A step-by-step approach to study the influence of N-acetylation on the adjuvanticity of N,N,N-trimethyl chitosan (TMC) in an intranasal nanoparticulate influenza virus vaccine.
Recently we reported that reacetylation of N,N,N-trimethyl chitosan (TMC) reduced the adjuvant effect of TMC in mice after intranasal (i.n.) administration of whole inactivated influenza virus (WIV) vaccine. The aim of the present study was to elucidate the mechanism of this lack of adjuvanticity. Reacetylated TMC (TMC-RA, degree of acetylation 54%) was compared with TMC (degree of acetylation 17%) at six potentially critical steps in the induction of an immune response after i.n. administration in mice. TMC-RA was degraded in a nasal wash to a slightly larger extent than TMC. The local i.n. distribution and nasal clearance of WIV were similar for both TMC types. Fluorescently labeled WIV was taken up more efficiently by Calu-3 cells when formulated with TMC-RA compared to TMC and both TMCs significantly reduced transport of WIV over a Calu-3 monolayer. Murine bone-marrow derived dendritic cell activation was similar for plain WIV, and WIV formulated with TMC-RA or TMC. The inferior adjuvant effect in mice of TMC-RA over that of TMC might be caused by a slightly lower stability of TMC-RA-WIV in the nasal cavity, rather than by any of the other factors studied in this paper.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
Rolf J
RJ
Verheul
Niels
N
Hagenaars
Thomas
T
van Es
Ethlinn V B
EV
van Gaal
Pascal H J L F
PH
de Jong
Sven
S
Bruijns
Enrico
E
Mastrobattista
Bram
B
Slütter
Ivo
I
Que
Jacco G M
JG
Heldens
Han
H
van den Bosch
Harrie L
HL
Glansbeek
Wim E
WE
Hennink
Wim
W
Jiskoot
D000107:Acetylation; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry*; D000281:Administration, Intranasal; D000818:Animals; D002460:Cell Line; D048271:Chitosan / Q000008:administration & dosage / Q000737:chemistry*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000737:chemistry*
D000276:Adjuvants, Immunologic; D007252:Influenza Vaccines; C118071:N-trimethyl chitosan chloride; D015164:Vaccines, Inactivated; D048271:Chitosan