Hyla Allouche-Arnon^1,2, Trevor Wade³, Rachel Katz-Brull^1,2, Lanette Friesen Waldner³, Valentina N. Miller ¹, J. Moshe Gomori ¹, and Charles A. McKenzie^3
1Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, ²BrainWatch Ltd., Tel-Aviv, Israel, ³Medical Biophysics, The University of Western Ontario, London, Ontario, Canada

A new noninvasive approach for glucose imaging using spin hyperpolarization technology and stable isotope labeling is presented. A glucose analog fully labeled with 13C and directly bonded deuterons, was intravenously injected to rats. Hyperpolarized glucose images in the live rat showed time-dependent organ distribution patterns. At 8 s, during bolus injection, the inferior vena cava was demonstrated at angiographic quality. Distribution of hyperpolarized glucose in the kidneys, vasculature, and heart was demonstrated at 12- and 20 s. The heart-to-vasculature intensity ratio at 20 s suggests myocardial uptake.

Justin Yat Cheong Lau^1,2, Albert P. Chen³, Yi-Ping Gu², Jennifer Barry², and Charles H. Cunningham^1,2
1Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, ²Imaging Research, Sunnybrook Research Institute, Toronto, Ontario, Canada, ³GE Healthcare, Toronto, Ontario, Canada

In order to obtain concentrations of metabolites in physical units from in vivo measurements with hyperpolarized pyruvate, it is necessary to monitor the instantaneous polarization as it decays. We present an empirical model for [1,2-¹³C₂]-pyruvate based on the correlation between the C₂ upfield-to-downfield partial integral ratio and the C₁ polarization in whole pig blood. Using the blood calibration data, we estimate real-time in vivo C₁polarization decay curves from whole pig heart spectroscopic measurements. Polarization estimates obtained by this method are effectively independent of signal amplitude variations due to perfusion and metabolism.

Subramaniam Sukumar¹, Simon Hu¹, Peder E. Larson¹, Vickie Y. Zhang¹, Michael Ohliger¹, Robert Bok¹, John Kurhanewicz¹, and Daniel B. Vigneron^1
1Radiology and Biomedical Imaging, UCSF, San Francisco, CA, United States

13C imaging using hyperpolarized biomarkers require special pulse sequences to efficiently capture the limited magnetization and to measure the dynamically varying metabolite signals. We developed single shot, 2D and 3D dynamic imaging sequences for selectively observing 13C metabolites at 14.1T. The sequences also address some of the limitations on high field systems, such as, wide spectral width and T2* effects. We have applied these new sequences to acquire dynamic, lactate and alanine images from a mouse cancer model with prostate tumor.

Florian Wiesinger¹, Oleksandr Khegai^1,2, Jonathan I Sperl¹, Eliane Weidl², Axel Haase², Markus Schwaiger², and Rolf F Schulte^1
1GE Global Research, Munich, Germany, ²Technische Universitaet Muenchen, Munich, Germany

In this work an efficient and novel frequency-domain signal quantification framework is presented for the analysis and interpretation of dynamically acquired hyperpolarized 13C data. The method is used to compare simple signal normalization versus apparent rate constant estimation for dynamically-acquired, slice-selective FID spectra and IDEAL spiral CS imaging animal rat experiments.

William Dominguez-Viqueira¹, Albert P Chen², and Charles H Cunningham^1,3
1Imaging Research, Sunnybrook Research Institute, Toronto, Ontario, Canada, ²GE Healthcare, Toronto, Ontario, Canada, ³Dept. of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

A rapid spectral-spatial echo-planar imaging pulse sequence was developed previously for time-resolved 3D metabolic imaging with correction for the spatial shifts that occur in practice due to field inhomogeneities. In this work, an automated method was developed to create higher SNR images by correcting the spatial shifts and summing k-space data from multiple time points. Higher SNR maps of the hyperpolarized ¹³C metabolites with excellent contrast were obtained and shown. The tradeoffs between spatial-temporal resolution and image quality inherent in this technique are discussed.

