Lymph-Node-Targeted Immune Activation by Engineered Block Copolymer Amphiphiles–TLR7/8 Agonist Conjugates

• DOI: 10.1021/jacs.8b08595
• Publication Date: 2018-10-02T16:24:56Z
• Authors: Simon Van Herck; Kim Deswarte; Lutz Nuhn; Zifu Zhong; Joao Paulo Portel...; Yupeng Li; Niek N. Sanders; Stefan Lienenklaus; Stefaan De Koker; Bart N. Lambrecht; Sunil A. David; Bruno G. De Geest
• Keywords: TLR7

Small molecule immuno-modulators such as agonists of Toll-like receptors (TLRs) are attractive compounds to stimulate innate immune cells toward potent antiviral and antitumor responses. However, small molecules rapidly enter the systemic circulation cause "wasted inflammation". Hence, synthetic strategies confine their radius action lymphoid tissue great relevance, both enhance efficacy concomitantly limit toxicity. Here, we demonstrate that covalent conjugation a TLR7/8 agonist immunomodulatory micelle-forming amphiphilic block copolymer greatly alters pharmacokinetic profile, resulting in highly efficient lymphatic delivery. Moreover, designed copolymers way form thermodynamically stable micelles through π-π stacking between aromatic moieties, engineered undergo an irreversible hydrophilic transition response acidic endosomal pH.