title: Delivery-corrected imaging of fluorescently-labeled glucose reveals distinct metabolic phenotypes in murine breast cancer.
abstract: When monitoring response to cancer therapy, it is important to differentiate changes in glucose tracer uptake caused by altered delivery versus a true metabolic shift. Here, we propose an optical imaging method to quantify glucose uptake and correct for in vivo delivery effects. Glucose uptake was measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-D-glucose (2-NBDG) in mice implanted with dorsal skin flap window chambers. Additionally, vascular oxygenation (SO2) was calculated using only endogenous hemoglobin contrast. Results showed that the delivery factor proposed for correction, "RD", reported on red blood cell velocity and injected 2-NBDG dose. Delivery-corrected 2-NBDG uptake (2-NBDG60/RD) inversely correlated with blood glucose in normal tissue, indicating sensitivity to glucose demand. We further applied our method in metastatic 4T1 and nonmetastatic 4T07 murine mammary adenocarcinomas. The ratio 2-NBDG60/RD was increased in 4T1 tumors relative to 4T07 tumors yet average SO2 was comparable, suggesting a shift toward a "Warburgian" (aerobic glycolysis) metabolism in the metastatic 4T1 line. In heterogeneous regions of both 4T1 and 4T07, 2-NBDG60/RD increased slightly but significantly as vascular oxygenation decreased, indicative of the Pasteur effect in both tumors. These data demonstrate the utility of delivery-corrected 2-NBDG and vascular oxygenation imaging for differentiating metabolic phenotypes in vivo.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Frees
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.
authors.forename: Narasimhan
authors.initials: N
authors.lastname: Rajaram
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: McCachren
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Fontanella
authors.affiliation: Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.
authors.forename: Nimmi
authors.initials: N
authors.lastname: Ramanujam
mesh_terms: D009327:4-Chloro-7-nitrobenzofurazan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D061848:Optical Imaging / Q000379:methods*; D010101:Oxygen Consumption
chemical_list: D001786:Blood Glucose; D005456:Fluorescent Dyes; D003847:Deoxyglucose; D009327:4-Chloro-7-nitrobenzofurazan; C098340:2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose