title: Membrane-destabilizing activity of pH-responsive cationic lysine-based surfactants: role of charge position and alkyl chain length.
abstract: Many strategies for treating diseases require the delivery of drugs into the cell cytoplasm following internalization within endosomal vesicles. Thus, compounds triggered by low pH to disrupt membranes and release endosomal contents into the cytosol are of particular interest. Here, we report novel cationic lysine-based surfactants (hydrochloride salts of N(ε)- and N(α)-acyl lysine methyl ester) that differ in the position of the positive charge and the length of the alkyl chain. Amino acid-based surfactants could be promising novel biomaterials in drug delivery systems, given their biocompatible properties and low cytotoxic potential. We examined their ability to disrupt the cell membrane in a range of pH values, concentrations and incubation times, using a standard hemolysis assay as a model of endosomal membranes. Furthermore, we addressed the mechanism of surfactant-mediated membrane destabilization, including the effects of each surfactant on erythrocyte morphology as a function of pH. We found that only surfactants with the positive charge on the α-amino group of lysine showed pH-sensitive hemolytic activity and improved kinetics within the endosomal pH range, indicating that the positive charge position is critical for pH-responsive behavior. Moreover, our results showed that an increase in the alkyl chain length from 14 to 16 carbon atoms was associated with a lower ability to disrupt cell membranes. Knowledge on modulating surfactant-lipid bilayer interactions may help us to develop more efficient biocompatible amino acid-based drug delivery devices.
authors: Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, Barcelona, Spain.
authors: Daniele Rubert
authors: DR
authors: Nogueira
authors: Montserrat
authors: M
authors: Mitjans
authors: M Carmen
authors: MC
authors: Morán
authors: Lourdes
authors: L
authors: Pérez
authors: M Pilar
authors: MP
authors: Vinardell
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000648:ultrastructure; D006461:Hemolysis / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009996:Osmotic Fragility / Q000187:drug effects; D051381:Rats; D013501:Surface-Active Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C576946:Nepsilon-myristoyl lysine methyl ester; C576947:Nepsilon-palmitoyl lysine methyl ester; D013501:Surface-Active Agents; D008239:Lysine