A pH-sensitive Macromolecular Prodrug as TLR7/8 Targeting Immune Response Modifier
Sprache des Titels:
Englisch
Original Kurzfassung:
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.
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