title: Effect of fatty acids on the permeability barrier of model and biological membranes.
abstract: Because of the amphipathicity and conical molecular shape of fatty acids, they can efficiently incorporate into lipid membranes and disturb membrane integrity, chain packing, and lateral pressure profile. These phenomena affect both model membranes as well as biological membranes. We investigated the feasibility of exploiting fatty acids as permeability enhancers in drug delivery systems for enhancing drug release from liposomal carriers and drug uptake by target cells. Saturated fatty acids, with acyl chain length from C8 to C20, were tested using model drug delivery liposomes of 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and the breast cancer MCF-7 cell line as a model cell. A calcein release assay demonstrated reduction in the membrane permeability barrier of the DPPC liposomes, proportionally to the length of the fatty acid. Differential scanning calorimetry (DSC) and dynamic light scattering (DLS) experiments revealed that C12 to C20 fatty acids can stabilize DPPC liposomal bilayers and induce the formation of large structures, probably due to liposome aggregation and bilayer morphological changes. On the other hand, the short fatty acids C8 and C10 tend to destabilize the bilayers and only moderately cause the formation of large structures. The effect of fatty acids on DPPC liposomes was not completely transferrable to the MCF-7 cell line. Using cytotoxicity assays, the cells were found to be relatively insensitive to the fatty acids at apoptotic sub-millimolar concentrations. Increasing the fatty acid concentration to few millimolar substantially reduced the viability of the cells, most likely via the induction of necrosis and cell lysis. A bioluminescence living-cell-based luciferase assay showed that saturated fatty acids in sub-cytotoxic concentrations cannot reduce the permeability barrier of cell membranes. Our results confirm that the membrane perturbing effect of fatty acids on model membranes cannot simply be carried over to biological membranes of live cells.
authors.affiliation: MEMPHYS-Center for Biomembrane Physics, Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark; The Lundbeck Foundation Nanomedicine Research Center for Cancer Stem Cell Targeting Therapeutics (NanoCAN), University of Southern Denmark, Odense, Denmark. Electronic address: arouri@memphys.sdu.dk.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Arouri
authors.affiliation: MEMPHYS-Center for Biomembrane Physics, Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark.
authors.forename: Kira E
authors.initials: KE
authors.lastname: Lauritsen
authors.affiliation: MEMPHYS-Center for Biomembrane Physics, Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark.
authors.forename: Henriette L
authors.initials: HL
authors.lastname: Nielsen
authors.affiliation: MEMPHYS-Center for Biomembrane Physics, Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark; The Lundbeck Foundation Nanomedicine Research Center for Cancer Stem Cell Targeting Therapeutics (NanoCAN), University of Southern Denmark, Odense, Denmark. Electronic address: ogm@memphys.sdu.dk.
authors.forename: Ole G
authors.initials: OG
authors.lastname: Mouritsen
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D005452:Fluoresceins / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008163:Luminescent Measurements; D061986:MCF-7 Cells; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D005227:Fatty Acids; D005452:Fluoresceins; D005456:Fluorescent Dyes; D008081:Liposomes; D015060:1,2-Dipalmitoylphosphatidylcholine; C007740:fluorexon
keywords: Cytotoxicity; Drug delivery; Dye release; Fatty acid; Liposome; Membrane perturbation; Permeability enhancing effect