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) b ioadhesive 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 th e release of vinblastine and fluconazole, respectively, from collagen- ULV. (b) For a given drug, that rate constant can be shifted (up or do wn) by the choice of liposome type and collagen-surface density and th e latter, if high enough, lead to the formation of an additional lipos ome-associated drug reservoir. (c) Using monolayers of the A431 cell l ine to model the in vivo targets, the bioadhesive (but not the regular ) liposomes were found to bind with high affinity to the monolayers. F or example, equilibrium dissociation constants of 6.3(+/-3) mu M and 2 .7(+/-0.5) mu M were determined for bioadhesive MLV and ULV, respectiv ely, with corresponding saturation occupancies of 3.7(+/- 1) and 4.0(/- 0.2) pmoles liposomal collagen/monolayer of 10(5) cells. (d) Follow ing the retention of bioadhesive MLV at A431 monolayers for 24 h, it w as found that: at 4 degrees C, 24 h did not suffice to reach equilibri um, but at 37 degrees C equilibrium binding was obtained within 3-5 h and there was quantitative liposome retention (per viable monolayer) t hereafter. It is concluded that these liposomes are bioadhesive sustai ned-release carriers, as desired, meriting further cellular and in viv o studies.