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A pH-sensitive Macromolecular Prodrug as TLR7/8 Targeting Immune Response Modifier.

ABSTRACT: The chemical synthesis and biological activity of novel functionalized imidazoquinoline derivatives (ImQ) to generate Toll-like receptor (TLR) 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 (ImQ-polymer), the macromolecular prodrugs were designed to undergo intracellular pH-sensitive release of ImQs to induce inflammation through binding to endosomal TLR7/8 (danger signal). 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-? release. ImQ prodrugs presented here are suggested to form the basis of novel nanovaccines, for example, for intravenous or intratumoral cancer immunotherapeutic applications to trigger physiological antitumor immune responses.

SUBMITTER: Aichhorn S

PROVIDER: S-EPMC5763314 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A pH-sensitive Macromolecular Prodrug as TLR7/8 Targeting Immune Response Modifier.

Aichhorn Stefan S Linhardt Anne A Halfmann Angela A Nadlinger Markus M Kirchberger Stefanie S Stadler Manuela M Dillinger Barbara B Distel Martin M Dohnal Alexander A Teasdale Ian I Schöfberger Wolfgang W

Chemistry (Weinheim an der Bergstrasse, Germany) 20170904 70

The chemical synthesis and biological activity of novel functionalized imidazoquinoline derivatives (ImQ) to generate Toll-like receptor (TLR) 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 (ImQ-polymer), the macromolecular prodrugs were designed to undergo intracellular pH-sensitive release of ImQs to induce inflammation through binding to endosomal TLR7/8 (da ...[more]

PMID: 28758266

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A pH-sensitive Macromolecular Prodrug as TLR7/8 Targeting Immune Response Modifier.

Publications

A pH-sensitive Macromolecular Prodrug as TLR7/8 Targeting Immune Response Modifier.

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