In situ Oxygen Generation by Low-Toxicity Ruthenium Electrocatalyst for Multimodal Radiotherapy Sensitization

Abstract

The efficacy of radiotherapy is often significantly compromised due to tumor hypoxia. In this work, we develop a novel strategy to overcome tumor hypoxia and enhance radiotherapy by using low-toxicity catalyst with high-Z atom to in situ electrocatalytic generate oxygen in tumor to effectively improve the hypoxic state and sensitize the radiotherapy. By employing multi-dentate chelating ligands in conjunction with high-Z Ru metal center, we successfully constructed a low-toxicity electrocatalyst for water oxidation, Ru(bbp)(Py)2Cl. On one hand, Ru(bbp)(Py)2Cl serves as a low-toxicity catalyst for electrocatalytic oxygen production, improving the hypoxic condition in the tumor; on the other hand, Ru enhances the sensitivity of radiotherapy in response to X-ray, significantly boosting the therapeutic effect. In vitro and vivo experimental results confirm that the in situ electrocatalytic oxygen production strategy can directly generate oxygen within the body, effectively alleviating tumor hypoxia. Furthermore, this strategy employs a multi-faceted sensitization mechanism by producing excess reactive oxygen species, which disrupt mitochondrial function and induce the activation of apoptosis-regulating proteins Caspase-3 and Caspase-9, ultimately triggering the apoptotic process and achieving significant anti-cancer effects. This research not only 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.