Bioadhesive liposomes as topical drug delivery systems: molecular and cellular studies

Regular liposomes were modified by the covalent anchoring of bioadhesive ligands to the liposomal surface. The ligands are macromolecules capable of binding to membrane-embedded receptors or to components of the extracellular matrix. These modified liposomes have the potential, as bioadhesive drug delivery systems, for topical and local therapies. The first step in developing such delivery systems is reported here for three types of liposomes with epidermal growth factor (EGF), gelatin or collagen as the surface-anchored ligands. Each of these ligands was crosslinked, using glutaraldehyde, to amine residues on the liposomal surface, the latter supplied by the inclusion of phosphatidylethanolamine in the liposome formulation. The kinetics of drug release from EGF-modified liposomes encapsulating vinblastine and from gelatin-modified liposomes encapsulating progesterone or fluconazole were studied. A single rate constant (0.05 h −1 ), was found for the diffusion of encapsulated vinblastine from the EGF-modified and from the nonbioadhesive liposomes. Rate constants for the diffusion of encapsulated progesterone or fluconazole were similar from the gelatin-modified and from the nonbioadhesive liposomes. Typical magnitudes obtained are 0.04 and 0.024 h −1, for progesterone and fluconazole, respectively. An additional liposome-associated drug pool was found for the gelatin-modified systems, which may be attributed to drug entrapped within the gelatin layer at the liposomal surface. Typical magnitudes obtained for the rate constants of drug diffusion from this pool are 0.4 and 0.7 h −1, for progesterone and fluconazole, respectively. Binding studies were performed using monolayers of the A431 cell line. The present bioadhesive liposomes showed significant binding whereas nonbioadhesive liposomes did not bind at all. The magnitudes obtained for the dissociation constants ( K d) are in the range of: 0.5 nM, 800 μg/ml and 400 μg/ml for the bioadhesive liposomes carrying EGF, collagen or gelatin, respectively. The data suggest that these bioadhesive liposomes can meet the requirements essential for site-adherent sustained release drug depots.