2.50
Hdl Handle:
http://hdl.handle.net/10033/618490
Title:
pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation.
Authors:
Nuhn, Lutz; Vanparijs, Nane; De Beuckelaer, Ans; Lybaert, Lien; Verstraete, Glenn; Deswarte, Kim; Lienenklaus, Stefan; Shukla, Nikunj M; Salyer, Alex C D; Lambrecht, Bart N; Grooten, Johan; David, Sunil A; De Koker, Stefaan; De Geest, Bruno G
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.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation. 2016, 113 (29):8098-103 Proc. Natl. Acad. Sci. U.S.A.
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
19-Jul-2016
URI:
http://hdl.handle.net/10033/618490
DOI:
10.1073/pnas.1600816113
PubMed ID:
27382168
Type:
Article
Language:
en
ISSN:
1091-6490
Appears in Collections:
publications of the research group molecular Immunology (MOLI)

Full metadata record

DC FieldValue Language
dc.contributor.authorNuhn, Lutzen
dc.contributor.authorVanparijs, Naneen
dc.contributor.authorDe Beuckelaer, Ansen
dc.contributor.authorLybaert, Lienen
dc.contributor.authorVerstraete, Glennen
dc.contributor.authorDeswarte, Kimen
dc.contributor.authorLienenklaus, Stefanen
dc.contributor.authorShukla, Nikunj Men
dc.contributor.authorSalyer, Alex C Den
dc.contributor.authorLambrecht, Bart Nen
dc.contributor.authorGrooten, Johanen
dc.contributor.authorDavid, Sunil Aen
dc.contributor.authorDe Koker, Stefaanen
dc.contributor.authorDe Geest, Bruno Gen
dc.date.accessioned2016-08-17T12:21:11Z-
dc.date.available2016-08-17T12:21:11Z-
dc.date.issued2016-07-19-
dc.identifier.citationpH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation. 2016, 113 (29):8098-103 Proc. Natl. Acad. Sci. U.S.A.en
dc.identifier.issn1091-6490-
dc.identifier.pmid27382168-
dc.identifier.doi10.1073/pnas.1600816113-
dc.identifier.urihttp://hdl.handle.net/10033/618490-
dc.description.abstractAgonists 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.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titlepH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen

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