title: Characterization of the membrane-destabilizing properties of different pH-sensitive methacrylic acid copolymers.
abstract: The intracellular delivery of active biomacromolecules from endosomes into the cytoplasm generally requires a membrane-disrupting agent. Since endosomes have a slightly acidic pH, anionic carboxylated polymers could be potentially useful for this purpose since they can destabilize membrane bilayers by pH-triggered conformational change. In this study, five different pH-sensitive methacrylic acid (MAA) copolymers were characterized with respect to their physicochemical and membrane lytic properties as a function of pH. pH-dependent conformational changes were studied in aqueous solution by turbidimetry and spectrofluorimetry. The hydrophobic domains that formed upon a decrease in pH were found to be dependent on copolymer's composition. Hemolysis and cytotoxicity assays demonstrated that the presence of the hydrophobic ethyl acrylate monomer and/or sufficient protonation of the carboxylic acid groups were important parameters for efficient membrane destabilization. Excessive copolymer hydrophobicity was not associated with membrane destabilization, but resulted in high macrophage cytotoxicity. Overall, this study gave more insights into the structure-activity relationship of MAA copolymers with membrane bilayers. Gaining knowledge of modulation of the physicochemical properties of copolymers and the optimization of copolymer-lipid interactions may lead to the elaboration of much more efficient drug delivery systems.
authors.affiliation: Faculty of Pharmacy, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, Quebec, Canada H3C 3J7.
authors.forename: Marie-Andrée
authors.initials: MA
authors.lastname: Yessine
authors.forename: Michel
authors.initials: M
authors.lastname: Lafleur
authors.forename: Christian
authors.initials: C
authors.lastname: Meier
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Petereit
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006863:Hydrogen-Ion Concentration; D008567:Membranes, Artificial; D008968:Molecular Conformation; D008970:Molecular Weight; D011109:Polymethacrylic Acids / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D013053:Spectrophotometry
chemical_list: D008567:Membranes, Artificial; D011109:Polymethacrylic Acids