Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on bilayer properties, biodistribution, and immune responses

Randip Kaur, Malou Henriksen-Lacey, Jitinder Wilkhu, Andrew Devitt, Dennis Christensen, Yvonne Perrie

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Cholesterol is an abundant component of mammalian cell membranes and has been extensively studied as an artificial membrane stabilizer in a wide range of phospholipid liposome systems. In this study, the aim was to investigate the role of cholesterol in cationic liposomal adjuvant system based on dimethyldioctadecylammonium (DDA) and trehalose 6,6'-dibehenate (TDB) which has been shown as a strong adjuvant system for vaccines against a wide range of diseases. Packaging of cholesterol within DDA:TDB liposomes was investigated using differential scanning calorimetery and surface pressure-area isotherms of lipid monolayers; incorporation of cholesterol into liposomal membranes promoted the formation of a liquid-condensed monolayer and removed the main phase transition temperature of the system, resulting in an increased bilayer fluidity and reduced antigen retention in vitro. In vivo biodistribution studies found that this increase in membrane fluidity did not alter deposition of liposomes and antigen at the site of injection. In terms of immune responses, early (12 days after immunization) IgG responses were reduced by inclusion of cholesterol; thereafter there were no differences in antibody (IgG, IgG1, IgG2b) responses promoted by DDA:TDB liposomes with and without cholesterol. However, significantly higher levels of IFN-gamma were induced by DDA:TDB liposomes, and liposome uptake by macrophages in vitro was also shown to be higher for DDA:TDB liposomes compared to their cholesterol-containing counterparts, suggesting that small changes in bilayer mechanics can impact both cellular interactions and immune responses.

LanguageEnglish
Pages197-207
Number of pages11
JournalMolecular Pharmaceutics
Volume11
Issue number1
Early online date30 Oct 2013
DOIs
Publication statusPublished - 6 Jan 2014

Fingerprint

Liposomes
Cholesterol
Membrane Fluidity
Immunoglobulin G
Artificial Membranes
Antigens
Transition Temperature
Phase Transition
Product Packaging
dimethyldioctadecylammonium
trehalose 6,6'-dibehenate
Mechanics
Cellular Immunity
Immunization
Phospholipids
Vaccines
Macrophages
Cell Membrane
Lipids
Pressure

Keywords

  • adjuvants, Immunologic
  • animals
  • calorimetry, differential Scanning
  • cholesterol
  • female
  • glycolipids
  • humans
  • immunization
  • immunoglobulin G
  • interferon-gamma
  • lipid bilayers
  • liposomes
  • macrophages
  • membrane fluidity
  • mice
  • mice, inbred BALB C
  • mice, inbred C57BL
  • phase transition
  • phospholipids
  • quaternary ammonium compounds
  • spleen
  • tissue distribution

Cite this

Kaur, Randip ; Henriksen-Lacey, Malou ; Wilkhu, Jitinder ; Devitt, Andrew ; Christensen, Dennis ; Perrie, Yvonne. / Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on bilayer properties, biodistribution, and immune responses. In: Molecular Pharmaceutics. 2014 ; Vol. 11, No. 1. pp. 197-207.
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Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on bilayer properties, biodistribution, and immune responses. / Kaur, Randip; Henriksen-Lacey, Malou; Wilkhu, Jitinder; Devitt, Andrew; Christensen, Dennis; Perrie, Yvonne.

In: Molecular Pharmaceutics, Vol. 11, No. 1, 06.01.2014, p. 197-207.

Research output: Contribution to journalArticle

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T1 - Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on bilayer properties, biodistribution, and immune responses

AU - Kaur, Randip

AU - Henriksen-Lacey, Malou

AU - Wilkhu, Jitinder

AU - Devitt, Andrew

AU - Christensen, Dennis

AU - Perrie, Yvonne

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N2 - Cholesterol is an abundant component of mammalian cell membranes and has been extensively studied as an artificial membrane stabilizer in a wide range of phospholipid liposome systems. In this study, the aim was to investigate the role of cholesterol in cationic liposomal adjuvant system based on dimethyldioctadecylammonium (DDA) and trehalose 6,6'-dibehenate (TDB) which has been shown as a strong adjuvant system for vaccines against a wide range of diseases. Packaging of cholesterol within DDA:TDB liposomes was investigated using differential scanning calorimetery and surface pressure-area isotherms of lipid monolayers; incorporation of cholesterol into liposomal membranes promoted the formation of a liquid-condensed monolayer and removed the main phase transition temperature of the system, resulting in an increased bilayer fluidity and reduced antigen retention in vitro. In vivo biodistribution studies found that this increase in membrane fluidity did not alter deposition of liposomes and antigen at the site of injection. In terms of immune responses, early (12 days after immunization) IgG responses were reduced by inclusion of cholesterol; thereafter there were no differences in antibody (IgG, IgG1, IgG2b) responses promoted by DDA:TDB liposomes with and without cholesterol. However, significantly higher levels of IFN-gamma were induced by DDA:TDB liposomes, and liposome uptake by macrophages in vitro was also shown to be higher for DDA:TDB liposomes compared to their cholesterol-containing counterparts, suggesting that small changes in bilayer mechanics can impact both cellular interactions and immune responses.

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KW - calorimetry, differential Scanning

KW - cholesterol

KW - female

KW - glycolipids

KW - humans

KW - immunization

KW - immunoglobulin G

KW - interferon-gamma

KW - lipid bilayers

KW - liposomes

KW - macrophages

KW - membrane fluidity

KW - mice

KW - mice, inbred BALB C

KW - mice, inbred C57BL

KW - phase transition

KW - phospholipids

KW - quaternary ammonium compounds

KW - spleen

KW - tissue distribution

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