Affiliation:
1. Department of Chemistry University of Warwick CV4 7AL Coventry UK
2. School of Engineering & Physical Sciences Heriot‐Watt University EH14 4AS Edinburgh UK
3. School of Chemistry University of Birmingham Edgbaston B15 2TT Birmingham UK
Abstract
AbstractHypoxia 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 RuNH2 complex. Thus, the aniline mustard triggers generation of reactive oxygen species (ROS) and mtDNA crosslinking. Meanwhile, the resultant biologically benign phosphorescent RuNH2 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 (IC50 = 2.3 µm for hypoxic HepG2 cancer cells vs 58.2 µm for normoxic THL‐3 normal cells). This is the first report of a metal‐based compound developed as a multimodal theranostic agent for hypoxia.
Funder
Natural Science Foundation of Guangdong Province
Engineering and Physical Sciences Research Council
Subject
Mechanical Engineering,Mechanics of Materials,General Materials Science
Cited by
5 articles.
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