To obtain temperature-sensitive liposomes which release their contents around the physiological temperature, we designed dioleoylphosphatidylethanolamine liposomes modified with copolymers of N-isopropylacrylamide and acryloylpyrrolidine. Copolymers of acryloylpyrrolidine and N-isopropylacrylamide, which exhibit a lower critical solution temperature around the physiological temperature, were prepared by free radical copolymerization using azobis(isobutyronitrile) as the initiator. The copolymers with anchors to the liposome membrane were obtained by using N, N-didodecylacrylamide as an additional comonomer. The copolymer having the anchor group at the terminal of the polymer chain was also synthesized by copolymerization of these monomers in the presence of 2-aminoethanethiol and subsequent conjugation of N, N-didodecyl succinamic acid to the terminal amino group of the copolymer. Calcein-loaded dioleoylphosphatidylethanolamine liposomes modified with these copolymers were prepared and release of the contents from these liposomes was investigated. It was found that the release from these copolymer-modified liposomes was promoted around and above the lower critical temperature of the copolymer. Also, the liposomes modified with the terminal anchor-type copolymer released the contents more drastically responding to a small temperature change than the liposomes modified with random copolymers containing N,N-didodecylacrylamide units as the anchor.

No abstract

Copolymers of acrylic acid and styrene with styrene unit contents of 2.7, 5.7, and 9.5% were synthesized by free radical copolymerization. Poly(ethylenimine)s with benzylated unit contents of 2.4, 6.0, 10.6, and 16.7% were obtained by the reaction of poly(ethylenimine) with benzyl bromide. Polyelectrolyte complex capsules consisting of these polymers were prepared. Influence of the hydrophobic units on pH-responsive release property of the capsules was studied using phenylethylene glycol as a permeant. When the copolymer with styrene unit content of 5.7% or the poly(ethylenimine) with the benzylated unit content of 2.4 -10.6% was used as the membrane components, the permeability of the capsule membrane became minimum and was 10 -20 fold lower than that of the poly(acrylic acid)-poly(ethylenimine) complex capsule membrane in the pH region between 3 and 7. In contrast, the hydrophobic units did not lower the permeability of the capsule membranes significantly below pH 3 and above pH 7. Thus, the capsule membranes containing hydrophobic units exhibited remarkable permeability changes in the narrow pH regions of 2-3 and 7-9. Also, the capsule containing the benzylated PEI in the membrane changed the release rate of the contents very quickly, in response to the ambient pH alteration. Therefore, polyelectrolyte complex capsules, which are highly sensitive to pH change, were obtained by using the polyelectrolytes with the hydrophobic units as membrane components.

Egg yolk phosphatidylcholine liposomes modified with a copolymer of N-acryloylpyrrolidine and N-isopropylacrylamide having a lower critical solution temperature at ca. 40³C were prepared and an effect of temperature on their interaction with CV1 cells was investigated. The unmodified liposomes were taken up by the cells approximately to the same extent after 3 h incubation at 37 and 42³C. In contrast, uptake of the polymermodified liposomes by CV1 cells decreased slightly at 37³C but increased greatly at 42³C, compared to the unmodified liposomes. Proliferation of the cells was partly prohibited by the incubation with the unmodified liposomes encapsulating methotrexate at 37 and 42³C. The treatment with the polymermodified liposomes containing methotrexate at 37³C hardly effected the cell growth. However, the treatment at 42³C inhibited the cell growth completely. It is considered that the highly hydrated polymer chains attached to the liposome surface suppressed the liposome-cell interaction below the lower critical solution temperature of the polymer but the dehydrated polymer chains enhanced the interaction above this temperature. Because interaction of the polymer-modified liposomes with cells can be controlled by the ambient temperature, these liposomes may have potential usefulness as efficient site-specific drug delivery systems.z 1999 Federation of European Biochemical Societies.

No abstract