title: Delivery rate affects uptake of a fluorescent glucose analog in murine metastatic breast cancer.
abstract: We demonstrate an optical strategy using intravital microscopy of dorsal skin flap window chamber models to image glucose uptake and vascular oxygenation in vivo. Glucose uptake was imaged using a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). SO2 was imaged using the differential absorption properties of oxygenated [HbO2] and deoxygenated hemoglobin [dHb]. This study was carried out on two sibling murine mammary adenocarcinoma lines, 4T1 and 4T07. 2-NBDG uptake in the 4T1 tumors was lowest when rates of delivery and clearance were lowest, indicating perfusion-limited uptake in poorly oxygenated tumor regions. For increasing rates of delivery that were still lower than the glucose consumption rate (as measured in vitro), both 2-NBDG uptake and the clearance rate from the tumor increased. When the rate of delivery of 2-NBDG exceeded the glucose consumption rate, 2-NBDG uptake decreased with any further increase in rate of delivery, but the clearance rate continued to increase. This inflection point was not observed in the 4T07 tumors due to an absence of low delivery rates close to the glucose consumption rate. In the 4T07 tumors, 2-NBDG uptake increased with increasing rates of delivery at low rates of clearance. Our results demonstrate that 2-NBDG uptake in tumors is influenced by the rates of delivery and clearance of the tracer. The rates of delivery and clearance are, in turn, dependent on vascular oxygenation of the tumors. Knowledge of the kinetics of tracer uptake as well as vascular oxygenation is essential to make an informed assessment of glucose demand of a tumor.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.
authors.forename: Narasimhan
authors.initials: N
authors.lastname: Rajaram
authors.forename: Amy E
authors.initials: AE
authors.lastname: Frees
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Fontanella
authors.forename: Jim
authors.initials: J
authors.lastname: Zhong
authors.forename: Katherine
authors.initials: K
authors.lastname: Hansen
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Nirmala
authors.initials: N
authors.lastname: Ramanujam
mesh_terms: D009327:4-Chloro-7-nitrobenzofurazan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000378:metabolism*; D000860:Hypoxia; D007700:Kinetics; D051379:Mice; D009362:Neoplasm Metastasis; D010101:Oxygen Consumption; D012039:Regional Blood Flow; D013458:Sulfur Dioxide / Q000378:metabolism; D013997:Time Factors
chemical_list: D005456:Fluorescent Dyes; D013458:Sulfur Dioxide; D003847:Deoxyglucose; D009327:4-Chloro-7-nitrobenzofurazan; C098340:2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose