Anticancer Agent with Inexplicable Potency in Extreme Hypoxia: Characterizing a Light-Triggered Ruthenium Ubertoxin

Tumor hypoxia renders treatments ineffective that are directly (e.g., radiotherapy and photodynamic therapy) or indirectly (e.g., chemotherapy) dependent on tumor oxygenation. This study introduces a ruthenium compound as a light-responsive anticancer agent that is water-soluble, has minimal dark cytotoxicity, is active at concentrations as low as 170 pM in ∼18.5% O₂ normoxia and near 10 nM in 1% O₂ hypoxia, and exhibits phototherapeutic indices as large as >500,000 in normoxia and >5,800 in 1% O₂ hypoxia using broadband visible and monochromatic blue light treatments. These are the largest values reported to date for any compound class. We highlight the response in four different cell lines to improve rigor and reproducibility in the identification of promising clinical candidates.