Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications

Abstract

This review paper attempts to provide an overview of the principles and techniques that are often termed electron paramagnetic resonance (EPR) oximetry. The paper discusses the potential of such methods and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment. To help the reader understand the motivation for carrying out these measurements, the importance of tumor hypoxia is first discussed: the basic issues of why a tumor is hypoxic, why these hypoxic microenvironments promote processes driving malignant progression and why hypoxia dramatically influences the response of tumors to cytotoxic treatments will be explained. The different methods that have been used to estimate the oxygenation in tumors will be reviewed. To introduce the basics of EPR oximetry, the specificity of in vivo EPR will be discussed by comparing this technique with NMR and MRI. The different types of paramagnetic oxygen sensors will be presented, as well as the methods for recording the information (EPR spectroscopy, EPR imaging, dynamic nuclear polarization). Several applications of EPR for characterizing tumor oxygenation will be illustrated, with a special emphasis on pharmacological interventions that modulate the tumor microenvironment. Finally, the challenges for transposing the method into the clinic will also be discussed.

Intracellular Hypoxia of Tumor Tissue Estimated by Noninvasive Electron Paramagnetic Resonance Oximetry Technique Using Paramagnetic Probes

“…2,3) Electron paramagnetic resonance (EPR) oximetry can quantify oxygen concentration in a sample using stable nitroxides that can physically interact with molecular oxygen. 4) The EPR linewidth of the paramagnetic probe and oxygen concentration surrounding the probe display a linear relation. When a paramagnetic probe is implanted or administered to a living animal, oxygen concentration in specific tissue can be obtained by EPR spectroscopy or imaging.…”

Botulinum toxin potentiates cancer radiotherapy and chemotherapy.

“…Our data present a paradigm according to which BoNT-A could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of neurogenic contractions of tumor vessels and therefore improving tumor perfusion and oxygenation. To characterize the changes in the tumor microenvironment induced by BoNT-A, we used several powerful tools: contrast-enhanced magnetic resonance imaging (MRI) has been used to measure tumor perfusion noninvasively (13); electron paramagnetic resonance (EPR) oximetry has made it now possible to monitor pO 2 in vivo repeatedly and relatively noninvasively (14,15); and myograph setup has been used to study the particular reactivity of arterioles co-opted by the tumor. We showed a substantial increase in tumor perfusion and oxygenation after BoNT-A administration, which led to a substantial improvement in the response of tumors to radiotherapy and chemotherapy.…”

Complex relationship between changes in oxygenation status and changes in R: The case of insulin and NS‐398, two inhibitors of oxygen consumption

“…It is also unlikely that our paramagnetic or fiberoptic probes would have been systematically implanted in a region with a particular behavior in R* 2 , especially since pixels with changes in R* 2 were randomly distributed rather than grouped in a given region. EPR imaging using soluble materials that are able to diffuse into the area of interest could potentially extend the application of this technique to 3D measurements of oxygen tension, albeit with diminished sensitivity (max 5 mmHg accuracy) (19).…”

“…For postprocessing, tumor voxels that showed no signal enhancement, a linear increase of SI, or atypical signal enhancement curves were excluded by means of a power spectrum analysis and cluster analysis (18,19). Contrast agent concentration as a function of time after P792 injection (C(t)) was estimated using the following equation:…”