Squaric Ester-Based, pH-Degradable Nanogels: Modular Nanocarriers for Safe, Systemic Administration of Toll-like Receptor 7/8 Agonistic Immune Modulators

• DOI: 10.1021/jacs.1c03772
• Publication Date: 2021-06-24T21:11:31Z
• Authors: Anne Huppertsberg; Leonard Kaps; Zifu Zhong; Sascha Schmitt; Judith Stickdorn; Kim Deswarte; Francis Combes; Christian Czysch; Jana De Vrieze; Sabah Kasmi; Niklas Choteschovsky; Adrian Klefenz; Carolina Medina-M...; Pia Winterwerber; Chaojian Chen; Matthias Bros; Stefan Lienenklaus; Niek N. Sanders; Kaloian Koynov; Detlef Schuppan; Bart N. Lambrecht; Sunil A. David; Bruno G. De Geest; Lutz Nuhn
• Keywords: Nanocarriers; Nanogel; Squaric acid; Systemic administration

Small-molecular Toll-like receptor 7/8 (TLR7/8) agonists hold promise as immune modulators for a variety of therapeutic purposes including cancer therapy or vaccination. However, due to their rapid systemic distribution causing difficult-to-control inflammatory off-target effects, application is still problematic, in particular systemically. To address this problem, we designed and robustly fabricated pH-responsive nanogels serving versatile immunodrug nanocarriers safe delivery TLR7/8-stimulating imidazoquinolines after intravenous administration. aim, primary amine-reactive methacrylamide monomer bearing pendant squaric ester amide introduced, which polymerized under controlled RAFT polymerization conditions. Corresponding PEG-derived block copolymers self-assemble into precursor micelles polar protic solvents. Their cores are can sequentially be transformed by acid-sensitive cross-linkers, dyes, imidazoquinolines. Remaining amides hydrophilized affording fully hydrophilic with profound stability human plasma but stimuli-responsive degradation upon exposure endolysosomal pH The immunomodulatory behavior the alone conjugated was demonstrated macrophages