Absolute oxygen R_1eimaging in vivo with pulse electron paramagnetic resonance

Abstract

Purpose Tissue oxygen (O2) levels are among the most important and most quantifiable stimuli to which cells and tissues respond through inducible signaling pathways. Tumor O2 levels are major determinants of the response to cancer therapy. Developing more accurate measurements and images of tissue O2 partial pressure (pO2), assumes enormous practical, biological, and medical importance. Methods We present a fundamentally new technique to image pO2 in tumors and tissues with pulse electron paramagnetic resonance (EPR) imaging enabled by an injected, nontoxic, triaryl methyl (trityl) spin probe whose unpaired electron’s slow relaxation rates report the tissue pO2. Heretofore, virtually all in vivo EPR O2 imaging measures pO2 with the transverse electron spin relaxation rate, R2e, which is susceptible to the self-relaxation confounding O2 sensitivity. Results We found that the trityl electron longitudinal relaxation rate, R1e, is an order of magnitude less sensitive to confounding self-relaxation. R1e imaging has greater accuracy and brings EPR O2 images to an absolute pO2 image, within uncertainties. Conclusion R1e imaging more accurately determines oxygenation of cancer and normal tissue in animal models than has been available. It will enable enhanced, rapid, noninvasive O2 images for understanding oxygen biology and the relationship of oxygenation patterns to therapy outcome in living animal systems.

In VivoImaging of Tumor Physiological, Metabolic, and Redox Changes in Response to the Anti-Angiogenic Agent Sunitinib: Longitudinal Assessment to Identify Transient Vascular Renormalization

“…EPRI is a method that can noninvasively provide quantitative oxygen images in living subjects (12)(13)(14)27). The information obtained from the serial and quantitative pO 2 imaging experiments with EPRI was found to be useful in monitoring tumor microenvironmental changes during antiangiogenic therapy, and it enables radiation therapy to be delivered during the vascular renormalization window for maximum effect (26,34).…”

“…Epel at al. recently reported the use of longitudinal relaxation time T 1 -based EPR oxygen imaging using the inversion-recovery spin echo method (14). Such T 1 -based EPR oximetry can minimize the effect of self-relaxation and may improve the accuracy of pO 2 measurements during anti-angiogenic treatment.…”

Towards Human Oxygen Images with Electron Paramagnetic Resonance Imaging

“…The rate at which the longitudinal magnetization of an unpaired spin relaxes from an excitation provided by a short (50 ns) pulse of 250 MHz radiofrequency is nearly absolutely proportional to the local concentration of O 2 through Heisenberg spin exchange with one of either of the unpaired O 2 electron spins. 2 Small animal experiments provide a proof of principle that EPR O 2 images can direct local therapies such as radiation to resistant portions of tumors, hypoxic subregions lacking O 2 , that can be a major source of therapeutic failure. 3 …”

A DTI study to probe tumor microstructure and its connection with hypoxia

“…We used pulse EPR inversion recovery methodology for pO 2 image acquisition [8]. 208 equal solid angle projections were acquired with maximum gradient of 15 mT/m and a isotropic field of view of 4.24 cm.…”

“…Oxygen concentration with high precision (<1 torr) can be measured using the established technique, known as electron paramagnetic resonance oxygen imaging (EPROI) [7, 8]. It has been shown recently that by using EPROI pO 2 information, tumor radiation treatment outcome can be predicted, based on a high or low fraction of image voxels less than 10 torr [7].…”