title: Enhanced in vivo targeting of murine nonparenchymal liver cells with monophosphoryl lipid A functionalized microcapsules.
abstract: A broad spectrum of infectious liver diseases emphasizes the need of microparticles for targeted delivery of immunomodulatory substances to the liver. Microcapsules (MCs) are particularly attractive for innovative drug and vaccine formulations, enabling the combination of antigen, drugs, and adjuvants. The present study aimed to develop microcapsules characterized by an enhanced liver deposition and accelerated uptake by nonparenchymal liver cells (NPCs). Initially, two formulations of biodegradable microcapsules were synthesized from either hydroxyethyl starch (HES) or mannose. Notably, HES-MCs accumulated primarily in the liver, while mannose particles displayed a lung preference. Functionalization of HES-MCs with anti-CD40, anti-DEC205, and/or monophosphoryl lipid A (MPLA) enhanced uptake of MCs by nonparenchymal liver cells in vitro. In contrast, only MPLA-coated HES-MCs promoted significantly the in vivo uptake by NPCs. Finally, HES-MCs equipped with MPLA, anti-CD40, and anti-DEC205 induced the secretion of TNF-α, IL-6 by Kupffer cells (KCs), and IFN-γ and IL-12p70 by liver dendritic cells (DCs). The enhanced uptake and activation of KCs by MPLA-HES-MCs is a promising approach to prevent or treat infection, since KCs are exploited as an entry gate in various infectious diseases, such as malaria. In parallel, loading and activating liver DCs, usually prone to tolerance, bears the potential to induce antigen specific, intrahepatic immune responses necessary to prevent and treat infections affecting the liver.
authors.affiliation: Children's Hospital, University Medical Center, Johannes Gutenberg University , Mainz 55131, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Pietrzak-Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Fichter
authors.forename: Marvin
authors.initials: M
authors.lastname: Dedters
authors.forename: Leah
authors.initials: L
authors.lastname: Pretsch
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gregory
authors.forename: Claudius
authors.initials: C
authors.lastname: Meyer
authors.forename: Aysefa
authors.initials: A
authors.lastname: Doganci
authors.forename: Mustafa
authors.initials: M
authors.lastname: Diken
authors.forename: Katharina
authors.initials: K
authors.lastname: Landfester
authors.forename: Grit
authors.initials: G
authors.lastname: Baier
authors.forename: Stephan
authors.initials: S
authors.lastname: Gehring
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D002214:Capsules / Q000737:chemistry / Q000493:pharmacokinetics; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008107:Liver Diseases / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D053758:Nanoparticles / Q000737:chemistry; D010587:Phagocytosis / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D019013:CD40 Antigens; D002214:Capsules; C093569:DEC-205 receptor; D015850:Interleukin-6; D037181:Lectins, C-Type; D008050:Lipid A; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C048436:monophosphoryl lipid A