Yi-Fen Yen¹, Sonal Josan^2,3, Lasitha Senadheera⁴, Jae Mo Park^3,5, Atsushi Takahashi¹, Taichang Jang⁶, Milton Merchant⁶, Priti Balchandani³, James Tropp¹, Dirk Mayer^2,3, Lawrence Recht⁶, Lei Xing⁴, Daniel Spielman³, Ralph Hurd¹, and Patrick Le Roux^7
1Global ASL, GE Healthcare, Menlo Park, CA, United States, ²Neuroscience Program, SRI International, Menlo Park, CA, United States, ³Dept. of Radiology, Stanford University, Stanford, CA, United States, ⁴Dept. of Radiation Oncology, Stanford University, Stanford, CA, United States, ⁵Dept. of Electrical Engineering, Stanford University, Stanford, CA, United States, ⁶Dept. of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States, ⁷Global ASL, GE Healthcare, Palaiseau, France

High resolution T₂ mapping of hyperpolarized [1-¹³C]pyruvate and its metabolic products was accomplished by using a novel pulse sequence comprised of a non-CPMG echo train. Approximately 3-fold increase in signal-to-noise ratio (SNR) was obtained by averaging echo-train signals as compared to the SNR of the first spin-echo. This technique was demonstrated in vivo on normal rat liver, mouse prostate cancer model and rat glioma model.

Lin Z Li^1,2, Stephen Kadlececk¹, Ben Pullinger¹, He N. Xu¹, Dania Daye^3,4, Lewis Chodosh³, and Rahim Rizi^1
1Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²Britton Chance Lab of Redox Imaging, Johnson Research Foundation, University of Pennsylvania, Philadelphia, PA, United States, ³Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, United States, ⁴Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States

Various modeling methods have been used to analyze in vivo hyperpolarized ¹³C-NMR data from the lactate dehydrogenase (LDH) reaction, which converts pyruvate to lactate. However, these models make certain assumptions about transport in the blood, across cell membranes, and/or enzymatic kinetics, and require at least 3 modeling parameters. Here we present a new method which relaxes some of these assumptions and minimizes the modeling parameters. By fitting the lactate/pyruvate ratio in mouse tumor models we quantify both the forward and reverse exchange rate constants of the LDH reaction. First order temporal derivatives of the lactate/pyruvate ratio help to determine the proper time range for fitting.

Sonal Josan^1,2, Tao Xu³, Ralph Hurd⁴, Adam Kerr³, Yi-Fen Yen⁴, Dirk Mayer^1,2, and Daniel Spielman^2,3
1Neuroscience Program, SRI International, Menlo Park, CA, United States, ²Radiology, Stanford University, Stanford, CA, United States, ³Electrical Engineering, Stanford University, Stanford, CA, United States, ⁴Applied Science Laboratory, GE Healthcare, Menlo Park, CA, United States

 

Jae Mo Park^1,2, Ralph E Hurd³, Sonal Josan^2,4, Yi-Fen Yen³, Adolf Pfefferbaum^4,5, Dirk Mayer^2,4, and Daniel M Spielman^1,2
1Electrical Engineering, Stanford University, Stanford, CA - California, United States, ²Radiology, Stanford University, Stanford, CA - California, United States, ³Applied Science Laboratory, GE Healthcare, Menlo Park, CA - California, United States, ⁴Neuroscience Program, SRI International, Menlo Park, CA - California, United States, ⁵Psychiatry, Stanford University, Stanford, CA - California, United States

Bi-directional metabolic conversion can be estimated by simultaneously injecting both co-polarized substrates. The amount of flux and isotopic exchange can be estimated by the difference in flow of each substrate. We demonstrate the differentiation of flux and isotopic exchange between Pyr and Lac by injecting polarized [2-13C]Pyr and [1-13C]Lac together, and observed increased flux from Pyr to Lac after EtOH infusion.

