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

Area of Science:

• Immunology
• Materials Science
• Pharmacology

Background:

• Toll-like receptors (TLRs) 7/8 are crucial in innate immunity, recognizing pathogen-associated molecular patterns.
• Imidazoquinoline derivatives (ImQ) are known TLR7/8 agonists, but their direct application is limited.
• Developing targeted drug delivery systems can enhance the efficacy and safety of immunomodulatory compounds.

Purpose of the Study:

• To synthesize novel functionalized imidazoquinoline derivatives (ImQ) as prodrugs for TLR7/8 activation.
• To develop biodegradable polyphosphazene-based macromolecular prodrugs (ImQ-polymers) for targeted intracellular release.
• To evaluate the in vivo and in vitro biological activity of ImQ prodrugs for potential nanovaccine applications.

Main Methods:

• Chemical synthesis of functionalized ImQ derivatives.
• Covalent ligation of ImQ to biodegradable polyphosphazenes.
• In vivo studies in zebrafish larvae to assess inflammatory responses.
• In vitro studies using murine splenocytes to evaluate T cell activation (proliferation, CD25 expression, IFN-γ release).
• pH-dependent release studies to confirm endosomal degradability.

Main Results:

• ImQ derivatives were successfully synthesized and demonstrated in vivo inflammatory activity.
• ImQ-polymers showed pH-sensitive release of ImQ at pH 5, indicating endosomal degradability.
• ImQ-polymers significantly activated ovalbumin-specific T cells, increasing proliferation and CD25 expression on CD8+ T cells.
• Elevated levels of IFN-γ were observed, indicating a robust immune response.

Conclusions:

• ImQ-polyphosphazene prodrugs enable targeted delivery and pH-sensitive release of ImQ.
• These macromolecular prodrugs effectively activate T cells and induce key immune mediators.
• ImQ prodrugs represent a promising platform for developing novel nanovaccines for cancer immunotherapy.