title: Metabolic imaging of tumors using intrinsic and extrinsic fluorescent markers.
abstract: One of the biochemical "hallmarks" of malignancy is enhanced tumor glycolysis, which is primary due to the overexpression of glucose transporters (GLUTs) and the increased activity of mitochondria-bound hexokinase in tumors. Easy methods for assessing glucose utilization in vitro and in vivo should find widespread application in biological and biomedical studies, as illustrated by the adoption of FDG PET imaging in medicine. We have recently synthesized a new NIR fluorescent pyropheophorbide conjugate of 2-deoxyglucose (2DG), Pyro-2DG, as a GLUT-targeted photosensitizer. In this study, we have evaluated the in vivo uptake of Pyro-2DG and found that Pyro-2DG selectively accumulated in two tumor models, 9L glioma in the rat and c-MYC-induced mammary tumor in the mouse, compared to surrounding normal muscle tissues at a ratio of about 10:1. By simultaneously performing redox ratio and fluorescence imaging, a high degree of correlation between the PN/(Fp+PN) redox ratio, where PN denotes reduced pyridine nucleotides (NADH) and Fp denotes oxidized flavoproteins, and the Pyro-2DG uptake was found in both murine tumor models, indicating that Pyro-2DG could serve as an extrinsic NIR fluorescent metabolic index for the tumors. The fact that only a low level of correlation was observed between the redox ratio and the uptake of Pyro-acid (the free fluorophore without the 2-deoxyglucose moiety) supports the hypothesis that Pyro-2DG is an index of the mitochondrial status (extent of PN reduction) of a tumor.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Lanlan
authors.initials: L
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Qingming
authors.initials: Q
authors.lastname: Luo
authors.forename: Jerry
authors.initials: J
authors.lastname: Glickson
authors.forename: Britton
authors.initials: B
authors.lastname: Chance
authors.forename: Gang
authors.initials: G
authors.lastname: Zheng
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D005260:Female; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008657:Metabolic Clearance Rate; D008856:Microscopy, Fluorescence / Q000379:methods*; D009928:Organ Specificity; D051381:Rats; D011916:Rats, Inbred F344; D013050:Spectrometry, Fluorescence / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D014408:Biomarkers, Tumor; D005456:Fluorescent Dyes; C500580:pyropheophorbide 2-deoxyglucose; D003847:Deoxyglucose