Jeremy Gordon¹, Sean B. Fain^1,2, and Kevin Johnson^1
1Medical Physics, University of Wisconsin-Madison, Madison, WI, United States, ²Radiology, University of Wisconsin-Madison, Madison, WI, United States

Hyperpolarization dramatically improves signal from ¹³C labeled molecules; however, the transient polarization must be used efficiently. Highly efficient acquisition trajectories, such as spirals, are well-suited to maximize utilization of hyperpolarization but are limited by off-resonance blurring, forcing short readout duration spirals for imaging. Here, we propose to use ¹H data to provide a field-map estimate, reducing reconstruction of chemically-shifted species to a linear problem. A least-squares technique is presented to directly solve for ¹³C metabolites, generating images corrected for B_oinhomogeneity and with minimal off-resonance blurring. This technique permits non-Cartesian acquisitions with longer readouts, greatly increasing ¹³C spiral CSI efficiency.

Heeseung Lim¹, Kundan Thind¹, Jian-xiong Wang², Andrew Alejski³, Francisco Martinez³, and Timothy J. Scholl^1,3
1Medical Biophysics, University of Western Ontario, London, Ontario, Canada, ²GE Healthcare, Applied Science Laboratory, London, Ontario, Canada,³Imaging Research Laboratories, Robarts Research Institute

A novel dual-frequency birdcage RF coil that is electronically switchable between 13C and 1H imaging modes has been developed for molecular imaging with hyperpolarized substances. PIN diodes in parallel with end-ring capacitors were used to switch the resonator between a band-pass (1H: 127.7 MHz) and a low-pass (13C: 32.1 MHz) configuration using a DC bias. The SNR-efficiency of this combined coil has been systematically compared with that of identical single-frequency coils for each nucleus using phantoms. In vivo imaging of pyruvate metabolism in a healthy rat brain has been demonstrated and co-registered with detailed proton morphology.

Fabio Tedoldi¹, Sonia Colombo Serra^1,2, Magnus Karlsson³, Giovanni Battista Giovenzana^4,5, Camilla Cavallotti⁵, Fulvio Uggeri¹, and Silvio Aime^6
1Centro Ricerche Bracco, Bracco Imaging Spa, Colleretto Giacosa, Torino, Italy, ²Dipartimento di Fisica Sperimentale, Università degli Studi di Torino, Torino, Italy, ³Albeda Research, Copenhagen, Denmark, ⁴Dipartimento di Scienze Chimiche Alimentari Farmaceutiche e Farmacologiche, Università degli Studi del Piemonte Orientale, Novara, Italy, ⁵CAGE Chemicals srl, Novara, Italy, ⁶Dipartimento di Chimica IFM, Università degli Studi di Torino, Torino, Italy

Hyperpolarized 13-C labelled butyric and acetic acids are potentially valuable tracers for investigating cardiac metabolism. Unfortunately they can not be polarized as neat compounds, but only after addition of a glass forming agents which could affect their metabolic fate. Symmetric anhydrides are here proposed as chemical precursors, which can be polarized as such and provide, upon dissolution and hydrolysis, a highly concentrated neat solution of the corresponding acid. In addition, tailored lipophilic derivatives of trityl radicals have been investigated and shown to be suitable polarization agents for anhydrides, that can be easily removed by filtration upon dissolution in aqueous media.

Pedro A Gómez Damian^1,2, Jonathan I Sperl¹, Oleksandr Khegai¹, Stefan Grott¹, Eliane Weidl³, Martin A Janich³, Florian Wiesinger¹, Steffen J Glaser⁴, Axel Haase⁵, Markus Schwaiger³, Rolf F Schulte¹, and Marion I Menzel^1
1GE Global Research, Munich, Germany, ²Tecnologico de Monterrey, Monterrey, Mexico, ³Nuclear Medicine, Technische Universität München, Munich, Germany, ⁴Department Chemie, Technische Universität München, Munich, Germany, ⁵IMETUM, Technische Universität München, Munich, Germany

Quantitation of metabolite conversion through a multi-side kinetic model that involves all downstream metabolites present in MR spectroscopy after injection of [1-13C]pyruvate is presented. This method provides more kinetic data than previously existing methods and parameter interdependency allows a more accurate quantitation that can be useful for the monitoring of metabolic activity. The results are compared to kinetic modeling obtained with two-side integral and two-side differential models.

Simon Hu¹, Peder E Larson¹, Mark VanCriekinge¹, Andrew M Leach², Ilwoo Park¹, Peter J Shin¹, Galen Reed¹, Hikari Yoshihara¹, Robert A Bok¹, Sarah J Nelson¹, John Kurhanewicz¹, and Daniel B Vigneron^1
1Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States, ²Global Research Center, General Electric, Niskayuna, NY, United States

Development of hyperpolarized technology utilizing dynamic nuclear polarization has enabled the measurement of ¹³C metabolism in vivo at very high SNR. Traditionally, consecutive injections of a hyperpolarized compound in an animal have been separated temporally by approximately 1 hour, with the practical minimum time between injections determined by the sample build-up time. The effects of greatly reducing the time separation between injections have not been investigated. In this study, using the new GE SpinLab DNP polarizer with the capability of simultaneously polarizing up to 4 samples, we performed dynamic and 3D echo-planar spectroscopic imaging of [1-¹³C]pyruvate in normal rats. For each rat, three hyperpolarized scans were performed 5 minutes apart. The results demonstrate the feasibility of detecting the uptake and metabolic conversion of HP-pyruvate within sequential acquisitions with repeat injections with a temporal resolution of 5 minutes. In normal rats this method shows minimal changes, indicating the potential for rapid monitoring of the metabolic effects of treatments and/or physiologic interventions on this time scale.

Ralph Hurd¹, Daniel Spielman², Sonal Josan³, Jae Mo Park⁴, Yi-Fen Yen¹, Adolf Pfefferbaum^3,5, and Dirk Mayer^2,3
1GE Healthcare, Menlo Park, CA, United States, ²Radiology, Stanford University, Stanford, CA, United States, ³Neuroscience Program, SRI International, Menlo Park, CA, United States, ⁴Electrical Engineering, Stanford University, Stanford, California, United States, ⁵Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States

In hyperpolarized [1-13C]pyruvate and hyperpolarized [1-13C]lactate metabolic imaging, the pool size of the exchange partner may limit the rate of isotopic mixing. This is especially true for hyperpolarized [1-13C]lactate metabolic imaging, given the small steady-state pyruvate pool. Under conditions where addition of unlabeled exchange partner to the bolus results in a linear increase in rate, absolute values for exchange rate constant (Kexchange) can be determined in both directions. In this study we show that such conditions appear to be true for a bolus of 80mM pyruvate and 40 mM lactate in rat kidney, and use the dynamic imaging data to calculate Kexchange.

Huseyin Kara^1,2, Nicholas N. Kuzma², Philip Manasseh³, Mehrdad Pourfathi², Stephen J. Kadlecek², and Rahim R. Rizi^2
1Astronomy and Physics, University of Pennsylvania, Philadelphia, PA, United States, ²Radiology, University of Pennsylvania, Philadelphia, PA, United States, ³Department of Chemistry, Earlham College, Richmond, IN, United States

In light of ³He shortages, Dynamic Nuclear Polarization (DNP) offers a promising alternative method of producing bulk quantities of hyperpolarized ¹²⁹Xe for human lung imaging. We studied T₁ spin relaxation of ¹²⁹Xe in typical DNP mixtures (xenon/1-propanol/trytil radical) at 1.43 K and 5 T. Specifics of sample preparation as well as thermal history are shown to promote spontaneous creation of pure xenon clusters in the solid matrix, leading to a wide range (100 min - 35 hours) of ¹²⁹Xe T₁ values.

