BIOADHESIVE, COLLAGEN-MODIFIED LIPOSOMES - MOLECULAR AND CELLULAR-LEVEL STUDIES ON THE KINETICS OF DRUG-RELEASE AND ON BINDING TO CELL MONOLAYERS

Liposomes, modified by covalently-anchoring collagen to their surface, were investigated for their abilities to be bioadhesive and to act as sustained-release drug carriers. These bioadhesive liposomes have the potential to induce significant improvements in topical and regional therapies. The major findings for uni- (ULV) and multilamellar (MLV) bioadhesive liposomes are: (a) Both ULV and MLV release small molecular weight drugs over prolonged periods. For example, rate constants of (6 +/- 0.5).10(-3) and (2.6 +/- 0.8).10(-3) h(-1), were obtained for the release of vinblastine and fluconazole, respectively, from collagen-ULV. (b) For a given drug, that rate constant can be shifted (up or down) by the choice of liposome type and collagen-surface density and the latter, if high enough, lead to the formation of an additional liposome-associated drug reservoir. (c) Using monolayers of the A431 cell line to model the in vivo targets, the bioadhesive (but not the regular) liposomes were found to bind with high affinity to the monolayers. For example, equilibrium dissociation constants of 6.3(+/-3) mu M and 2.7(+/-0.5) mu M were determined for bioadhesive MLV and ULV, respectively, with corresponding saturation occupancies of 3.7(+/- 1) and 4.0(+/- 0.2) pmoles liposomal collagen/monolayer of 10(5) cells. (d) Following the retention of bioadhesive MLV at A431 monolayers for 24 h, it was found that: at 4 degrees C, 24 h did not suffice to reach equilibrium, but at 37 degrees C equilibrium binding was obtained within 3-5 h and there was quantitative liposome retention (per viable monolayer) thereafter. It is concluded that these liposomes are bioadhesive sustained-release carriers, as desired, meriting further cellular and in vivo studies.