title: pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation.
abstract: Agonists of Toll-like receptors (TLRs) are potent activators of the innate immune system and hold promise as vaccine adjuvant and for anticancer immunotherapy. Unfortunately, in soluble form they readily enter systemic circulation and cause systemic inflammatory toxicity. Here we demonstrate that by covalent ligation of a small-molecule imidazoquinoline-based TLR7/8 agonist to 50-nm-sized degradable polymeric nanogels the potency of the agonist to activate TLR7/8 in in vitro cultured dendritic cells is largely retained. Importantly, imidazoquinoline-ligated nanogels focused the in vivo immune activation on the draining lymph nodes while dramatically reducing systemic inflammation. Mechanistic studies revealed a prevalent passive diffusion of the nanogels to the draining lymph node. Moreover, immunization studies in mice have shown that relative to soluble TLR7/8 agonist, imidazoquinoline-ligated nanogels induce superior antibody and T-cell responses against a tuberculosis antigen. This approach opens possibilities to enhance the therapeutic benefit of small-molecule TLR agonist for a variety of applications.
authors.affiliation: Department of Pharmaceutics, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent, 9052 Ghent, Belgium; lutz.nuhn@ugent.be sdavid@umn.edu stefaan.dekoker@ugent.be br.degeest@ugent.be.
authors.forename: Lutz
authors.initials: L
authors.lastname: Nuhn
authors.affiliation: Department of Pharmaceutics, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent, 9052 Ghent, Belgium;
authors.forename: Nane
authors.initials: N
authors.lastname: Vanparijs
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium;
authors.forename: Ans
authors.initials: A
authors.lastname: De Beuckelaer
authors.affiliation: Department of Pharmaceutics, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent, 9052 Ghent, Belgium;
authors.forename: Lien
authors.initials: L
authors.lastname: Lybaert
authors.affiliation: Department of Pharmaceutics, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent, 9052 Ghent, Belgium;
authors.forename: Glenn
authors.initials: G
authors.lastname: Verstraete
authors.affiliation: VIB Inflammation Research Center, Ghent University, 9052 Zwijnaarde, Belgium; Department of Respiratory Medicine, University Hospital Ghent, 9000 Ghent, Belgium;
authors.forename: Kim
authors.initials: K
authors.lastname: Deswarte
authors.affiliation: Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hanover, Germany; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, 30625 Hanover, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Nikunj M
authors.initials: NM
authors.lastname: Shukla
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Alex C D
authors.initials: AC
authors.lastname: Salyer
authors.affiliation: VIB Inflammation Research Center, Ghent University, 9052 Zwijnaarde, Belgium; Department of Respiratory Medicine, University Hospital Ghent, 9000 Ghent, Belgium;
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium;
authors.forename: Johan
authors.initials: J
authors.lastname: Grooten
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455 lutz.nuhn@ugent.be sdavid@umn.edu stefaan.dekoker@ugent.be br.degeest@ugent.be.
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium; lutz.nuhn@ugent.be sdavid@umn.edu stefaan.dekoker@ugent.be br.degeest@ugent.be.
authors.forename: Stefaan
authors.initials: S
authors.lastname: De Koker
authors.affiliation: Department of Pharmaceutics, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent, 9052 Ghent, Belgium; lutz.nuhn@ugent.be sdavid@umn.edu stefaan.dekoker@ugent.be br.degeest@ugent.be.
authors.forename: Bruno G
authors.initials: BG
authors.lastname: De Geest
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005782:Gels; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D007114:Immunization; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000819:agonists; D051379:Mice; D008810:Mice, Inbred C57BL; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D005782:Gels; D007093:Imidazoles; D008562:Membrane Glycoproteins; C524728:PPE44 protein, Mycobacterium tuberculosis; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8
keywords: Toll-like receptor; dendritic cells; lymph node; nanotechnology; vaccine