In vivo mapping of tumor oxygen consumption using ¹⁹F MRI relaxometry

Abstract

Recently, we have developed a new electron paramagnetic resonance (EPR) protocol in order to estimate tissue oxygen consumption in vivo. Because it is crucial to probe the heterogeneity of response in tumors, the aim of this study was to apply our protocol, together with (19)F MRI relaxometry, to the mapping of the oxygen consumption in tumors. The protocol includes the continuous measurement of tumor po(2) during the following respiratory challenge: (i) basal values during air breathing; (ii) increasing po(2) values during carbogen breathing until saturation of tissue with oxygen; (iii) switching back to air breathing. We have demonstrated previously using EPR oximetry that the kinetics of return to the basal value after oxygen saturation are mainly governed by tissue oxygen consumption. This challenge was applied in hyperthyroid mice (generated by chronic treatment with L-thyroxine) and control mice, as hyperthyroidism is known to dramatically affect the oxygen consumption rate of tumor cells. Our recently developed snapshot inversion recovery MRI fluorocarbon oximetry technique allowed the po(2) return kinetics to be measured with a high temporal resolution. The kinetic constants (i.e. oxygen consumption rates) were higher for tumors from hyperthyroid mice than from control mice, data that are consistent with our previous EPR study. The corresponding histograms of the (19)F MRI data showed that the kinetic constants displayed a shift to the right for the hyperthyroid group, indicating a higher oxygen consumption in these tumors. The color maps showed a large heterogeneity in terms of oxygen consumption rate within a tumor. In conclusion, (19)F MRI relaxometry allows the noninvasive mapping of the oxygen consumption in tumors. The ability to assess the heterogeneity of tumor response is critical in order to identify potential tumor regions that might be resistant to treatment and therefore produce a poor response to therapy.

Qualification of a Noninvasive Magnetic Resonance Imaging Biomarker to Assess Tumor Oxygenation

“…Although the response to a carbogen breathing challenge does not depend on basal pO 2 (Fig. 5A), as already published (42), the fall in pO 2 induced by CA4 is greater when the basal oxygenation level is higher. This is also assessed using the R 1 of lipids (Fig.…”

“…For that purpose, three MR measurements of each type (global R 1 and R 1 of lipids) were taken sequentially and repeated three times while the subject was breathing air. The gas was then switched to carbogen, and MR measurements were repeated at 10, 15, and 20 minutes after the switch, as it is known that oxygenation is significantly increased after 10 minutes' breathing (42). EPR experiments were subsequently performed on the same tumors.…”

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 .…”

“…Many current methods, such as Eppendorf electrodes [5], near-infrared spectroscopy [6], electron paramagnetic resonance imaging [7], susceptibility magnetic resonance imaging based methods [8] or 19 F magnetic resonance imaging oximetry [6,9] have been used in preclinical studies but have either been highly invasive, nonquantitative, or have lacked spatial resolution. As far as clinically available devices are concerned, MR-based techniques may be of interest, whereby, proton-based-imaging can be used to access blood oxygen change using the BOLD (Blood Oxygen Level-Dependent)…”

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]. ).…”