Flux through multicellular layers of a technetium-99m-nitroimidazole for imaging hypoxia.
BRU59-21 is a technetium-99m-nitroimidazole being investigated as a noninvasive marker of tumor hypoxia. Metabolic depletion of BRU59-21, which is used at picomolar concentrations, could limit its ability to reach all hypoxic tumor cells. The multicellular layer (MCL) system, an in vitro model of the extravascular space, was used to assess the ability of BRU59-21 to diffuse to, and beyond, the target population of hypoxic cells. The flux of radioactivity through the MCL system was dependent on the oxygen concentration in the gas phase. Decreased flux and increased metabolism of BRU59-21 were observed under hypoxic compared with aerobic conditions. Analysis of the radioactivity, which passes through the hypoxic MCL, revealed that a proportion of the radioactivity was unmetabolized BRU59-21, but a significant fraction was free pertechnetate. The oxygen dependency of the flux of BRU59-21 required the presence of the nitroimidazole group and was not observed at 4 degrees C, indicating an enzymatic process is required to observe this effect. These findings suggest that metabolic depletion of BRU59-21 is not a major limit to its ability to reach hypoxic cells, but drug metabolism resulting in release of the radioactive label may reduce the ability of BRU59-21 to selectively label hypoxic cells in solid tumors.
Melo
Tricia
T
Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, Toronto, Canada.
Tunggal
Jonathan K
JK
Ballinger
James R
JR
Rauth
A Michael
AM
D015687:Cell Hypoxia; D002478:Cells, Cultured; D005110:Extracellular Space; D007093:Imidazoles / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D015609:Organotechnetium Compounds / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D014018:Tissue Distribution
C403973:BRU 59-21; D007093:Imidazoles; D015609:Organotechnetium Compounds; D010100:Oxygen