*; D048271:Chitosan / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000737:chemistry*; D005998:Glycine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy
D001897:Boronic Acids; D002116:Calcitonin; D048271:Chitosan; C010686:benzeneboronic acid; D005998:Glycine