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dc.contributor.authorNuhn, Lutz
dc.contributor.authorVanparijs, Nane
dc.contributor.authorDe Beuckelaer, Ans
dc.contributor.authorLybaert, Lien
dc.contributor.authorVerstraete, Glenn
dc.contributor.authorDeswarte, Kim
dc.contributor.authorLienenklaus, Stefan
dc.contributor.authorShukla, Nikunj M
dc.contributor.authorSalyer, Alex C D
dc.contributor.authorLambrecht, Bart N
dc.contributor.authorGrooten, Johan
dc.contributor.authorDavid, Sunil A
dc.contributor.authorDe Koker, Stefaan
dc.contributor.authorDe Geest, Bruno G
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.
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
refterms.dateFOA2017-01-20T00:00:00Z
html.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.


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