Time Domian Electron Paramagnetic Resonance Imaging

Division Of Basic Sciences - Nci

Investigators

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Abstract

Goals and Summary: The goals of this project are to develop instrumentation, concepts in imaging physics and image reconstruction to provide the ability to non-invasively image properties associated tumor physiology such as tumor oxygenation, tumor microvessel density and tumor blood flow. Using such capabilities, we propose to use them to longitudinally monitor changes in tumor physiology in response to tumor growth, treatment with chemotherapeutic agents and ionizing radiation and the combination. Such capabilities will make it possible to identify temporal profiles of changes in these factors to optimize treatment. Of the various imaging modalities available to determine these properties pertaining to tumor physiology, Electron Paramagnetic Resonance Imaging (EPRI) using paramagnetic tracers has a unique ability to quantitatively provide such information and can be used serially during the tumor growth and also treatment phase. This capability enables monitoring changes in tumor oxygen status in response to treatments such as chemotherapy, anti-angiogenic drug therapy, and radiotherapy and correlate such information with anatomic images and information pertaining to blood vessel density and blood flow. The specific goals of this project are summarized below: 1) Develop and optimize EPR Imaging instrumentation for small animal imaging with capabilities to image tissue oxygen concentration with a spatial resolution of 2 mm in an imaging time of 2 minutes with a pO2 discriminating capability of +/- 3 mm Hg. 2) Develop imaging algorithms improving temporal, spectral (Physiologic) and spatial resolution and co-register the images with those from MRI and also additional physiologic information such as tumor blood vessel density, blood flow, and metabolic profile. 3) Develop image formation methods capable of serially monitoring changes in tumor oxygen status, physiology, and metabolic status in response to treatment. 4) Evaluate strategies to scale up this modality for human applications. Implementation of Slice Selection in EPR Imaging: Imaging two-dimensional (2D) slices of a 3-d object instead of imaging three-dimensional (3D) volume has its own benefits. The scan time of 2D slice is faster by orders of magnitude, data visualization and interpretation is easier with 2D images and there are several software readily available to process 2D images. In MRI, the 3D volume is routinely imaged by collecting a series of 2D slices using slice selecting gradient to confine the signal to only desired slice. After the slice selecting gradient is turned off, the phase-encoding and frequency read out gradients are turned on sequentially to generate the 2D image of desired object. This approach is not practical for EPR imaging because the gradient settling times are much longer than the EPR echo time. Since EPR imaging uses static field gradients, we proposed using modulated field gradient (MFG) to obtain image information from the center area of MFG, the so-called sensitive zero crossover point of the subject. A series of slices of the object are scanned by mechanically shifting the resonator using a high precision slider attached to it. All the images were scanned by FT-EPRI in single point imaging (SPI). This capability in EPR imaging greatly enhances the spatial and temporal resolutions and presents EPR imaging data to the end user in exactly the same format as conventional MRI. Increasing Temporal Resolution of FT-EPRI: The principles of the FT-EPR imager developed in our laboratory are similar to MRI though fundamentally it deals with electron paramagnetic resonance instead of nuclear magnetic resonance. Increasing the scan speed is an active research area in MRI and numerous methods to improve the scan speed and temporal resolution were reported in MRI literature. The similarity between the imaging methods of single point imaging FT-EPRI and MRI allows application of many of those techniques in FTEPRI. Time domain signals are acquired in both FT-EPRI and MRI defining the k-space matrix from which image reconstruction is done by Fourier transformation. The k-space has Hermitian symmetry in which the complex conjugates are equivalent. These properties offer a variety of options to optimize the scan speed. In case of imaging a static object, partial k-space acquisition, exploitation of conjugate symmetry or compressed sensing methods using sparse sampling can speed up data acquisition. In the case of imaging a dynamically changing object, the temporal resolution may be improved by considering static and dynamic regions of the image. The key-hole method is an ancient simple dynamic data acquisition scheme where the central k-space region alone is acquired at each time point (t) in dynamic run. The remaining k space data are substituted from a reference of full k-space acquired either before or after the dynamic acquisition. More comprehensive methods such as k-t BLAST and k-t SENSE allow accelerated data acquisition of k-t space in a specified pattern using single or multiple receiver coils. Further quality improvement of reconstructed image can be accomplished by k-t FOCUSS method using compressed sensing. Incorporating these methods to enhance the temporal resolution of EPR imaging allows probing the dynamics of tumor physiology, which is an active area of interest to probe the phenomenon of cycling tumor hypoxia. Imaging tumor physiology changes with NQO1-mediated cycling in HLRCC: In Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), patients are at risk for aggressive renal tumors caused by the mutation of the TCA cycle enzyme fumarate hydratase. In collaboration with the Urologic Oncology Branch, we identified a therapeutic agent,b-lapachone, that exploits the high level of expression of quinone reductase NQO1 in HLRCC tumors. We found that b-lapachone significantly increased the rate of non-mitochondrial oxygen consumption in cultured HLRCC tumor cells and showed selective toxicity in vitro by the induction of futile NQO1-mediated cycling, which consumes both cytosolic NAD(P)H and oxygen and produces reactive oxygen species (ROS). A pilot experiment demonstrated a reduction in partial pressure of oxygen in an HLRCC tumor xenograft following b-lapachone treatment. We are presently exploring the in vivo therapeutic efficacy and mechanisms of b-lapachone using metabolic imaging. Current efforts include expansion of in vivo metabolic imaging studies to include additional RCC subtypes and imaging modalities such as hyperpolarized 13C MRI to interrogate altered tumor metabolism induced by b-lapachone treatment, as well as testing the in vivo therapeutic efficacy of b-lapachone with rationally chosen combination therapies (i.e. evofosamide) in HLRCC xenograft models. The dynamics of pO2 changes will be probed in tumor xenografts with the imaging capabilities of EPR with enhanced spatial and temporal resolution.