Nicholas N. Kuzma¹, Pär Håkansson², Rajat K. Ghosh¹, Huseyin Kara^1,3, Mehrdad Pourfathi¹, Stephen J. Kadlecek¹, Giuseppe Pileio², Malcolm H. Levitt², and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²School of Chemistry, Southampton University, Southampton, Hempshire, United Kingdom, ³Astronomy and Physics, University of Pennsylvania, Philadelphia, PA, United States

A theoretical model of the solid-state ¹⁵N NMR spectrum in an isotropic ¹⁵N₂O/1-proponal/trityl-radical mixture is presented, which makes it possible to calculate in-situ ¹⁵N polarization directly from the powder-spectrum shape of the measured ¹⁵N NMR peaks. The model is in excellent agreement with the experimental line shape. The maximum ¹⁵N polarization was calculated to be (114)%.

Michael Abram Ohliger¹, Peder E. Z. Larson¹, Robert Bok¹, Simon Hu¹, Peter Shin¹, James Tropp², Lucas Carvajal¹, Sarah J. Nelson¹, John Kurhanewicz¹, and Daniel Vigneron^1
1Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States, ²General Electric Healthcare, Fremont, CA, United States

We implement a combined partial Fourier and self-calibrating parallel MR reconstruction for acquisition of hyperpolarized ¹³C spectroscopic imaging in a rat, achieving an added reduction in scan time of 39% when compared with parallel MRI alone. Using an echo planar spectroscopic imaging sequence, we acquire a 30 x 10 x 16 matrix of spectroscopic voxels within 13 s. The shorter scan time is critical to combat signal loss due to T1 decay, metabolism, and RF saturation. In addition, this acquisition enables the time scale and imaging coverage required for human imaging in vivo.

Lin Z Li^1,2, He N. Xu^1,2, Stephen Kadlececk¹, Kavindra Nath¹, Kejia Cai¹, Hari Hariharan¹, Jerry D. Glickson¹, and Rahim Rizi^1
1Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, University of Pennsylvania, Philadelphia, PA, United States

NAD⁺ (nicotinamide adenine dinucleotide)-coupled redox potential NAD⁺/NADH is a key mediator in many biological processes including metabolism, growth, survival, motility and signaling. It is implicated in pathologies of cardiovascular diseases, diabetes, cancer etc. Despite its importance, non-invasive method for measuring NAD⁺/NADH in tissue has not been developed. This work presents hyperpolarized ¹³C-NMR detection of pyruvate and lactate in tissue as the first non-invasive method to quantify the intracellular NAD⁺/NADH in vivo. We quantified cytosolic redox state in human breast cancer mouse xenografts along with intracellular pH measurement by ³¹P-NMR.

Albert P Chen¹, C.T. Tan², and Charles H Cunningham^3,4
1GE Healthcare, Toronto, ON, Canada, ²Sigma-Aldrich/Isotec, Miamisburg, Ohio, United States, ³Imaging Research, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, ⁴Medical Biophysics, University of Toronto, Toronto, ON, Canada

One of the requirements for obtaining high polarization for organic substrates is that the DNP samples become amorphous solids at low temperature. Although neat pyruvic acid is typically used as the sole substrate in the DNP sample matrix, it may be feasible to use pyruvic acid as the solvent and dissolve other substrates of interest. Not only would this solvent-substrate mixture form a glass at solid state, the safety profile of pyruvate has been determined for administration in humans. In this work, N-acetyl-[1-¹³C]methionine was used to demonstrate the feasibility of utilizing pyruvic acid as the solvent for DNP sample preparation.

