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Nanosized bilayer disks: Attractive model membranes for drug partition studies
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
2007 (English)In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1768, no 6, 1518-1525 p.Article in journal (Refereed) Published
Abstract [en]

Stable nanosized bilayer disks were prepared from either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol, or lipid mixtures with a composition reflecting that of the porcine brush border membrane. Two different polyethylene glycol (PEG)-grafted lipids, the negatively charged 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-5000] (DSPE-PEG5000) and the neutral N-palmitoyl-sphingosine-1-[succinyl (methoxy (polyethylene glycol) 5000] (Ceramide-PEG5000), were used to stabilize the disks. The disks were employed as model membranes in drug partition studies based on a fast chromatography method. Results show that the lipid composition, as well as the choice of PEG-lipid, have an important influence on the partition behavior of charged drugs. Comparative studies using multilamellar liposomes indicate that bilayer disks have the potential to generate more accurate partition data than do liposomes. Further, initial investigations using bacteriorhodopsin suggest that membrane proteins can be reconstituted into the bilayer disks. This fact further strengthens the potential of the bilayer disk as an attractive model membrane.

Place, publisher, year, edition, pages
2007. Vol. 1768, no 6, 1518-1525 p.
Keyword [en]
Bilayer disk, Drug partitioning, Liposome, Model membrane, PEG-lipid, Phospholipid, Bacteriorhodopsin
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96190DOI: 10.1016/j.bbamem.2007.03.006ISI: 000247455700019PubMedID: 17451640OAI: oai:DiVA.org:uu-96190DiVA: diva2:170680
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2011-03-29Bibliographically approved
In thesis
1. Bilayer Discs - Fundamental Investigations and Applications of Nanosized Membrane Models
Open this publication in new window or tab >>Bilayer Discs - Fundamental Investigations and Applications of Nanosized Membrane Models
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The bilayer disc is a flat, lipid aggregate structure in the nanometre regime. It is composed of a bilayer of amphiphilic molecules with micelle-forming amphiphilic molecules supporting the rim, which prevent disc fusion and self-closure. Stable discs have been found in lipid mixtures containing polyethylene glycol (PEG)-lipids as a rim-stabilizing component. One of the aims of the work described in this thesis was to increase the fundamental knowledge and understanding of the systems in which these discs are formed. Other micelle-forming surfactants apart from PEG-lipids were also explored to see if they could be used to stabilize the disc aggregate structure. Due to the similarities of these lipid discs with natural membranes it was hypothesized that they could be used as models for biological membranes.

It was demonstrated that discs are formed in PEG-lipid/lipid systems when the lipid mixture contains components that reduce the spontaneous curvature and increase the monolayer bending rigidity. Discoidal structures are furthermore preferred when the lipids are in the gel phase, probably due to a combination of high bending rigidity and reduced PEG-lipid/lipid miscibility. The disc size could be varied by changing the PEG-lipid concentration. The size and size homogeneity of the discs could also be varied by changing the preparation path. Generally, the preferences of certain lipid systems to form discs remained when the PEG-lipid was replaced by more conventional surfactants. However, discs prepared in PEG-lipid/lipid systems are more useful as model membranes because of their relatively large size and good temperature, dilution and long-term stability. Data obtained with isothermal titration calorimetry and drug partition chromatography indicate that these bilayer discs may serve as an attractive and sometimes superior alternative to liposomes in studies of drug-membrane interactions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 340
Keyword
Chemistry, disc, threadlike micelle, liposome, model membrane, drug partitioning, cryo-TEM, Kemi
Identifiers
urn:nbn:se:uu:diva-8200 (URN)978-91-554-6962-7 (ISBN)
Public defence
2007-10-05, B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2010-03-04Bibliographically 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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Lundquist, AnnaEdwards, Katarina

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