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Structure of mixed micelles formed in PEG-lipid/lipid dispersions
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 Physical and Analytical Chemistry.
2007 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 23, no 8, 4192-4198 p.Article in journal (Refereed) Published
Abstract [en]

Polyethylene glycol (PEG)-conjugated lipids are commonly employed for steric stabilization of liposomes. When added in high concentrations PEG-lipids induce formation of mixed micelles, and depending on the lipid composition of the sample, these may adapt either a discoidal or a long threadlike shape. The factors governing the type of micellar aggregate formed have so far not been investigated in detail. In this study we have systematically varied the lipid composition in lipid/PEG-lipid mixtures and characterized the aggregate structure by means of cryo-transmission electron microscopy (cryo-TEM). The effects caused by adding sterols, phosphatidylethanolamines, and phospholipids with saturated acyl chains to egg phosphatidylcholine/1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[methoxy(polyethylene glycol)-2000 (EPC/DSPE-PEG2000) mixtures with a fixed amount (25 mol %) of DSPE-PEG2000 was studied. Further, the aggregate structure in 1,2-dimyristoyl1-sn-glycero-3-phosphatidylcholine/1,2-dimyristoyl-sn-glycero-3-phosphatidylethanolamine-N- [methoxy(polyethylene glycol)-2000] (DMPC/DMPE-PEG2000) samples above and below the gel to liquid crystalline phase transition temperature (Tc) was investigated. Our results revealed that lipid components, as well as environmental conditions, that reduce the lipid spontaneous curvature and increase the monolayer bending modulus tend to promote formation of discoidal micelles. At temperatures below the gel-to-liquid crystalline phase transition temperature reduced lipid/PEG-lipid miscibility, furthermore, likely contribute to the observed formation of discoidal rather than threadlike micelles.

Place, publisher, year, edition, pages
2007. Vol. 23, no 8, 4192-4198 p.
Keyword [en]
Miscibility, Bending, Monolayer, Curvature, Transition temperature, Phase transitions, Crystalline phase, Liquid phase, Phosphatidylcholine, Egg, Phospholipid, Phosphatidylethanolamine, Transmission electron microscopy, Aggregate, Shape, Composition, Liposome, Stabilization, Ethylene oxide polymer, Dispersion, Lipids, Mixed micelle, Structure
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95516DOI: 10.1021/la063501sISI: 000245370100014PubMedID: 17343401OAI: oai:DiVA.org:uu-95516DiVA: diva2:169763
Available from: 2007-03-09 Created: 2007-03-09 Last updated: 2011-02-08Bibliographically approved
In thesis
1. 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
2. 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

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