title: Monophosphoryl lipid A coating of hydroxyethyl starch nanocapsules drastically increases uptake and maturation by dendritic cells while minimizing the adjuvant dosage.
abstract: Enhancing delivery of antigens to dendritic cells (DCs) is essential for the induction of vigorous antigen-specific cellular immune responses. Aim of the present study was to evaluate the properties of hydroxyethyl starch nanocapsules (HES-NCs) functionalized with anti-CD40, anti-DEC205, interferon-γ (IFNγ) and/or monophosphoryl lipid A (MPLA) with respect to the overall uptake, the released cytokine profile, and the influence on phenotypic maturation of human monocyte-derived DCs using flow cytometry, confocal microscopy and enzyme-linked immunosorbent assays. NC uptake by DCs was significantly enhanced by functionalizing NCs with anti-CD40 or MPLA. With respect to the cytokine profile and the maturation status, coating with MPLA evoked a strong Th1-type cytokine response and significantly increased CD80 and CD83 expression on DCs, contrasting the moderate effects of MPLA in solution. Notably, an at least 20 fold higher amount of MPLA in solution was needed compared to the dosage of MPLA attached to HES-NCs in order to induce comparable effects, evidencing the intense dose-sparing potential of particle-bound MPLA. Reducing the amount of the vaccine adjuvant MPLA, while maintaining or even surpassing the effects on human DCs, reveals the potential of HES-NCs as a promising carrier system for the simultaneous delivery of antigen along with compounds promoting a Th1-prone cellular immune response.
authors.affiliation: Children's Hospital, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fichter
authors.affiliation: Children's Hospital, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Marvin
authors.initials: M
authors.lastname: Dedters
authors.affiliation: Children's Hospital, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Pietrzak-Nguyen
authors.affiliation: Children's Hospital, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Leah
authors.initials: L
authors.lastname: Pretsch
authors.affiliation: Children's Hospital, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Claudius U
authors.initials: CU
authors.lastname: Meyer
authors.affiliation: I. Department of Internal Medicine, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Strand
authors.affiliation: Children's Hospital, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
authors.forename: Fred
authors.initials: F
authors.lastname: Zepp
authors.affiliation: Max-Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Baier
authors.affiliation: Max-Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Landfester
authors.affiliation: Children's Hospital, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany. Electronic address: stephan.gehring@uni-mainz.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gehring
mesh_terms: D000276:Adjuvants, Immunologic; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D006801:Humans; D006895:Hydroxyethyl Starch Derivatives / Q000737:chemistry*; D018664:Interleukin-12 / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry; D018613:Microscopy, Confocal; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D050997:Nanomedicine / Q000379:methods*; D018417:Th1 Cells / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D006895:Hydroxyethyl Starch Derivatives; D008050:Lipid A; D053769:Nanocapsules; D051197:Toll-Like Receptor 4; D018664:Interleukin-12; C048436:monophosphoryl lipid A
keywords: Dendritic cell targeting; Hydroxyethyl starch; Monophosphoryl lipid A; Nanocapsules; TLR4; Vaccine