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

Area of Science:

• Oncology
• Nanomedicine
• Biochemistry

Background:

• Oesophageal adenocarcinoma (OAC) shows poor response to neoadjuvant chemoradiotherapy, necessitating improved treatment strategies.
• Pyrazinib (P3) exhibits radiosensitizing, anti-angiogenic, and anti-inflammatory properties but suffers from poor solubility and bioavailability.
• Enhancing radiation therapy response is crucial for improving outcomes in locally advanced OAC.

Purpose of the Study:

• To develop a novel formulation of pyrazinib (P3) with enhanced solubility, bioavailability, and targeted delivery capabilities.
• To evaluate the radiosensitizing, anti-angiogenic, and anti-metabolic effects of pyrazinib conjugated with gold nanoparticles (AuNP-P3).

Main Methods:

• Conjugation of pyrazinib with gold nanoparticles (AuNP-P3) to improve its physicochemical properties.
• Assessment of AuNP-P3's radiosensitizing effect in an isogenic model of OAC radioresistance.
• Evaluation of mitochondrial metabolism and inflammatory mediator secretion in OAC models.
• In vivo assessment of anti-angiogenic activity using zebrafish embryo models.

Main Results:

• AuNP-P3 significantly reduced the surviving fraction of radioresistant OAC cells post-irradiation.
• The formulation decreased mitochondrial metabolism and modulated inflammatory mediator secretion in OAC models.
• AuNP-P3 demonstrated potent anti-angiogenic activity in vivo, inhibiting blood vessel formation.

Conclusions:

• Pyrazinib retains its therapeutic properties when conjugated with gold nanoparticles.
• AuNP-P3 shows significant potential as a novel radiosensitizer for oesophageal adenocarcinoma.
• The findings support further clinical development of AuNP-P3 for OAC treatment.