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Flux through multicellular layers of a technetium-99m-nitroimidazole for imaging hypoxia
Tricia Melo1, Jonathan K Tunggal, James R Ballinger
1Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, Toronto, Canada.
Abstract:
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.
Insights
BRU59-21, a tumor hypoxia marker, shows metabolism that releases its radioactive label. This metabolism, not depletion, may limit its ability to selectively label hypoxic tumor cells.
Area of Science:
- Radiopharmaceutical chemistry
- Tumor biology
- Medical imaging
Background:
- BRU59-21 is a technetium-99m-nitroimidazole evaluated for noninvasive tumor hypoxia detection.
- Potential limitations include metabolic depletion affecting its tumor cell penetration.
Purpose of the Study:
- To assess BRU59-21 diffusion and metabolism in hypoxic environments using an in vitro model.
- To determine if metabolic depletion or drug metabolism impacts its efficacy in targeting hypoxic cells.
Main Methods:
- Utilized a multicellular layer (MCL) system, an in vitro model of the tumor's extravascular space.
- Measured the flux of radioactivity through the MCL under varying oxygen concentrations.
- Analyzed the composition of radioactivity passing through hypoxic MCLs.
Main Results:
- Radioactivity flux was oxygen-dependent, decreasing under hypoxia.
- Increased metabolism of BRU59-21 was observed in hypoxic conditions compared to aerobic conditions.
- Metabolites included unmetabolized BRU59-21 and significant amounts of free pertechnetate.
- The observed oxygen dependency required the nitroimidazole group and an enzymatic process.
Conclusions:
- Metabolic depletion is not the primary limitation for BRU59-21 reaching hypoxic cells.
- Drug metabolism, leading to radioactive label release, may hinder selective labeling of hypoxic cells in solid tumors.