In vitro analysis of acetalated dextran microparticles as a potent delivery platform for vaccine adjuvants.
Toll-like receptor (TLR) agonists induce potent innate immune responses and can be used in the development of novel vaccine adjuvants. However, access to TLRs can be challenging as exemplified by TLR 7, which is located intracellularly in endosomal compartments. To increase recognition and subsequent stimulatory effects of TLR 7, imiquimod was encapsulated in acetalated dextran (Ac-DEX) microparticles. Ac-DEX, a water-insoluble and biocompatible polymer, is relatively stable at pH 7.4, but degrades rapidly under acidic conditions, such as those found in lysosomal vesicles. To determine the immunostimulatory capacity of encapsulated imiquimod, we compared the efficacy of free versus encapsulated imiquimod in activating RAW 264.7 macrophages, MH-S macrophages, and bone marrow derived dendritic cells. Encapsulated imiquimod significantly increased IL-1 beta, IL-6, and TNF-alpha cytokine expression in macrophages relative to the free drug. Furthermore, significant increases were observed in classic macrophage activation markers (iNOS, PD1-L1, and NO) after treatment with encapsulated imiquimod over the free drug. Also, bone marrow derived dendritic cells produced significantly higher levels of IL-1 beta, IL-6, IL-12p70, and MIP-1 alpha as compared to their counterparts receiving free imiquimod. These results suggest that encapsulation of TLR ligands within Ac-DEX microparticles results in increased immunostimulation and potentially better protection from disease when used in conjunction with vaccine formulations.
Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.
Eric M
EM
Bachelder
Tristan T
TT
Beaudette
Kyle E
KE
Broaders
Jean M J
JM
Fréchet
Mark T
MT
Albrecht
Alfred J
AJ
Mateczun
Kristy M
KM
Ainslie
John T
JT
Pesce
Andrea M
AM
Keane-Myers
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000737:chemistry; D000634:Aminoquinolines / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D003911:Dextrans / Q000737:chemistry*; D000077271:Imiquimod; D018664:Interleukin-12 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D016133:Polymerase Chain Reaction
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D003911:Dextrans; D053583:Interleukin-1beta; D015850:Interleukin-6; D018664:Interleukin-12; D000077271:Imiquimod