Manipulation of the surface pegylation in combination with reduced vesicle size of cationic liposomal adjuvants modifies their clearance kinetics from the injection site, and the rate and type of T cell response.
The mechanism behind the immunostimulatory effect of the cationic liposomal vaccine adjuvant dimethyldioctadecylammonium and trehalose 6,6'-dibehenate (DDA:TDB) has been linked to the ability of these cationic vesicles to promote a depot after administration, with the liposomal adjuvant and the antigen both being retained at the injection site. This can be attributed to their cationic nature, since reduction in vesicle size does not influence their distribution profile yet neutral or anionic liposomes have more rapid clearance rates. Therefore the aim of this study was to investigate the impact of a combination of reduced vesicle size and surface pegylation on the biodistribution and adjuvanticity of the formulations, in a bid to further manipulate the pharmacokinetic profiles of these adjuvants. From the biodistribution studies, it was found that with small unilamellar vesicles (SUVs), 10% PEGylation of the formulation could influence liposome retention at the injection site after 4 days, whilst higher levels (25mol%) of PEG blocked the formation of a depot and promote clearance to the draining lymph nodes. Interestingly, whilst the use of 10% PEG in the small unilamellar vesicles did not block the formation of a depot at the site of injection, it did result in earlier antibody response rates and switch the type of T cell responses from a Th1 to a Th2 bias suggesting that the presence of PEG in the formulation not only control the biodistribution of the vaccine, but also results in different types of interactions with innate immune cells.
School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
Randip
R
Kaur
Vincent W
VW
Bramwell
Daniel J
DJ
Kirby
Yvonne
Y
Perrie
D000818:Animals; D002412:Cations; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D005260:Female; D006017:Glycolipids / Q000008:administration & dosage / Q000737:chemistry; D007074:Immunoglobulin G / Q000097:blood; D007273:Injections, Intramuscular; D008081:Liposomes; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013499:Surface Properties; D013601:T-Lymphocytes / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics
C557979:Ag85B-ESAT-6 fusion antigen; D002412:Cations; D016207:Cytokines; D004337:Drug Carriers; D006017:Glycolipids; D007074:Immunoglobulin G; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines; C507803:trehalose 6,6'-dibehenate; C015831:dimethyldioctadecylammonium; D011092:Polyethylene Glycols