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Development and initial evaluation of PEG-stabilized disks as novel model membranes
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, Biochemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
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2005 (English)In: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 113, no 2, 183-192 p.Article in journal (Refereed) Published
Abstract [en]

We show in this study that stable dispersions dominated by flat bilayer disks may be prepared from a carefully optimized mixture of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-5000] [PEG-DSPE(5000)]. By varying the content of the latter component, the average diameter of the disks can be changed in the interval from about 15 to 60 nm. The disks show excellent long-term stability, and their size and structure remain unaltered in the temperature range between 25 and 37 degrees C. The utility of the disks as artificial model membranes was confirmed and compared to uni- and multilamellar liposomes in a series of drug partition studies. Data obtained by isothermal titration calorimetry and drug partition chromatography (also referred to as immobilized liposome chromatography) indicate that the bilayer disks may serve as an attractive and sometimes superior alternative to liposomes in studies aiming at the investigation of drug-membrane interactions. The disks may, in addition, hold great potential for structure/function studies of membrane-bound proteins. Furthermore, we suggest that the sterically stabilized bilayer disks may prove interesting as carriers for in vivo delivery of protein/peptide, as well as conventional amphiphilic and/or hydrophobic, drugs.

Place, publisher, year, edition, pages
2005. Vol. 113, no 2, 183-192 p.
Keyword [en]
bilayer disks, drug partitioning, liposome, model membrane, PEG lipid, phospholipid, immobilized liposome chromatography
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96189DOI: 10.1016/j.bpc.2004.09.006PubMedID: 15617826OAI: oai:DiVA.org:uu-96189DiVA: diva2:170679
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2011-04-07Bibliographically 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. Drug Partitioning into Natural and Artificial Membranes: Data Applicable in Predictions of Drug Absorption
Open this publication in new window or tab >>Drug Partitioning into Natural and Artificial Membranes: Data Applicable in Predictions of Drug Absorption
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

When drug molecules are passively absorbed through the cell membrane in the small intestine, the first key step is partitioning of the drug into the membrane. Partition data can therefore be used to predict drug absorption. The partitioning of a solute can be analyzed by drug partition chromatography on immobilized model membranes, where the chromatographic retention of the solute reflects the partitioning. The aims of this thesis were to develop the model membranes used in drug partition chromatography and to study the effects of different membrane components and membrane structures on drug partitioning, in order to characterize drug–membrane interactions.

Electrostatic effects were observed on the partitioning of charged drugs into liposomes containing charged detergent, lipid or phospholipid; bilayer disks; proteoliposomes and porcine intestinal brush border membrane vesicles (BBMVs), and on the retention of an oligonucleotide on positive liposomes. Biological membranes are naturally charged, which will affect drug partitioning in the human body.

Proteoliposomes containing transmembrane proteins and cholesterol, BBMVs and bilayer disks were used as novel model membranes in drug partition chromatography. Partition data obtained on proteoliposomes and BBMVs demonstrated how cholesterol and transmembrane proteins interact with drug molecules. Such interactions will occur between drugs and natural cell membranes. In the use of immobilized BBMVs for drug partition chromatography, yet unsolved problems with the stability of the membrane were encountered. A comparison of partition data obtained on bilayer disks with data on multi- and unilamellar liposomes indicated that the structure of the membrane affect the partitioning. The most accurate partition values might be obtained on bilayer disks.

Drug partition data obtained on immobilized model membranes include both hydrophobic and electrostatic interactions. Such partition data should preferably be used when deriving algorithms or computer programs for prediction of drug absorption.

Place, publisher, year, edition, pages
Uppsala: Institutionen för naturvetenskaplig biokemi, 2005. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 40
Keyword
Biochemistry, Bilayer disk, Cholesterol, Drug partitioning, Drugs, Electrostatic effects, Immobilized liposome chromatography, Liposome, Membrane protein, Model membrane, Oligonucleotide-liposome complex, Phospholipid, Phospholipid bilayer, Proteoliposome, Surfactant, Biokemi
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-5752 (URN)91-554-6224-3 (ISBN)
Public defence
2005-05-20, B21, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-04-27 Created: 2005-04-27 Last updated: 2011-04-07Bibliographically approved
3. Physico-Chemical Investigations of Bilayer Discs and Related Lipid Structures Formed in Liposomal Systems Intended for Triggered Release
Open this publication in new window or tab >>Physico-Chemical Investigations of Bilayer Discs and Related Lipid Structures Formed in Liposomal Systems Intended for Triggered Release
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes results from fundamental studies of liposomes intended for drug delivery and pH or temperature triggered release. In addition, the effect of lipid composition on bilayer disc formation and a potential application of the bilayer discs were investigated.

The lower pH encountered by endocytosed liposomes can be utilized to trigger drug release. The mechanisms behind cytosolic drug delivery were investigated using two different kinds of pH-sensitive liposomes. The results indicate that incorporation of non-lamellar forming lipids into the endosome membrane may allow for drug escape into the cytosol.

Temperature-sensitive liposomes containing lysolipid (LTSL) release their content almost instantly when heated to temperatures close to the gel to liquid crystalline phase transition temperature (TC). Morphological changes of the liposomes in response to temperature cycling were studied. Temperature cycling induced liposome openings and disintegration of the liposomes into bilayer discs. Incubation of LTSL in the presence of multilamellar liposomes (MLVs) resulted in relocalisation of lysolipid into the MLVs, which affected the rapid release from LTSL. We propose that the presence of micelle-forming components, such as lysolipids and PEG-lipids, facilitates the formation of defects and membrane openings during the initial phase of membrane melting, resulting in the observed rapid release. Similar to added lysolipids, also hydrolysis generated lysolipids induce disc-formation upon heating through TC of the lipid mixture.

Two fundamentally different micelles may form in PEG-lipid/lipid mixtures. We found that discoidal structures are preferred over cylindrical micelles when the mixture contains components that reduce the spontaneous curvature, increase the monolayer bending modulus, or reduce PEG-lipid/lipid miscibility. The large discoidal micelles found at low PEG-lipid content are better described as bilayer discs. We evaluated such discs as model membranes in drug partitioning studies, and suggest that they, in some cases, produce more accurate data than liposomes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 276
Keyword
Physical chemistry, liposome, triggered release, pH-sensitive liposomes, temperature-sensitive liposomes, drug partitioning, cryo-TEM, discs, Fysikalisk kemi
Identifiers
urn:nbn:se:uu:diva-7606 (URN)978-91-554-6812-5 (ISBN)
Public defence
2007-03-30, B42, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Supervisors
Available from: 2007-03-09 Created: 2007-03-09 Last updated: 2011-04-07Bibliographically approved

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