pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation.
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Authors
Nuhn, LutzVanparijs, 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
Issue Date
2016-07-19
Metadata
Show full item recordAbstract
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.Citation
pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation. 2016, 113 (29):8098-103 Proc. Natl. Acad. Sci. U.S.A.Affiliation
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.PubMed ID
27382168Type
ArticleLanguage
enISSN
1091-6490ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1600816113
Scopus Count
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- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/