4.8 Article

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

期刊

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 142, 期 28, 页码 12133-12139

出版社

AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c01928

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资金

  1. Ghent University
  2. European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [817938, 813086, 864121]
  3. China Scholarship Council
  4. European Union (European Fund for Regional Development: I3-STM) [0800387]
  5. German Research Foundation [D.F.G.: GRK/RTG 2375, 331065168, SFB 1066]
  6. Aachen Interdisciplinary Center for Clinical Research (IZKF) [O3-2]
  7. European Union (European Fund for Regional Development: TAKTIRA) [EFRE-0801767]

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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.

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