Targeting Radiation Resistance in Oesophageal Adenocarcinoma with Pyrazinib-Functionalised Gold Nanoparticles

Background/Objectives: Only 20-30% of oesophageal adenocarcinoma (OAC) patients achieve a complete response to neoadjuvant chemo-radiotherapy for locally advanced tumours. Enhancing the response to radiation therapy is critical for improving outcomes in this aggressive cancer. Pyrazinib (P3) is a promising compound with radiosensitizing, anti-angiogenic, anti-inflammatory, and anti-metabolic properties. However, its limited solubility and bioavailability have hindered its therapeutic potential.

To overcome these limitations, pyrazinib was conjugated with gold nanoparticles (AuNP-P3), creating a novel formulation designed to enhance solubility, maintain bioactivity, and enable targeted delivery to tumour sites.

In an isogenic model of OAC radioresistance, AuNP-P3 significantly reduced the surviving fraction following irradiation, demonstrating its radiosensitizing properties. It also reduced mitochondrial metabolism and modulated the secretion of inflammatory mediators in both in vitro models of OAC radioresistance and human ex vivo OAC tumour explants. Furthermore, AuNP-P3 exhibited potent anti-angiogenic activity, significantly inhibiting blood vessel formation in vivo using zebrafish embryo models.

These results collectively confirm that P3, in its conjugated formulation with gold nanoparticles, retains its therapeutic properties, highlighting the potential of AuNP-P3 as a novel therapeutic radiosensitizer for oesophageal adenocarcinoma and supporting its further development for clinical applications.