Hypoxia is the condition of low tissue oxygenation that is present in various disease states such as cancer and pulmonary disease. Hypoxia arises from solid tumors outgrowing their own vasculature. Hypoxia inducible factor 1a (HIF-1a) is a subunit of the HIF-1 heterodimer that is activated in hypoxic conditions. Its binding with HIF-1b affects a multitude of downstream targets including upregulation of reductive enzymes such as nitroreductase to suppress apoptosis and promote angiogenesis in the tumor micro-environment. Much of the current research to detect hypoxia in living systems revolves around the production of optical dyes sensitive to O2. However, fluorescence-based detection inherently lacks sensitivity due to background autofluorescence, light scattering, and photobleaching effects. Chemiluminescence (CL) overcomes key drawbacks of fluorescence-based imaging through light production by an endogenous source, drastically increasing signal-to-noise contrast while providing high spatiotemporal resolution. Here, we present HyCL-3 as a CL reporter for the detection of hypoxia in vivo. HyCL-3 contains a nitroaromatic group that is reduced under hypoxic conditions. Electron donation into the benzene ring from the newly formed amine causes self-immolative cleavage of the handle from the scaffold, initiating decomposition of the highly energetic dioxetane bond through chemically initiated electron exchange luminescence. HyCL-3 is a stark improvement on previous hypoxia probes developed in our laboratory, as molecular changes in the chemiluminescent scaffold dramatically increase CL emission efficiency and quantum yields. HyCL-3 is highly sensitive and selective, and will be applied for in vivo imaging of hypoxia.

Reaction based chemiluminescent probe for nitroreductase and hypoxia in vivo

255th National Meeting (2018)

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