Lithium phthalocyanine (LiPc) is a prototype of another generation of synthetic, metallic-organic, paramagnetic crystallites that appear very useful for in vitro and in vivo electron paramagnetic resonance oximetry. The peak-to-peak line width of the electron paramagnetic resonance spectrum of LiPc is a linear function ofthe partial pressure ofoxygen (PO2); this linear relation is independent of the medium surrounding the LiPc. It has an extremely exchange-narrowed spectrum (peak-to-peak line width = 14 mG in the absence of 02). Physicochemically LiPc is very stable; its response to pO2 does not change with conditions and environments (e.g., pH, temperature, redox conditions) likely to occur in viable biological systems. These characteristics provide the sensitivity, accuracy, and range to measure physiologically and pathologically pertinent 02 tensions (0.1-50 mmHg; 1 mmHg = 133 Pa). The application of LiPc in biological systems is demonstrated in measurements of PO2 in vivo in the heart, brain, and kidney of rats.The purpose of this article is to describe a technology based on electron paramagnetic resonance (EPR or equivalently, electron spin resonance, ESR) that can significantly improve the ability to measure the partial pressure of 02 (PO2) under biologically pertinent conditions in vitro, in vivo, and potentially in human subjects. This article focuses on a prototype ofa class of crystalline paramagnetic probes, lithium phthalocyanine (LiPc), and aims at providing sufficient detail to facilitate the use of these probes in viable biological systems. The critical capabilities of this technology are the ability to measure PO2 at the levels (usually <40 mmHg and can be as low as 0.1 mmHg; 1 mmHg = 133 Pa) and sites (e.g., in tissues in vivo and inside cells) needed to understand biological processes.
The development and use of in vivo techniques for strictly experimental applications in animals has been very successful, and these results now have made possible some very attractive potential clinical applications. The area with the most obvious immediate, effective and widespread clinical use is oximetry, where EPR almost uniquely can make repeated and accurate measurements of pO 2 in tissues. Such measurements can provide clinicians with information that can impact directly on diagnosis and therapy, especially for oncology, peripheral vascular disease and wound healing. The other area of immediate and timely importance is the unique ability of in vivo EPR to measure clinically significant exposures to ionizing radiation 'after-the-fact', such as may occur due to accidents, terrorism or nuclear war. There are a number of other capabilities of in vivo EPR that also potentially could become extensively used in human subjects. In pharmacology the unique capabilities of in vivo EPR to detect and characterize free radicals could be applied to measure free radical intermediates from drugs and oxidative process. A closely related area of potential widespread applications is the use of EPR to measure nitric oxide. These often unique capabilities, combined with the sensitivity of EPR spectra to the immediate environment (e.g. pH, molecular motion, charge) have already resulted in some very productive applications in animals and these are likely to expand substantially in the near future. They should provide a continually developing base for extending clinical uses of in vivo EPR. The challenges for achieving full implementation include adapting the spectrometer for safe and comfortable measurements in human subjects, achieving sufficient sensitivity for measurements at the sites of the pathophysiological processes that are being measured, and establishing a consensus on the clinical value of the measurements.
Localized electron spin resonance spectroscopy in live mice was performed using a surface coil operating at 1.1 GHz with sufficient sensitivity and stability to measure quantitatively the time course of the distribution, uptake, and reduction of nitroxides in selected organs/regions (liver, bladder, head) of mice. The ability to measure regional concentrations of nitroxides in vivo could be used for pharmacokinetic analysis of drugs labeled with nitroxides and for measurement of oxygen concentrations and redox metabolism.
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