Potent and Prolonged Innate Immune Activation by Enzyme-Responsive Imidazoquinoline TLR7/8 Agonist Prodrug Vesicles
| Autor: | Niek N. Sanders, Sunil A. David, Hans W. Scheeren, Yang Shi, Stefan Lienenklaus, Bart N. Lambrecht, Bi Wang, Kim Deswarte, Twan Lammers, Zifu Zhong, Xiangyang Bai, Simon Van Herck, Bruno G. De Geest, Fabian Kiessling, Yong Chen |
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| Přispěvatelé: | Biomaterials Science and Technology, Pulmonary Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Agonist
Surface Properties medicine.drug_class 010402 general chemistry Endocytosis 01 natural sciences Biochemistry Article Catalysis Polyethylene Glycols Mice chemistry.chemical_compound Colloid and Surface Chemistry In vivo medicine Animals Prodrugs Particle Size Receptor Antigen-presenting cell Membrane Glycoproteins Innate immune system Molecular Structure Vesicle Imidazoles General Chemistry beta-Galactosidase Immunity Innate 0104 chemical sciences 3. Good health Cell biology Imidazoquinoline Toll-Like Receptor 7 chemistry Toll-Like Receptor 8 Quinolines |
| Zdroj: | Journal of the American Chemical Society, 142(28), 12133-12139. American Chemical Society Journal of the American Chemical Society J Am Chem Soc |
| ISSN: | 0002-7863 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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