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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)12133-12139
Number of pages7
JournalJournal of the American Chemical Society
Volume142
Issue number28
DOIs
Publication statusPublished - 15 Jul 2020

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