PUBLICATION
A pH-sensitive macromolecular prodrug as TLR7/8 targeting immune response modifier
- Authors
- Aichhorn, S., Linhardt, A., Halfmann, A., Nadlinger, M., Kirchberger, S., Stadler, M., Dillinger, B., Distel, M., Dohnal, A., Teasdale, I., Schoefberger, W.
- ID
- ZDB-PUB-170802-18
- Date
- 2017
- Source
- Chemistry (Weinheim an der Bergstrasse, Germany) 23(70): 17721-17726 (Journal)
- Registered Authors
- Distel, Martin, Kirchberger, Stefanie, Stadler, Manuela
- Keywords
- Imidazoquinoline, TLR7/8 agonists, cancer immunotherapy, immune response modifiers, pH-sensitive polymer
- MeSH Terms
-
- Animals
- Animals, Genetically Modified/metabolism
- CD8-Positive T-Lymphocytes/drug effects
- CD8-Positive T-Lymphocytes/metabolism
- Dendritic Cells/cytology
- Dendritic Cells/drug effects
- Dendritic Cells/metabolism
- Hydrogen-Ion Concentration
- Inflammation/etiology
- Interferon-gamma/metabolism
- Larva/drug effects
- Larva/metabolism
- Mice
- Microscopy, Confocal
- NF-kappa B/metabolism
- Prodrugs/chemical synthesis
- Prodrugs/chemistry*
- Prodrugs/toxicity
- Quinolines/chemical synthesis
- Quinolines/chemistry
- Quinolines/toxicity
- Receptors, Interleukin-2/genetics
- Receptors, Interleukin-2/metabolism
- Toll-Like Receptor 7/antagonists & inhibitors*
- Toll-Like Receptor 7/metabolism
- Toll-Like Receptor 8/antagonists & inhibitors*
- Toll-Like Receptor 8/metabolism
- Zebrafish/growth & development
- PubMed
- 28758266 Full text @ Chemistry
Citation
Aichhorn, S., Linhardt, A., Halfmann, A., Nadlinger, M., Kirchberger, S., Stadler, M., Dillinger, B., Distel, M., Dohnal, A., Teasdale, I., Schoefberger, W. (2017) A pH-sensitive macromolecular prodrug as TLR7/8 targeting immune response modifier. Chemistry (Weinheim an der Bergstrasse, Germany). 23(70):17721-17726.
Abstract
The chemical synthesis and biological activity of novel functionalized imidazoquinoline derivatives to generate Toll-like receptor 7/8 specific prodrugs are presented. In vivo activity of ImQs to induce inflammation was confirmed in zebrafish larvae. After covalent ligation to fully biodegradable polyphosphazenes, the macromolecular prodrugs were designed to undergo intracellular pH-sensitive release of ImQs to induce inflammation through binding to endosomal TLR7/8. We showed ImQ dissociation from prodrugs at a pH 5 pointing towards endosomal prodrug degradability. ImQ-polymers strongly activated ovalbumin-specific T cells in murine splenocytes as shown by increased proliferation and expression of the IL-2 receptor (CD25) on CD8+ T cells accompanied by strong IFN-γ release. ImQ prodrugs presented here are suggested to form the basis of novel nanovaccines, e.g. for intravenous or intratumoral cancer immunotherapeutic applications to trigger physiological antitumor immune responses.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping