Improvement of temperature-sensitivity of poly(N-isopropylacrylamide)-modified liposomes.

As a novel temperature-sensitive drug delivery system, we have designed liposomes coated with poly(N-isopropylacrylamide), which exhibits a coil-globule transition at 32-35 degrees C. In a previous study [ K. Kono, H. Hayashi, T. Takagishi, J. Control. Release 30 (1994) 69-75], it was shown that the release of contents from the polymer-coated liposomes is enhanced above the transition temperature of the polymer but the release is not controlled completely by the conformational change of the polymer. In this study, to improve temperature-sensitivity of the poly(N-isopropylacrylamide)-modified liposomes, the influence of lipid composition on the temperature-sensitivity of the liposomes was investigated. A copolymer of N-isopropylacrylamide and N, N-didodecylacrylamide was synthesized by free radical copolymerization. While the copolymer was insoluble in water, it exhibited a coil-globule transition around 28 degrees C when incorporated into an egg yolk phosphatidylcholine membrane. The copolymer-modified egg yolk phosphatidylcholine/dioleoylphosphatidylethanolamine liposomes were prepared by sonication or reverse phase evaporation. Release of calcein from the copolymer-modified liposomes was very slow below the transition temperature of the copolymer, whereas the release was enhanced above the transition temperature. Incorporation of dioleoylphosphatidylethanolamine into liposome membranes enhanced release greatly above the transition temperature of the copolymer. Fluorometric measurements using 8-anilino-1-naphthalenesulfonate and 1,6-diphenyl-1,3,5-hexatriene suggested that the copolymer decreases membrane fluidity of the liposomes near and above the transition temperature of the copolymer and that interaction between the copolymer and the liposome membranes is enhanced by inclusion of dioleoylphosphatidylethanolamine.