Modulating tumour metabolism enhances gold nanoparticle radiosensitisation in HPV-negative head and neck cancer

Abstract

Background: Radiotherapy is a major therapeutic modality for locally advanced head and neck cancer. However, the effectiveness of radiotherapy is hindered by resistance mechanisms, most notably hypoxia, leading to unfavourable treatment outcomes. In this study, we investigate the radiosensitising potential of AuNPs in combination with the complex III electron transport chain inhibitor, using models of head and neck cancer. Results: AuNP intracellular accumulation occurred in a concentration-dependent manner and was not influenced by microenvironmental oxygen levels, with citrate capped 15 nm AuNPs readily internalised, accumulating primarily within the cytoplasmic compartment. Pre-treatment with atovaquone had a profound and rapid impact on oxygen consumption, promoting a glycolytic switch under both normoxic and hypoxic conditions, a finding underlined by the concurrent increase in extracellular acidification. AuNPs alone sensitised FaDu cells to radiation under atmospheric oxygen conditions, producing a sensitiser enhancement ratio (SER) of 1.37. In combination with atovaquone, maximum dose enhancements were achieved yielding a SER value of 1.43 and 2.1 under normoxic and hypoxic conditions, respectively. Studies to elucidate the underlying mechanism of radiosensitisation revealed S-phase accumulation and a significant increase in apoptosis. Additionally, combined treatment significantly increased yields of unrepaired DNA double strand breaks, indicating increased yields of DNA double strand break damage. Conclusions: Taken together, we believe this to be the first work providing evidence that AuNP radiosensitisation can be enhanced via metabolic modulation. This study reveals the dual action of both physical and biological pathways of AuNPs radiosensitisation, resulting in superior radiotherapeutic effects.