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...
Tumor oxygenation predicts cancer therapy response and malignant phenotype. This has spawned a number of oxymetries. Comparison of different oxymetries is crucial for the validation and understanding of these techniques. Electron paramagnetic resonance (EPR) imaging is a novel technique for providing quantitative high-resolution images of tumor and tissue oxygenation. This work compares sequences of tumor pO 2 values from EPR oxygen images with sequences of oxygen measurements made along a track with an Oxylite oxygen probe. Four-dimensional (three spatial and one spectral) EPR oxygen images used spectroscopic imaging techniques to measure the width of a spectral line in each image voxel from a trityl spin probe (OX063, Amersham Health R&D) in the tissues and tumor of mice after spin probe injection. A simple calibration allows direct, quantitative translation of each line width to an oxygen concentration. These four-dimensional EPR images, obtained in 45 minutes from FSa fibrosarcomas grown in the legs of C3H mice, have a spatial resolution of f1mm and oxygen resolution of f3 Torr. The position of the Oxylite track was measured within a 2-mm accuracy using a custom stereotactic positioning device. A total of nine images that involve 17 tracks were obtained. Of these, most showed good correlation between the Oxylite measured pO 2 and a track located in the tumor within the uncertainties of the Oxylite localizability. The correlation was good both in terms of spatial distribution pattern and pO 2 magnitude. The strong correlation of the two modalities corroborates EPR imaging as a useful tool for the study of tumor oxygenation.
The in vivo in situ detection of hydroxyl radical (HO ؒ ) in real time has been one of the great challenges of free radicals in biology. While we have been able to identify this free radical as a secondary biomarker of HO ؒ , the discovery that 5-carboxy-5-methyl-1-pyrroline N-oxide 2 can specifically spin trap HO ؒ at the expense of superoxide (O 2 ؒϪ ) opens new avenues of research. In particular, nitrone 2 will allow us to detect HO ؒ from low doses of radiation in animal tumors in real time.
Custom disposable patient immobilization systems that conform to the patient's body contours are commonly used to facilitate accurate repeated patient setup for imaging and treatment in radiation therapy. However, in small-animal imaging, immobilization is often overlooked or done in a way that is not conducive to reproducible positioning. This has a negative impact on the potential for accurate analysis of serial or multimodality imaging. We present the use of vinyl polysiloxane dental impression material for immobilization of mice for imaging. Four different materials were examined to identify any potential artifacts using magnetic resonance techniques. A water phantom placed inside the cast was used at 4.7 T with magnetic resonance imaging and showed no effect at the center of the image when compared with images without the cast. A negligible effect was seen near the ends of the coil. Each material had no detectable signal using electron paramagnetic resonance imaging at 9 mT. The use of dental material also greatly enhances the use of fiducial markers that can be embedded in the mold. Therefore, image registration is simplified as the immobilization of the animal and fiducials together helps in translating from one image coordinate system to another.
In electron paramagnetic resonance imaging (EPRI), the accumulation of contrast agent in the bladder can create a very large source of signal, often far greater than that of the organ of interest. Mouse model images have become increasingly important in preclinical testing. To minimize bladder accumulation on mouse images, we developed a novel, minimally invasive, MRI/EPRI-friendly procedure for flushing a female mouse bladder. It is also applicable to other imaging techniques, for example, PET, SPECT, etc., where contrast agent accumulation in the bladder is also undesirable. A double-lumen urethral catheter was developed, using a standard IV catheter with a silicone tube extension, having a polyethylene tube threaded into the IV catheter. Flushing of the bladder provides a substantial reduction in artifacts, as shown in images of tumors in mice.
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