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. Methods: 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. Results: 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. Conclusions: 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.
背景/目的：对于局部晚期食管腺癌患者，仅20-30%对新辅助放化疗达到完全缓解。增强放射治疗敏感性对改善这种侵袭性癌症的预后至关重要。吡拉尼布（P3）是一种具有放射增敏、抗血管生成、抗炎和抗代谢特性的潜力化合物，但其溶解度和生物利用度有限制约了其治疗潜力。方法：为突破这些限制，本研究将吡拉尼布与金纳米颗粒结合（AuNP-P3），构建了一种旨在增强溶解度、保持生物活性并实现肿瘤靶向递送的新型制剂。结果：在食管腺癌放射抵抗的同基因模型中，AuNP-P3能显著降低辐照后的细胞存活分数，证实其放射增敏特性。该制剂在体外放射抵抗模型及人源离体肿瘤外植体中均能降低线粒体代谢并调节炎症介质分泌。此外，通过斑马鱼胚胎模型证实，AuNP-P3在体内表现出显著的抗血管生成活性，可有效抑制血管形成。结论：这些结果共同证实，与金纳米颗粒结合的吡拉尼布制剂能保留其治疗特性，凸显了AuNP-P3作为食管腺癌新型放射增敏剂的治疗潜力，为其进一步的临床应用开发提供了依据。
肿瘤(癌症)患者之家