title: In Vivo Chemiluminescent Imaging Agents for Nitroreductase and Tissue Oxygenation.
abstract: Tissue oxygenation is a driving parameter of the tumor microenvironment, and hypoxia can be a prognostic indicator of aggressiveness, metastasis, and poor response to therapy. Here, we report a chemiluminescence imaging (CLI) agent based on the oxygen-dependent reduction of a nitroaromatic spiroadamantane 1,2-dioxetane scaffold. Hypoxia ChemiLuminescent Probe 2 (HyCL-2) responds to nitroreductase with ∼170-fold increase in luminescence intensity and high selectivity for enzymatic reductase versus other small molecule reductants. HyCL-2 can image exogenous nitroreductase in vitro and in vivo in living mice, and total luminescent intensity is increased by ∼5-fold under low oxygen conditions. HyCL-2 is demonstrated to report on tumor oxygenation during an oxygen challenge in H1299 lung tumor xenografts grown in a murine model as independently confirmed using multispectral optoacoustic tomography (MSOT) imaging of hemoglobin oxygenation.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.affiliation: Prognostic Imaging Research Laboratory (PIRL), Pre-clinical Imaging Section, Department of Radiology, UT Southwestern Medical Center , Dallas, Texas 75390-9058, United States.
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Prognostic Imaging Research Laboratory (PIRL), Pre-clinical Imaging Section, Department of Radiology, UT Southwestern Medical Center , Dallas, Texas 75390-9058, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Prognostic Imaging Research Laboratory (PIRL), Pre-clinical Imaging Section, Department of Radiology, UT Southwestern Medical Center , Dallas, Texas 75390-9058, United States.
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Mason
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lippert
mesh_terms: D000818:Animals; D049408:Luminescent Agents / Q000737:chemistry*; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000378:metabolism; D009601:Nitroreductases / Q000378:metabolism*; D061848:Optical Imaging; D010100:Oxygen / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D049408:Luminescent Agents; D009601:Nitroreductases; D010100:Oxygen