Steven Reynolds¹, Joanne Bluff², Samira Kazan², Michael Port³, Emily Wholey², Gillian Tozer², and Martyn Paley^1
1Academic Unit of Radiology, University of Sheffield, Sheffield, South Yorkshire, United Kingdom, ²Tumour microcirculation group, University of Sheffield, Sheffield, United Kingdom, ³Department of Psychology, University of Sheffield, Sheffield, United Kingdom

Dose limitations required for animal well-being restrict the quantity of hyperpolarised substrate that may be administered. Physical constraints for an animal in a MRI scanner can require a long length of cannula for delivery of substrate into the animal, resulting in a significant dead volume. Typically, saline occupies the dead volume of the cannula that constitutes part of the dose but does not contribute to the signal. We have developed an automated flow diverter, which permits the dead volume to be cleared to waste before the desired substrate is injected. We show a significant increase in ¹³C signal as a result of injecting only hyperpolarised substrate.

Maxim Terekhov¹, Jan Krummenacker^1,2, Vasyl Denisenkov², Kathrin Gerz¹, Thomas Prisner², and Laura Maria Schreiber^1
1Section of Medical Physics, Radiology Department, University Medical Center Mainz, Mainz, Germany, ²Institute of Physical and Theoretical Chemistry, Center for Bimolecular Magnetic Resonance Goethe-University, Frankfurt-am-Main, Germany

Dynamic Nuclear Polarization (DNP) is a technique, in which hyperpolarization is achieved by microwave irradiation of electron spins in radicals. The NMR signal enhancement by factor 600 is potentially possible. Typically DNP is achieved in external polarizers at low temperatures. Being optimal for signal enhancements; the requirement to shuttle prohibits the use nuclei with short T1, e.g. 1H. To circumvent these we implemented liquid-state DNP at 1.5T for 1H that allows polarization inside MRI bore close to the imaging objects and continuous-flow delivery of hyperpolarized agent. The fluid micro-jets visualization with resolution of 100 µm was achieved in pilot experiments.

Jae Mo Park^1,2, Lawrence Recht³, Sonal Josan^2,4, Taichang Jang³, Milton Merchant³, Yi-Fen Yen⁵, Ralph E Hurd⁵, Daniel M Spielman^1,2, and Dirk Mayer^2,4
1Electrical Engineering, Stanford University, Stanford, CA - California, United States, ²Radiology, Stanford University, Stanford, CA - California, United States, ³Neurology and Neurological Sciences, Stanford University, Stanford, CA - California, United States, ⁴Neuroscience Program, SRI International, Menlo Park, CA - California, United States, ⁵Applied Science Laboratory, GE Healthcare, Menlo Park, CA - California, United States

We demonstrate that measuring 13C-Bic is feasible to assess PDH flux and effect of DCA in tumor-bearing rat brain by injecting hyperpolarized [1-13C]Pyr. Lac/Bic gave a better contrast between glioma and normal brain, and reflected both pathways to cytoplasmic and mitochondrial metabolism.

Aaron K Grant¹, Elena Vinogradov², Xiaoen Wang¹, Rupal Bhatt³, Robert E Lenkinski², and David C Alsop^1
1Department of Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States, ²Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, ³Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States

Anti-angiogenic therapies can dramatically reduce tumor perfusion and vascular permeability. Here we present the use of hyperpolarized 13C labeled tert-butanol for monitoring changes in tumor perfusion resulting from anti-angiogenic therapy in a model of renal cell carcinoma. Dynamic imaging of with balanced SSFP enables quantification of the reduction in blood flow following treatment. In addition, metabolic imaging was performed with hyperpolarized pyruvate to assess changes in metabolism. In a small pilot study, imaging with tert-butanol indicates reductions in blood flow on the order of 70%, while the change in lactate signal following treatment shows more variability.

