In situ oxygen generation by a low-toxicity ruthenium electrocatalyst for multimodal radiotherapy sensitization†

The efficacy of radiotherapy is often significantly compromised due to tumor hypoxia. We developed a novel strategy to overcome tumor hypoxia and enhance radiotherapy using a low-toxicity catalyst with high-Z atoms. We employed in situ electrocatalytic oxygen generation in the tumor to improve the hypoxic state and sensitize radiotherapy. By employing multi-dentate chelating ligands in conjunction with a high-Z Ru metal center, we constructed a low-toxicity electrocatalyst for water oxidation: Ru(bbp)(Py)₂Cl. On the one hand, Ru(bbp)(Py)₂Cl served as a low-toxicity catalyst for electrocatalytic oxygen production, improving the hypoxic condition in the tumor. On the other hand, Ru enhanced the sensitivity of radiotherapy in response to X-ray, significantly boosting the therapeutic effect. In vitro and vivo experimental results revealed that our in situ electrocatalytic oxygen-production strategy could directly generate oxygen within the body, effectively alleviating tumor hypoxia. Furthermore, this strategy employed a multi-faceted sensitization mechanism by producing excess reactive oxygen species, which disrupted mitochondrial function and induced activation of the apoptosis-regulating proteins caspase-3 and caspase-9, ultimately triggering apoptosis and achieving significant anti-cancer effects. This research provides a novel approach to improving the hypoxic environment in tumors, but also opens new avenues for sensitizing radiotherapy, potentially leading to breakthrough advancements in cancer treatment.