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Interactions between pH-sensitive liposomes and 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 Physical and Analytical Chemistry.
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2003 (English)In: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 104, no 1, 361-379 p.Article in journal (Refereed) Published
Abstract [en]

The structure and dynamics of two different pH-sensitive liposome systems were investigated by means of cryo-transmission electron microscopy and different photophysical techniques. Both systems consisted of dioleoylphosphatidylethanolamine (DOPE) and contained either oleic acid (OA) or a novel acid-labile polyethylene glycol-conjugated lipid (DHCho-MPEG5000) as stabiliser. Proton induced leakage, lipid mixing and structural changes were studied in the absence and presence of EPC liposomes, as well as in the presence of liposomes designed to model the endosome membrane. Neither DHCho-MPEG5000- nor OA-stabilised liposomes showed any tendency for fusion with pure EPC liposomes or endosome-like liposomes composed of EPC/DOPE/SM/Cho (40/20/6/34 mol.%). Our investigations showed, however, that incorporation of lipids from the pH-sensitive liposomes into the endosome membrane may lead to increased permeability and formation of non-lamellar structures. Taken together the results suggest that the observed ability of DOPE-containing liposomes to mediate cytoplasmic delivery of hydrophilic molecules cannot be explained by a mechanism based on a direct, and non-leaky, fusion between the liposome and endosome membranes. A mechanism involving destabilisation of the endosome membrane due to incorporation of DOPE, seems more plausible.

Place, publisher, year, edition, pages
2003. Vol. 104, no 1, 361-379 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95512DOI: 10.1016/S0301-4622(03)00011-5ISI: 000184020500034PubMedID: 12834854OAI: oai:DiVA.org:uu-95512DiVA: diva2:169759
Available from: 2007-03-09 Created: 2007-03-09 Last updated: 2017-12-14Bibliographically 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
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Supervisors
Available from: 2007-03-09 Created: 2007-03-09 Last updated: 2011-04-07Bibliographically approved

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Edwards, Katarina

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