A New EPR Oximetry Protocol to Estimate the Tissue Oxygen ConsumptionIn Vivo

Abstract

The oxygen consumption rate in tumors affects tumor oxygenation and response to therapies. A new EPR method was developed to measure tissue oxygen consumption non-invasively. The protocol was based on the measurement of pO(2) during a carbogen challenge. The following sequence was used: (1) basal value during air breathing; (2) saturation of tissue with oxygen by carbogen breathing; (3) switch back to air breathing. The assumption was that the kinetics of the return to the basal value after oxygen saturation would be governed mainly by tissue oxygen consumption. This challenge was applied in hyperthyroid mice (generated by chronic treatment with l-thyroxine) and control mice because hyperthyroidism is known to dramatically affect the oxygen consumption rate of tumor and muscle cells. Muscle and tumor cells from the hyperthyroid mice consumed oxygen faster than muscle and tumor cells from the control mice, which is consistent with the results of in vitro studies. Tumor perfusion was not affected by the treatment with l-thyroxine. This method gives an index that may reasonably be ascribed to the local oxygen consumption and has the unique advantage of being adaptable to in vivo studies.

Pulsation-limited oxygen diffusion in the tumour microenvironment

“…We take the decay length of the exponential reduction of the consumption rate λ c  = 120 μm from refs 24 and 25, and the diffusion constant of oxygen as measured both in blood and tissues2627) D  = 2 × 10 −9  m 2 /s. The rates of oxygen consumption in different areas of in vivo tumours have been elegantly and precisely measured, and they have been shown to vary in the range 1.66 10 −4 –5 10 −3  s −1 (mean value 2.16 10 −3  s −1 )282930. Finally, measurements on melanomas31 indicate that the average microvessel diameter is about 5 μm, i.e., R  = 2.5 μm, just enough to let one erythrocyte through.…”

“…Finally, in tumours in vivo the oxygen consumption rate spans the range 1.66 10 −4 –5 10 −3  s −1 (see refs 28-30, 29, 30) (this is very different in cultured tumour cells33 where the rate is contained in the interval 0.0078–1.9 s −1 ). Before attempting a comparison with actual measurements, we list a few distinct classes on the basis of the experimental observations in refs 15, 16, 19, 28, 32 and 34 and references cited therein, and we point out, at least qualitatively, the correspondence between such observations and our mathematical description of tumour hypoxia. We attempt to integrate the information from histological/biochemical analyses152832 with known facts about oxygen flow in solid tumours161934.…”

Perfluorocarbon-loaded lipid nanocapsules as oxygen sensors for tumor tissue pO2 assessment

“…When the vaporizing gas was switched to air, the tumor pO 2 dropped below 50mmHg within 10 minutes to tend to values below 10mmHg within 30 minutes in the presented primary grade IV brain tumor model (Figure 8 B). As previously described, the profile of the pO 2 change with time can be fitted with a monoexponential function whose time constant reflect mainly tumor oxygen consumption as perfusion has a limited effect [9,41]. In the type of tumor explored ( Figure 8C), this time constant (k) was calculated at k= 0.16 min -1 .…”

Perfluorocarbon-Loaded Lipid Nanocapsules to Assess the Dependence of U87-Human Glioblastoma Tumor pO2 on In Vitro Expansion Conditions

“…animals breathing air, as well as after a 20 minute challenge with O 2 . Upon switching back to air, tumor pO 2 was measured over time, and the profile of the pO 2 change was then fitted with a mono-exponential function whose time constant mainly reflected tumor oxygen consumption [20,21]. ).…”