Tiago B. Rodrigues^1,2, Mikko I. Kettunen^1,2, David Y. Lewis¹, Ferdia A. Gallagher^1,3, Eva Serrao^1,2, Dmitry Soloviev¹, and Kevin M. Brindle^1,2
1Cambridge Research Institute, Cancer Research UK, Cambridge, United Kingdom, ²Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom, ³Departments of Radiology and Biochemistry, University of Cambridge, Cambridge, United Kingdom

Our main goal was to assess if hyperpolarized [1-¹³C]-pyruvate MRS could detect response within 24 hours of cyclophosphamide treatment in a Myc-driven lymphoma model and to compare it with FDG. Our results showed a 70% reduction in the pyruvate-lactate flux following treatment, whereas a more modest change was seen in FDG-PET. This demonstrates the feasibility of using hyperpolarized ¹³C-pyruvate to detect early treatment response in a transgenic mouse of lymphoma, being potentially a complement of FDG-PET as a clinical tool.

Steven Reynolds¹, Samira Kazan², Joanne Bluff², Emily Wholey², Martyn Paley¹, and Gillian Tozer^2
1Academic Unit of Radiology, University of Sheffield, Sheffield, South Yorkshire, United Kingdom, ²Tumour microcirculation group, University of Sheffield, United Kingdom

The influence of tumour oxygenation state was determined by administering hyperpolarised 13C1-pyruvic acid (PA) and determining the conversion rate, kpl, to lactate. The tumour’s oxygenation state was concurrently monitored during MR experiments using invasive Oxylite fluorescent probes. P22 carcinosarcoma-bearing BD1X rats were anaesthetised and femoral cannulations performed for drug administration/blood pressure monitoring. Tumour pO2 was manipulated by supplying either normal air or hypoxia (10% O2, 4% CO2, balance N2). 5ml/kg of hyperpolarised 13C-PA was injected and slice-localised 13C spectroscopic data acquired using a 20mm 13C, 1H surface coil positioned over the tumour in a Bruker 7T MRI system Integral versus time responses curves for pyruvate and lactate were fitted to a one-way exchange model and kpl values extracted. Date for n=6 animals showed that rate of conversion of pyruvate to lactate, kpl, increases under hypoxic conditions.

Ilwoo Park¹, Cornelius von Morze¹, Jan H Ardenkjaer-Larsen², Janine M Lupo¹, Motokazu Ito³, Joydeep Mukherjee³, Joanna J Phillips³, Russell O Pieper³, Daniel B Vigneron¹, and Sarah J Nelson^1,4
1Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States, ²GE Healthcare, Broendby, Denmark, ³Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States,⁴Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States

We have demonstrated the feasibility of using hyperpolarized HP001 for investigating tumor perfusion in an orthotopic human GBM model. Distinct HP001 characteristics were found between tumor and normal tissues. HP001 data were strongly correlated with the data from the conventional Gd-based DSC imaging and consistent with the findings from immunohistochemical analysis. The results of this study suggest that this technique may provide an alternate way to evaluate tumor perfusion for brain tumors, which could be applied in patient studies.

Marion I Menzel¹, Eliane Weidl², Martin A Janich², Oleksandr Khegai¹, Florian Wiesinger¹, Axel Haase³, Rolf F Schulte¹, and Markus Schwaiger^2
1GE Global Research, Munich, Germany, ²Nuclear Medicine, Technische Universität München, Munich, Germany, ³IMETUM, Technische Universität München, Munich, Germany

In vivo biochemical imaging using hyperpolarized [1-13C]pyruvate and 18F-FDG PET in HCC tumor rats was compared. Findings for uptake, compartmentalization of signal and overall tumor visibility were correlated with physiological and biochemical data. While all tumors showed high signal in PET, integrated metabolite images shown only 40 % (pyruvate) and 70 % (lactate) of all tumors. Analysis of 13C signal dynamics revealed a statistically higher proportion of pyruvate reaching the gastrointestinal tract (GIT) than the tumors, with tumors exhibiting higher turnover of pyruvate to lactate and alanine than GIT, indicating a compartmentalization effect of [1-13C]pyruvate and its downstream me-tabolites.

