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Optimization of Lipodisk Properties by Modification of the Extent and Density of the PEG Corona
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.ORCID iD: 0000-0002-6733-3227
Chalmers, Biol Phys Div, Dept Phys, SE-41296 Gothenburg, Sweden.
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2016 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 484, 86-96 p.Article in journal (Refereed) Published
Abstract [en]

Lipodisks are nanosized flat, circular, phospholipid bilayers that are edge-stabilized by polyethylene glycol-conjugated lipids (PEG-lipids). Over the last decade, lipodisks stabilized with PEG of molecular weight 2000 or 5000 have been shown to hold high potential as both biomimetic membranes and drug carriers. In this study we investigate the possibilities to optimize the properties of the lipodisks, and widen their applicability, by reducing the PEG molecular weight and/or the density of the PEG corona. Results obtained by cryo-transmission electron microscopy and dynamic light scattering show that stable, well-defined lipodisks can be produced from mixtures of distearoylphosphatidylcholine (DSPC) and distearoylphosphatidylethanolamine conjugated to PEG of molecular weight 1000 (DSPE-PEG(1000)). Preparations based on the use of DSPE-PEG(750) tend, in contrast, to be polydisperse in size and structure. By comparing immobilization of lipodisks stabilized with DSPE-PEG(1000), DSPE-PEG(2000), and DSPE-PEG(5000) to porous and smooth silica surfaces, we show that the amount of surface bound disks can be considerably improved by the use of PEG-lipids with reduced molecular weight. Further, a modified preparation protocol that enables production of lipodisks with very low PEG-lipid content is described. The reduced PEG density, which facilitates the incorporation of externally added ligand-linked PEG-lipids, is shown to be beneficial for the production of targeting lipodisks.

Place, publisher, year, edition, pages
2016. Vol. 484, 86-96 p.
Keyword [en]
Lipid self-assembly; Bilayer disks; Biomimetic membranes; Surface immobilization; Drug delivery; Nanocarriers; Specific targeting
National Category
Physical Chemistry
URN: urn:nbn:se:uu:diva-274972DOI: 10.1016/j.jcis.2016.08.067ISI: 000385690200011PubMedID: 27592189OAI: diva2:898116
Swedish Research Council, 621-2011-3524Swedish Cancer Society, CAN 2014/617
Available from: 2016-01-27 Created: 2016-01-27 Last updated: 2016-11-21Bibliographically approved
In thesis
1. Development and Evaluation of Lipodisks Intended for Use as Biomimetic Membranes and Drug Carriers
Open this publication in new window or tab >>Development and Evaluation of Lipodisks Intended for Use as Biomimetic Membranes and Drug Carriers
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polyethylene glycol-stabilized lipodisks have emerged as a novel type of lipid-based nanoparticles with high potential as both drug carriers and biomimetic membranes. In this thesis we assess both of these applications, and show how the properties of the lipodisks can be further developed and optimized.

Initially, we show that the antimicrobial peptides melittin, alamethicin and magainin 2, in spite of their very different physico-chemical properties and suggested modes of action on membranes, all have high affinity to lipodisks. Using melittin as a model peptide, we confirm a maintained antimicrobial effect of disk-formulated peptides. We also show that melittin dissociates slowly from the disks, resulting in extended drug release and prolonged antibacterial effect. Additionally, we present evidence that the peptide is protected against enzymatic degradation when formulated in the disks.

Further, we develop a stable HPLC-MS system with immobilized lipodisks as model membranes. The stability of the system is confirmed by drug partitioning analysis using 15 different drug compounds. We also show how the lipodisk column can be supplemented with cyclooxygenase by in situ incorporation of the protein in the lipodisks. The specific binding of the protein to the disks is confirmed using QCM-D.

Finally, by changing the polymer length and applying a new preparation protocol, we have optimized the lipodisks for use as drug carriers and biomimetic membranes. Previous lipodisk studies have been conducted on systems containing PEG-lipids with polymer molecular weights of 2000 or 5000 Da. Also, conventional protocols for the preparation of lipodisks typically require a PEG-lipid concentration of 15 mol% or more. Here we show that stable lipodisks can also be produced using PEG-lipids with a 1000 Da molecular weight polymer and that the use of shorter PEG-lipids dramatically improve the amount of lipodisks that can be immobilized on silica surfaces. Moreover, through the development of a method in which lipid mixtures are sonicated at low temperatures, we produce lipodisks containing as little as 2 mol% PEG-lipid. We present data verifying that these disks are superior to disks with higher PEG-lipid content in terms of their ability to incorporate externally added PEG-lipids functionalized with targeting agents.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 58 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1340
model membranes, drug delivery, drug partitioning, antimicrobial peptides, nanocarriers, cryo-TEM, polymer-stabilized bilayer disks
National Category
Physical Chemistry
Research subject
Chemistry with specialization in Physical Chemistry
urn:nbn:se:uu:diva-268667 (URN)978-91-554-9466-7 (ISBN)
Public defence
2016-03-18, B22, BMC, Husargatan 3, Uppsala, 10:15 (English)
Available from: 2016-02-26 Created: 2015-12-09 Last updated: 2016-03-09

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