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.

Carboxylated hyperbranched poly(glycidol)s for preparation of pH-sensitive liposomes

“…The precipitation pH thresholds for MGlu-HPGs were estimated as presented in Table 2. The precipitation pH shifted to slightly higher pH values with increasing DP of MGlu-HPGs, indicating that hydrophobicity of MGlu-HPG increases concomitantly with increasing DP, consistent with previous observations for methacrylic acid copolymers with varying hydrophobicities and a previous report by the authors [7,20].…”

“…Hydrophobicity of carboxylated polymers affects their precipitation behaviors [20]. For that reason, it was estimated that the pH at which the polymers precipitate using the following optical densities of these polymer solutions as the solution pH was decreased (Fig.…”

Membrane-destabilizing activity of pH-responsive cationic lysine-based surfactants: role of charge position and alkyl chain length

“…The cationic lysine-based surfactants with pH-sensitive properties were studied on the basis of the hypothesis that pHresponsive membrane lytic activity in endosomes should facilitate membrane destabilization and allow surfactant-drug complexes to escape to the cytoplasm for efficient intracellular drug delivery. Numerous amphiphilic materials can mediate material transport across cell membranes, such as amphiphilic peptide sequences used by viruses (Janshoff et al 1999) and amphiphilic lipids (Wasungu and Hoekstra 2006 disruption (Wang et al 2007;Yessine et al 2003). Low concentrations of PKM and MKM induced membrane lysis only at the endosomal pH range and there was no significant hemolysis at blood stream pH (7.4), supporting these surfactants as potential biocompatible materials in novel non-viral drug delivery systems.…”

“…Cationic and anionic polymers with pH-sensitive activity, including derivatives of poly (acrylic acid) (Jones et al 2003;Kusonwiriyawong et al 2003;Kyriakides et al 2002), methacrylic acid copolymers (Yessine et al 2003), imidazole-containing polymers (Seo and Kim 2010) and pseudo-peptidic polymers (Chen et al 2008(Chen et al , 2009, have also been developed 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 to promote endosomal release. Cationic polymers have been described to enhance membrane lysis at low pH via electrostatic interactions between protonated amines and the negatively charged membranes (Yessine et al 2003).…”

“…Cationic polymers have been described to enhance membrane lysis at low pH via electrostatic interactions between protonated amines and the negatively charged membranes (Yessine et al 2003).…”