Potent and Prolonged Innate Immune Activation by Enzyme-Responsive Imidazoquinoline TLR7/8 Agonist Prodrug Vesicles

• DOI: 10.1021/jacs.0c01928
• Publication Date: 2020-06-11T09:47:42Z
• Authors: Bi Wang; Simon Van Herck; Yong Chen; Xiangyang Bai; Zifu Zhong; Kim Deswarte; Bart N. Lambrecht; Niek N. Sanders; Stefan Lienenklaus; Hans W. Scheeren; Sunil A. David; Fabian Kiessling; Twan Lammers; Bruno G. De Geest; Yang Shi
• Keywords: Membrane Glycoproteins; Molecular Structure; Surface Properties; Imidazoles; EMC MM-04-42-02; beta-Galactosidase; 01 natural sciences; Immunity, Innate; Polyethylene Glycols; 3. Good health; 0104 chemical sciences; Mice; Toll-Like Receptor 7; Toll-Like Receptor 8; Quinolines; Animals; Prodrugs; Particle Size

Synthetic immune-stimulatory drugs such as agonists of the Toll-like receptors (TLR) 7/8 are potent activators antigen-presenting cells (APCs), however, they also induce severe side effects due to leakage from site injection into systemic circulation. Here, we report on design and synthesis an amphiphilic polymer-prodrug conjugate imidazoquinoline TLR7/8 agonist that in aqueous medium forms vesicular structures 200 nm. The contains endosomal enzyme-responsive linker enabling degradation vesicles release native form after endocytosis, which results high vitro TLR activity. In a mouse model, locally administered provoke significantly more long-lasting immune stimulation terms interferon expression at draining lymphoid tissue compared nonamphiphilic control agonist. Moreover, robust activation dendritic lymph node vivo.