A Concerted Redox‐ and Light‐Activated Agent for Controlled Multimodal Therapy against Hypoxic Cancer Cells

Abstract Hypoxia represents a remarkably exploitable target for cancer therapy, is encountered only in solid human tumors, and is highly associated with cancer resistance and recurrence. Here, a hypoxia‐activated mitochondria‐accumulated Ru(II) polypyridyl prodrug functionalized with conjugated azo (Az) and nitrogen mustard (NM) functionalities, RuAzNM, is reported. This prodrug has multimodal theranostic properties toward hypoxic cancer cells. Reduction of the azo group in hypoxic cell microenvironments gives rise to the generation of two primary amine products, a free aniline mustard, and the polypyridyl RuNH 2 complex. Thus, the aniline mustard triggers generation of reactive oxygen species (ROS) and mtDNA crosslinking. Meanwhile, the resultant biologically benign phosphorescent RuNH 2 gives rise to a diagnostic signal and signals activation of the phototherapy. This multimodal therapeutic effect eventually elevates ROS levels, depletes reduced nicotinamide adenine dinucleotide (NADH) and adenosine triphosphate (ATP), and induces mitochondrial membrane damage, mtDNA damage, and ultimately cell apoptosis. This unique strategy allows controlled multimodal theranostics to be realized in hypoxic cells and multicellular spheroids, making RuAzNM a highly selective and effective cancer‐cell‐selective theranostic agent (IC 50 = 2.3 µ m for hypoxic HepG2 cancer cells vs 58.2 µ m for normoxic THL‐3 normal cells). This is the first report of a metal‐based compound developed as a multimodal theranostic agent for hypoxia.