Jeremy W. Gordon

Effect of lanthanide ions on dynamic nuclear polarization enhancement and liquid‐state T1 relaxation

In the dynamic nuclear polarization process, microwave irradiation facilitates exchange of polarization from a radicals unpaired electron to nuclear spins at cryogenic temperatures, increasing polarization by >10,000. Doping samples with Gd3+ ions further increases the achievable solid‐state polarization. However, on dissolution, paramagnetic lanthanide metals can be potent relaxation agents, decreasing liquid‐state polarization. Here, the effects of lanthanide metals on the solid and liquid‐state magnetic properties of [1‐13C]pyruvate are studied. The results show that in addition to gadolinium, holmium increases not only the achievable polarization but also the rate of polarization. Liquid‐state relaxation studies found that unlike gadolinium, holmium minimally affects T1. Additionally, results reveal that linear contrast agents dissociate in pyruvic acid, greatly reducing liquid‐state T1. Although macrocyclic agents do not readily dissociate, they yield lower solid‐state polarization. Results indicate that polarization with free lanthanides and subsequent chelation during dissolution produces the highest polarization enhancement while minimizing liquid‐state relaxation. Magn Reson Med, 2012.

In Vivo Imaging and Spectroscopy of Dynamic Metabolism Using Simultaneous

Hyperpolarized (HP) 13C-labeled pyruvate studies with magnetic resonance (MR) have been used to observe the kinetics of metabolism in vivo. Kinetic modeling to measure metabolic rates in vivo is currently limited because of nonspecific hyperpolarized signals mixing between vascular, extravascular, and intracellular compartments. In this study, simultaneous acquisition of both 1H and 13 C signals after contrast agent injection is used to resolve specific compartments to improve the accuracy of the modeling. We demonstrate a novel technique to provide contrast to the intracellular compartments by sequential injection of HP [1-13C] pyruvate followed by gadolinium-chelate to provide T1-shortening to extra-cellular compartments. A kinetic model that distinguishes the intracellular space and includes the T1-shortening effect of the gadolinium chelate can then be used to directly measure the intracellular 13C kinetics.

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New magnetic resonance (MR) molecular imaging techniques offer the potential for noninvasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a three-dimensional dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low- and high-grade tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL ) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1, and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans , attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials. Cancer Res; 77(12); 3207-16. ©2017 AACR.

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To develop symmetric echo planar imaging (EPI) and a reference scan framework for hyperpolarized 13C metabolic imaging.

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To develop a novel imaging technique to reduce the number of excitations and required scan time for hyperpolarized 13C imaging.

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ABSTRACT The availability of clinical-grade cytokines and artificial antigen-presenting cells has accelerated interest in using natural killer (NK) cells as adoptive cellular therapy (ACT) for cancer. One of the technological shortcomings of translating therapies from animal models to clinical application is the inability to effectively and non-invasively track these cells after infusion in patients. We have optimized the nonradioactive isotope fluorine-19 (19F) as a means to label and track NK cells in preclinical models using magnetic resonance imaging (MRI). Human NK cells were expanded with interleukin (IL)-2 and labeled in vitro with increasing concentrations of 19F. Doses as low as 2 mg/mL 19F were detected by MRI. NK cell viability was only decreased at 8 mg/mL 19F. No effects on NK cell cytotoxicity against K562 leukemia cells were observed with 2, 4 or 8 mg/mL 19F. Higher doses of 19F, 4 mg/mL and 8 mg/mL, led to an improved 19F signal by MRI with 3 × 1011 19F atoms per NK cell. The 4 mg/mL 19F labeling had no effect on NK cell function via secretion of granzyme B or interferon gamma (IFNγ), compared to NK cells exposed to vehicle alone. 19F-labeled NK cells were detectable immediately by MRI after intratumoral injection in NSG mice and up to day 8. When 19F-labeled NK cells were injected subcutaneously, we observed a loss of signal through time at the site of injection suggesting NK cell migration to distant organs. The 19F perfluorocarbon is a safe and effective reagent for monitoring the persistence and trafficking of NK cell infusions in vivo, and may have potential for developing novel imaging techniques to monitor ACT for cancer.

Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion

Hyperpolarized carbon-13 magnetic resonance imaging has enabled the real-time observation of perfusion and metabolism in vivo. These experiments typically aim to distinguish between healthy and diseased tissues based on the rate at which they metabolize an injected substrate. However, existing approaches to optimizing flip angle sequences for these experiments have focused on indirect metrics of the reliability of metabolic rate estimates, such as signal variation and signal-to-noise ratio. In this paper we present an optimization procedure that focuses on maximizing the Fisher information about the metabolic rate. We demonstrate through numerical simulation experiments that flip angles optimized based on the Fisher information lead to lower variance in metabolic rate estimates than previous flip angle sequences. In particular, we demonstrate a 20% decrease in metabolic rate uncertainty when compared with the best competing sequence. We then demonstrate appropriateness of the mathematical model used in the simulation experiments with in vivo experiments in a prostate cancer mouse model. While there is no ground truth against which to compare the parameter estimates generated in the in vivo experiments, we demonstrate that our model used can reproduce consistent parameter estimates for a number of flip angle sequences.

Development of a symmetric echo planar imaging framework for clinical translation of rapid dynamic hyperpolarized (13) C imaging.

Hyperpolarized (HP) (13)C labeled compounds can be used as MR contrast agents to investigate metabolic pathways in vivo in almost real time. To date, a high proportion of reported studies have utilized HP 1-(13)C pyruvate to investigate intracellular metabolism in tumors and other tissues. The long T(1) relaxation time of the carboxylate carbon enables the (13)C signal of the pyruvate to be followed for nearly 2 minutes following injection. During this time, pyruvate is rapidly metabolized to generate observable metabolites such as alanine and lactate. HP (13)C labeled compounds have, for example, also been used to non-invasively probe physiological parameters such as pH, which emphasizes the expanding potential of the technique. The commercial availability of dynamic nuclear polarization (DNP) systems to generate hyperpolarized material for injection has made the technique available to researchers worldwide. As a consequence, DNP (13)C MR has become a rapidly expanding area of research. The technique, with its specific strengths and weaknesses, has incredible potential coupled with inherent limitations, and this review aims to both present background to the technique and describe some of the necessary hardware and software essential to perform hyperpolarized (13)C studies. An overview of the current and future role of HP (13)C based molecular imaging is presented.

Joint spatial-spectral reconstruction and k-t spirals for accelerated 2D spatial/1D spectral imaging of 13C dynamics

To develop the use of bipolar gradients to suppress partial‐volume and flow‐related artifacts from macrovascular, hyperpolarized spins.

19F-MRI for monitoring human NK cells in vivo

Hyperpolarized carbon‐13 (13C) metabolic imaging is a noninvasive imaging modality for evaluating real‐time metabolism. The purpose of this study was to develop and implement experimental strategies for using [1‐13C]pyruvate to probe in vivo metabolism for patients with brain tumors and other neurological diseases.