Quantitative tumor oxymetric images from 4D electron paramagnetic resonance imaging (EPRI): Methodology and comparison with blood oxygen level‐dependent (BOLD) MRI

Abstract

This work presents a methodology for obtaining quantitative oxygen concentration images in the tumor-bearing legs of living C3H mice. The method uses high-resolution electron paramagnetic resonance imaging (EPRI). Enabling aspects of the methodology include the use of injectable, narrow, single-line triaryl methyl spin probes and an accurate model of overmodulated spectra. Both of these increase the signal-to-noise ratio (SNR), resulting in high resolution in space (1 mm) 3 and oxygen concentrations (ϳ3 torr). Thresholding at 15% the maximum spectral amplitude gives leg/tumor shapes that reproduce those in photographs. The EPRI appears to give reasonable oxygen partial pressures, showing hypoxia (ϳ0 -6 torr, 0 -10 3 Pa) in many of the tumor voxels. EPRI was able to detect statistically significant changes in oxygen concentrations in the tumor with administration of carbogen, although the changes were not in- The central role of oxygen in virtually all life processes as the ultimate oxidative substrate for metabolism is well known (1). Oxygenation has a crucial effect on the malignant state (2). Lack of oxygen in a tissue (hypoxia) appears to predispose its surviving cells to mutagenesis, thereby increasing the likelihood that a malignant state will develop (3). Hypoxia affects, most often detrimentally, treatment with conventional anticancer therapies (4). In particular, radiation has been known for nearly a century to be potentiated by oxygen and inhibited by hypoxia (5).Electron paramagnetic resonance imaging (EPRI) can provide a quantitative image of the oxygen concentrations in tissues and tumors of living animals (6,7). The image derives from the EPR spectrum of the unpaired electron from a stable injected spin probe. Oxygen is measured in the distributional compartment of the spin probe. The EPR linewidth is a direct measure of the frequency with which the spin probe encounters molecular oxygen, and is directly proportional to the oxygen concentration (8). One great advantage to imaging the EPR linewidth (and not the line height) is the desensitization to other aspects of the animal or tissue physiology, such as the vasculature. The spectral line height (but not the linewidth) depends on the effectiveness of the delivery of the spin probe to a voxel. Within broad limits, the line height depends on the operating conditions of the imager and the complicated RF distributions in an animal, whereas the linewidth does not.The approach described herein differs from that taken by other groups pursuing in vivo EPRI. Spectral-spatial imaging and in vivo spectral-spatial imaging have been described previously (9,10). In vivo spectral-spatial EPRI for small animals has also been discussed by us and other researchers (6,(11)(12)(13)(14)(15). The present work takes spectralspatial imaging to its logical conclusion: obtaining a full spectrum from each voxel and fitting that spectrum to an accurate spectral shape function with adjustable spectral parameters. These spectral parameters contain the physiologic information fr...

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

“…119 The recent development of triarylmethyl radicals (Fig. 4) has significantly expanded the potential for using oxygen-sensitive free radicals in EPR, [156][157][158] EPR imaging 128,159,160 and related techniques such as dynamic nuclear polarization. [161][162][163] In human blood, the stability of triarylmethyl radicals varies from a half-life of a few hours to one of more than 24 h depending on the particular structure of the compound.…”

“…129 Spectral-spatial EPR imaging encodes both the spatial distribution of the spin probe and the spectral information, which allows mapping of molecular oxygen. 159,160,[191][192][193][194][195][196][197][198] For this purpose, the use of soluble EPR materials such as trityl radicals is more convenient as they can diffuse in the whole tissue. Compared with one-site and multisite EPR spectroscopy, there is a significant gain in terms of spatial information.…”

Cardiac applications of EPR imaging

“…Halpern et al have recently succeeded in enhancing the capability of 4D spectral-spatial imaging and obtained well-resolved oxygen maps in murine tumors. 11,12 Further improvements in sensitivity and speed of data collection of this instrumentation should enable further extension and application of this powerful technique to obtain quantitative oxygen mapping in living tissues.…”

“…3,6 During the last few years significant progress has been made to enable the performance of EPR imaging of biological samples with improved image modality, resolution and quality to obtain useful information. [9][10][11][12][13][14][15][16][17][18] Over the last decade we have focused on developing instrumentation optimized for measurements of free radicals in isolated beating hearts, and in recent several years we have extended our efforts to develop hardware and software to enable spatial and spectral-spatial imaging of free radicals in the heart. 9,[19][20][21][22][23][24][25] This review provides a summary of the development and application of the imaging techniques with examples including imaging of stable free radical labels, oxygen concentrations and nitric oxide generation in the normal or ischemic heart.…”

Tissue oxygenation in sepsis; new insights from in vivo EPR

“…This area of work has attracted much recent interest with particular advances in imaging tumours. 35 Its limitation is currently the development of appropriate software capable of extrapolating accurate line widths from the accumulated data to generate a pO 2 map. In addition, unlike spectroscopy, the time required to acquire an image (>20 min) often limits the study of physiological events.…”