MOLECULAR AND CELLULAR STUDIES OF HYALURONIC ACID-MODIFIED LIPOSOMES AS BIOADHESIVE CARRIERS FOR TOPICAL DRUG-DELIVERY IN WOUND-HEALING

Liposomes, modified into bioadhesive systems by the covalent anchoring of hyaluronic acid (HA) to their surface, were investigated for their abilities to act as site-adherent and sustained-release carriers of d rugs for the topical therapy of wounds and burns. Epidermal growth fac tor (EGF) served as the test drug for growth factors and monolayers of the A431 cell line served as models of the in vivo designated targets . The hyaluronic acid was radiolabeled to carry H-3, through a deacety lation-reacetylation procedure, yielding specific activities in the ra nge of 1 X 10(6) dpm/mg. The HA was bound to the surface of the liposo mes, using carbodiimide to crosslink its carboxyl residues to amine re sidues at the liposomal surface. The latter was provided through the i nclusion of phosphatidylethanolamine in the liposome formulation. Vary ing the initial HA/lipid ratio over the range 1-500 mg HA/mmol lipid, it was found that the increase in bound HA was linear, providing up to 80 mg HA/mmol lipid. The HA-modified, but not the nonmodified, liposo mes were found to bind with high affinity (Delta G degrees in the rang e of -7 to -9 Kcal/mol) to monolayers of the A431 cell line. The HA-mo dified liposomes were found to encapsulate EGF at high yields (% encap sulation, >87) and to act as sustained-release depots, the rate consta nt for the release of the encapsulated EGF in the range of 1.4 X 10(-3 ) h(-1). Taking all of these findings together, it is concluded that t hese liposomes are bioadhesive sustained-release carriers of drugs, as desired, meriting further cellular and in vivo studies. (C) 1994 Acad emic Press, Inc.