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Bilayer disk capillary electrophoresis: a novel method to study drug partitioning into membranes
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (Johansson)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry. (Edwards)
Department of Chemistry and Biomedical Sciences, University of Kalmar, Kalmar, Sweden. (Isaksson)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry. (Edwards)
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2008 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 29, no 16, 3377-3383 p.Article in journal (Refereed) Published
Abstract [en]

CE in the presence of lipid bilayer disks was introduced as a new approach in membrane partitioning studies. The disks were used as a pseudostationary phase in the partial-filling mode of CE and the partitioning of cationic drugs was determined. The migration times of the analytes increased linearly with the lipid amount in the system. An appropriate algorithm for the calculation of a partition coefficient is presented. In the disk-shaped bilayers, which have excellent stability and shelf life, all of the lipids are readily available for interaction and the disks can be used as realistic cell membrane models.

Place, publisher, year, edition, pages
2008. Vol. 29, no 16, 3377-3383 p.
Keyword [en]
bilayer disks, capillary electrophoresis, drugs, model membrane, partitioning
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94751DOI: 10.1002/elps.200700682ISI: 000258856900012PubMedID: 18702061OAI: oai:DiVA.org:uu-94751DiVA: diva2:168718
Available from: 2006-09-08 Created: 2006-09-08 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Partitioning of Drugs and Lignin Precursor Models into Artificial Membranes
Open this publication in new window or tab >>Partitioning of Drugs and Lignin Precursor Models into Artificial Membranes
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main aim of this thesis was to characterize membrane-solute interactions using artificial membranes in immobilized liposome chromatography or capillary electrophoresis. The partitioning of a solute into a cell membrane is an essential step in diffusion across the membrane. It is a valid parameter in drug research and can be linked to the permeability as well as the absorption of drugs. Immobilized liposome chromatography was also used to study partitioning of lignin precursor models. Lignin precursors are synthesized within plant cells and need to pass the membrane to be incorporated into lignin in the cell wall.

In immobilized liposome chromatography, liposomes or lipid bilayer disks were immobilized in gel beads and the partitioning of solutes was determined. Capillary electrophoresis using disks as a pseudostationary phase was introduced as a new approach in drug partitioning studies. In addition, octanol/water partitioning was used to determine the hydrophobicity of the lignin precursor models.

Electrostatic interactions occurred between bilayers and charged drugs, whereas neutral drugs were less affected. However, neutral lignin precursor models exhibited polar interactions. Moreover, upon changing the buffer ionic strength or the buffer ions, the interactions between charged drugs and neutral liposomes were affected. Hydrophobic interactions were also revealed by including a fatty acid or a neutral detergent into the bilayer or by using a buffer with a high salt concentration. The bilayer manipulation had only a moderate effect on drug partitioning, but the high salt concentration had a large impact on partitioning of lignin precursor models.

Upon comparing the partitioning into liposomes and disks, the latter showed a more pronounced partitioning due to the larger fraction of lipids readily available for interaction. Finally, bilayer disk capillary electrophoresis was successfully introduced for partitioning studies of charged drugs. This application will be evaluated further as an analytical partitioning method and separation technique.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 207
Keyword
Biochemistry, Bilayer disk, Capillary electrophoresis, Detergent, Drug, Electrostatic interaction, Hydrophobic interaction, Immobilized liposome chromatography, Lignin, Lignin precursor model, Liposome, Membrane model, Octanol/water partitioning, Partitioning, Phospholipid, Phospholipid bilayer, Sterol, Biokemi
Identifiers
urn:nbn:se:uu:diva-7098 (URN)91-554-6628-1 (ISBN)
Public defence
2006-09-29, B42, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Supervisors
Available from: 2006-09-08 Created: 2006-09-08 Last updated: 2011-02-17Bibliographically approved
2. Nanosized Bilayer Disks as Model Membranes for Interaction Studies
Open this publication in new window or tab >>Nanosized Bilayer Disks as Model Membranes for Interaction Studies
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

PEG-lipid stabilized bilayer disks have been found in lipid mixtures containing polyethylene glycol (PEG)-lipids where the combination of a high bending rigidity and low PEG-lipid/lipid miscibility favours disk formation. The disks are planar and circular in shape and their long-term stability is excellent. Theoretical calculations and experimental observations suggest that the micelle forming PEG-lipid are situated at the rim of the aggregate, protecting the hydrophobic lipid chains in the bulk of the aggregate from contact with water. This thesis deals with fundamental aspects concerning the lipid distribution in the disks, as well as with development, optimization, and initial evaluation of the disks as model membranes in partition and interaction studies.

Small angle neutron scattering was used to study the partial segregation of components within the bilayer disk. The experiments verified that the PEG-lipids segregate and accumulate at the bilayer disk rim. The proof of component segregation is important from a fundamental point of view and useful, as exemplified in the below-mentioned study of melittin-lipid interaction, when interpreting partition or binding data obtained from studies based on bilayer disks.

Today liposomes are often used as model membranes in partition and interaction studies. Using liposomes to predict, e.g., drug partitioning can however have certain drawbacks. In this thesis the disks were proven to be attractive alternatives to liposomes as model membranes in partition studies. The formation of bilayer disks by a technique based on detergent depletion enabled incorporation of a transmembrane protein in the bilayer disks and opened up for the use of disks as model membranes in membrane protein studies. Further, bilayer disks were used in a comparative study focused on the effect of aggregate curvature on the binding of the peptide melittin. Various techniques were used to perform initial evaluations of the bilayer disks as model membranes. Of these, capillary electrophoresis and biosensor-based technology had not been used before in combination with bilayer disks.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 400
Keyword
Disk, disc, lipid bilayer, PEG-lipid, model membrane, interaction, partitioning, drug, liposome, cryo-TEM, neutron scattering, capillary electrophoresis, immobilization, biosensor, membrane protein, melittin
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-8495 (URN)978-91-554-7109-5 (ISBN)
Public defence
2008-03-28, B22, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2008-03-06 Created: 2008-03-06 Last updated: 2010-03-04Bibliographically approved

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Edwards, KatarinaJohansson, Gunnar

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