Browsing Department of molecular bacteriology (MOBA) by Authors
pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation.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; et al. (2016-07-19)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.