Lipid phase structure contributions to bilayer barrier function

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Title Lipid phase structure contributions to bilayer barrier function
Publication Type dissertation
School or College College of Pharmacy
Department Pharmaceutics & Pharmaceutical Chemistry
Author Feil, Michelle Marra
Date 1995-06
Description Drug delivery development and optimization require understanding of the roles of lipid phase on partitioning, permeation pathways, and barrier functions of bilayers on a molecular level. Quantitative contributions of lipid phase and chemical structure remain unknown for most biological membranes of pharmaceutical interest. Current investigations ascertained contributions of bilayer packing phases to solute partitioning into and permeation across lipid bilayers, an objective most effectively addressed with model bilayers of defined structure, composition, and phase. Well-characterized large unilamellar liposomes modeled different bilayer phases composed of tilted gel and liquid-crystalline dipalmitoylphosphatidylcholine and distearoyl-phosphatidylcholine, interdigitated gel and liquid-crystalline dihexadecylphosphatidyl-choline, and liquid-crystalline cholesterol-containing phases of these phospholipids. Variations in polar headgroup spacings versus acyl chain mobilities were exploited to systematically probe aspects of phospholipid bilayer packing phase that determine the bilayer's barrier function. Bilayer lipid composition strongly influenced the number of bilayers, average size, size distribution, and stability of liposomes extruded through a constant pore size polycarbonate filter. Liposome surface areas and internal volumes were calculated using diameters, number of bilayers/liposome, bilayer thicknesses, and headgroup surface areas. These variables and solute efflux were used to calculate permeability. Thus, effects of differing liposome sizes on permeation were differentiated. Quantitative permeabilities for hydrophilic nonelectrolytes ranging from thiourea to sucrose represented the first obtained for well-characterized large unilamellar liposomes. Permeability trends with varying solute size/hydrophilicity suggested selectivity to hydrophilicity dominated over molecular volume for the solutes studied. Gel phases were established to have different barrier properties than liquid-crystalline phases, with selectivity differing for different gel phases. Each bilayer phase studied possessed an overall diffusional barrier more lipophilic than an octanol environment. Contributions to lipophilic solute partitioning included both polar headgroup/interfacial and acyl chain bilayer structural regions. However, partitioning barriers for even fairly lipophilic molecules were not the same barriers as those for diffusion. Through systematic evaluation of permeabilities as a function of bilayer phase, the primary diffusional barrier was established to be within acyl chain regions, with a smaller but significant contribution by the polar headgroup spacing that has not been previously reported in the literature.
Type Text
Publisher University of Utah
Subject Drug Effects
Subject MESH Lipid Bilayers
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Lipid phase structure contributions to bilayer barrier function". Spencer S. Eccles Health Sciences Library.
Rights Management © Michelle Marra Feil.
Format application/pdf
Format Medium application/pdf
Format Extent 5,607,388 bytes
Identifier undthes,4231
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available)
Funding/Fellowship Osco/Skaggs Fellowship; University of Utah Research Fellowship; Advanced Predoctoral Fellowship from the Pharmaceutical Manufacturers Association; Grant from Abbott laboratoties, Pfizer, and NIH-HD-23000
Master File Extent 5,607,403 bytes
ARK ark:/87278/s6fx7c93
Setname ir_etd
ID 191269
Reference URL https://collections.lib.utah.edu/ark:/87278/s6fx7c93
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