Incorporation of the TLR4 agonist monophosphoryl lipid A into the bilayer of DDA/TDB liposomes: physico-chemical characterization and induction of CD8+ T-cell responses in vivo.
OBJECTIVE
The combination of delivery systems like cationic liposomes and immunopotentiators such as Toll-like receptor (TLR) ligands is a promising approach for rational vaccine adjuvant design. The purpose of this study was to investigate how the incorporation of the poorly soluble TLR4 agonist monophosphoryl lipid A (MPL) into cationic liposomes based on dimethyldioctadecylammonium (DDA) and trehalose 6,6'-dibehenate (TDB) influenced the physicochemical and immunological properties of the liposomes.


METHODS
The DDA/TDB/MPL liposomes were characterized with regard to particle size, poly dispersity, surface charge, stability and thermodynamic properties. The adjuvant formulations were tested in vivo in mice using ovalbumin (OVA) as model antigen.


RESULTS
Integration of MPL into the bilayer structure of DDA/TDB liposomes was evident from a decreased phase transition temperature, an improved membrane packing, and a reduction in surface charge. The particle size and favorable liposome storage stability were not affected by MPL. In mice, DDA/TDB/MPL liposomes induced an antigen-specific CD8(+) T-cell response and a humoral response.


CONCLUSIONS
Enhancing the solubility of MPL by inclusion into the bilayer of DDA/TDB liposomes changes the membrane characteristics of the adjuvant system and provides the liposomes with CD8(+) T-cell inducing properties without compromising humoral responses.
Department of Pharmaceutics and Analytical Chemistry The Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen Ø, Denmark. pn@farma.ku.dk
Pernille
P
Nordly
Else Marie
EM
Agger
Peter
P
Andersen
Hanne Mørck
HM
Nielsen
Camilla
C
Foged
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D055598:Chemical Phenomena; D005260:Female; D006017:Glycolipids / Q000378:metabolism*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008051:Lipid Bilayers / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D000644:Quaternary Ammonium Compounds / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism
D006017:Glycolipids; D008050:Lipid A; D008051:Lipid Bilayers; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C507803:trehalose 6,6'-dibehenate; C015831:dimethyldioctadecylammonium; C048436:monophosphoryl lipid A