N-isopropylacrylamide copolymers for the preparation of pH-sensitive liposomes and polymeric micelles

Hydrophobically-modified copolymers of N-isopropylacrylamide bearing a pH-s ensitive moiety were investigated for the preparation of pH-responsive lipo somes and polymeric micelles. The copolymers having the hydrophobic anchor randomly distributed within the polymeric chain were found to more efficien tly destabilize egg phosphatidylcholine (EPC)/cholesterol liposomes than th e alkyl terminated polymers. Release of both a highly-water soluble fluores cent contents marker, pyranine, and an amphipathic cytotoxic anti-cancer dr ug, doxorubicin, from copolymer-modified liposomes was shown to be dependen t on pH, the concentration of copolymer, the presence of other polymers suc h as polyethylene glycol, and the method of preparation. Both polymers were able to partially stabilize EPC liposomes in human serum. These polymers w ere found to self-assemble to form micelles. The critical association conce ntration was low (9-34 mg/l) and influenced by the position of the alkyl ch ains. In phosphate buffered saline, the micelles had a bimodal size distrib ution with the predominant population having a mean diameter of 35 nm. The polymeric micelles were studied as a delivery system for the photosensitize r aluminum chloride phthalocyanine, (AlClPc), currently evaluated in photod ynamic therapy. pH-Responsive polymeric micelles loaded with AlClPc were fo und to exhibit increased cytotoxicity against EMT-6 mouse mammary cells in vitro than the control Cremophor EL formulation. (C) 2001 Elsevier Science B.V. All rights reserved.