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...

Dynamic contrast-enhanced MRI (DCEMRI) data were acquired from metastatic and nonmetastatic tumors in rodents to follow the uptake and washout of a low-molecular-weight contrast agent (Gd-DTPA) and a contrast agent with higher molecular weight (P792). The concentration vs. time curves calculated for the tumor rims and centers were analyzed using the two-compartment model (TCM) and a newly developed empirical mathematical model (EMM). The EMM provided improved fits to the experimental data compared to the TCM. Parameters derived from the empirical model showed that the contrast agent washout rate was significantly slower in metastatic tumors than in nonmetastatic tumors for both Gd-DTPA (P < 0.03) and P792 (P < 0.04). The effects of the tumor on blood flow in "normal" tissue immediately adjacent to the tumors were evident: Gd-DTPA uptake and washout rates were much lower in muscle near the tumor (P < 0.05) than normal muscle farther from the tumor. The results suggest that accurate fits of DCEMRI data provide kinetic parameters that distinguish between metastatic and relatively benign cancers. In addition, a comparison of the dynamics of Gd-DTPA and P792 provides information regarding the microenvironment of tumors.

Perfluorocarbon (PFC) emulsions can be imaged directly by fluorine-19 MRI. We developed an optimized protocol for preparing PFC droplets of uniform size, evaluated use of the resulting droplets as blood pool contrast agents, studied their uptake by tumours and determined the spatial resolution with which they can be imaged at 4.7 T. Perfluorocarbon droplets of three different average sizes (324, 293 and 225 nm) were prepared using a microemulsifier. Images of PFC droplets with good signal-to-noise ratio were acquired with 625 microm in-plane resolution, 3 mm slice thickness and acquisition time of approximately 4.5 min per image. Kinetics of washout were determined using a simple mathematical model. The maximum uptake of the PFC droplets was three times greater at the tumour rim than in muscle, but the washout rate was two to three times slower in the tumour. The results are consistent with leakage of the droplets into the tumour extravascular space due to the hyper-permeability of tumour capillaries. PFC droplets may allow practical and quantitative measurements of blood volume and capillary permeability in tumours with reasonable spatial resolution.

No abstract

MRI detects changes in blood-oxygenation-level dependent (BOLD) contrast in tumors caused by tumor oxygenating agents. These changes can be used to guide the design of improved tumor oxygenating treatments (TOXs). The conventional approach to detection of BOLD effects assumes that the water resonance is a single, homogeneously broadened Lorentzian line, and that changes in the T2* of this line owing to changes in deoxyhemoglobin are spectrally homogeneous. This model may not adequately describe BOLD contrast changes in complex water resonances that are often detected in tumors. The present work investigated: (a) whether changes in the water resonance in very small voxels caused by tumor oxygenating agents are spectrally inhomogeneous; and (b) whether high spectral and spatial resolution (HiSS) MRI of the water and fat resonances detects these changes more accurately than conventional gradient-recalled echo (GRE) imaging. Carbogen (95% oxygen, 5% CO2) was used to increase tumor oxygenation. In two tumor models [mammary adenocarcinoma (R3230Ac; n=5) and rhabdomyosarcoma (BA1112; n=5)] proton signals were often complex and inhomogeneously broadened. Spectrally inhomogeneous changes during carbogen breathing occurred in at least 10% of the R3230AC tumor voxels that responded to carbogen and 18% of BA1112 tumor voxels. The largest changes during carbogen breathing in many voxels occurred at frequencies that were significantly different from the frequency of the primary water peak. Carbogen-induced changes in proton T2* detected by simulated GRE and HiSS differed by more than 75% in 67% of voxels in R3230Ac tumors and in 65% of voxels in BA1112 tumors. The spectrally inhomogeneous effects of tumor oxygenating agents may reflect changes in sub-voxelar microenvironements and thus may be important for accurate evaluation of the effects of therapy.