BIOADHESIVE LIPOSOMES AS TOPICAL DRUG DELIVERY SYSTEMS - MOLECULAR AND CELLULAR STUDIES

Regular liposomes were modified by the covalent anchoring of bioadhesi ve ligands to the liposomal surface. The ligands are macromolecules ca pable of binding to membrane-embedded receptors or to components of th e extracellular matrix. These modified liposomes have the potential, a s bioadhesive drug delivery systems, for topical and local therapies. The first step in developing such delivery systems is reported here fo r three types of liposomes with epidermal growth factor (EGF), gelatin or collagen as the surface-anchored ligands. Each of these ligands wa s crosslinked, using glutaraldehyde, to amine residues on the liposoma l surface, the latter supplied by the inclusion of phosphatidylethanol amine in the liposome formulation. The kinetics of drug release from E GF-modified liposomes encapsulating vinblastine and from gelatin-modif ied liposomes encapsulating progesterone or fluconazole were studied. A single rate constant (0.05 h-1), was found for the diffusion of enca psulated vinblastine from the EGF-modified and from the nonbioadhesive liposomes. Rate constants for the diffusion of encapsulated progester one or fluconazole were similar from the gelatin-modified and form 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 syst ems, which may be attributed to drug entrapped within the gelatin laye r at the liposomal surface. Typical magnitudes obtained for the rate c onstants of drug diffusion from this pool are 0.4 and 0.7 h-1, for pro gesterone and fluconazole, respectively. Binding studies were performe d using monolayers of the A431 cell line. The present bioadhesive lipo somes showed significant binding whereas nonbioadhesive liposomes did not bind at all. The magnitudes obtained for the dissociation constant s (Kd) are in the range of: 0.5 nM, 800-mu-g/ml and 400-mu-g/ml for th e bioadhesive liposomes carrying EGF, collagen or gelatin, respectivel y. The data suggest that these bioadhesive liposomes can meet the requ irements essential for site-adherent sustained release drug depots.