Peder E. Z. Larson¹, Kayvan R Keshari², David M Wilson², Simon Hu², Michael Lustig³, Adam B Kerr⁴, John M Pauly⁴, John Kurhanewicz², and Daniel B Vigneron^2
1UCSF, San Francisco, California, United States, ²UCSF, ³UC Berkeley, ⁴Stanford University

Copolarization followed by simultaneous injection of [1-13C]-pyruvate (metabolic marker) and 13C-urea (perfusion marker) was combined with a dynamic 3D EPSI acquisition using multiband excitation pulses and compressed sensing to better characterize perfusion and uptake of hyperpolarized agents. Using urea as a separate perfusion marker allowed for improved distinction between perfusion of metabolic products (ie [1-13C]-lactate) and tissue metabolic conversion.

Vickie Zhang^1,2, Robert Bok¹, Subramaniam Sukumar¹, Adam Cunha³, I-C. Hsu³, Jean Pouliot^2,3, Daniel B. Vigneron^1,2, and John Kurhanewicz^1,2
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, ²Graduate Program in Bioengineering, University of California, San Francisco - University of California, Berkeley, Berkeley, CA, United States, ³Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States

This study used multi-parametric ¹H and hyperpolarized ¹³C MR imaging in the TRAMP model to investigate early response in perfusion, diffusion and metabolism to the impact of increasing dose levels of radiation therapy. TRAMP mouse were treated with a radiation dose distribution from 14Gy to 5Gy within the tumor. Both ¹H (t₂-weighted, DCE and DWI) and hyperpolarized ¹³C ([1-¹³C] pyruvate and ¹³C urea) imaging was done before treatment and serially after treatment. HP ¹³C biomarkers correlated with conventional ¹H MR markers. Significant dose dependent changes in perfusion and pyruvate-to-lactate flux were observed following radiation therapy.

Mette Hauge Lauritzen¹, Peter Magnusson¹, Sadia Asghar Butt¹, Lise Vejby Søgaard¹, Jan Henrik Ardenkjær-Larsen², and Per Åkeson^1
1Danish Research Centre for Magnetic Resonance (DRCMR) Copenhagen University Hospital, Hvidovre, Denmark, ²GE Healthcare, Hillerød, Denmark

Changes in myocardial metabolism play an important role in the etiology of different cardiac diseases. MR Spectroscopy with hyperpolarized [1-¹³C]pyruvate can visualize myocardial metabolism. However, the usability of the technique can be complicated, because it depends on high myocardial glucose availability, which can be difficult to control during in vivo MR studies. This study demonstrate how infusion of glucose, insulin and potassium can increase the [¹³C]bicarbonate MRS-signal significantly after injection of hyperpolarized [1-¹³C]pyruvate in rats. This improves the sensitivity of the technique to assess metabolic changes in the myocardium as a result of disease.

Angus Z. Lau^1,2, Albert P. Chen³, William Dominguez-Viqueira², Yiping Gu², Jennifer Barry², Kim A. Connelly⁴, and Charles H. Cunningham^1,2
1Dept. of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, ²Imaging Research, Sunnybrook Research Institute, Toronto, Ontario, Canada, ³GE Healthcare, Toronto, Ontario, Canada, ⁴Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital and University of Toronto, Toronto, Ontario, Canada

We characterize the reproducibility of hyperpolarized cardiac metabolic measurements in a cohort of normal pigs using a time-resolved, dual respiratory and cardiac-gated, multi-slice, single-shot 13C pulse sequence. The time-resolved nature of the imaging sequence enabled normalization using the first pass of the pyruvate bolus through the heart. Normalization reduced the variability (%CV = mean/SD) for metabolic measurements, with 57% CV for bicarbonate and 29% CV for lactate signals in the heart. Along with increases in LDH activity in ischemia, our results suggest that lactate imaging may be a sensitive marker of metabolic remodeling in ischemic heart disease.

Sonal Josan^1,2, Jae Mo Park³, Yi-Fen Yen⁴, Ralph Hurd⁴, Adolf Pfefferbaum^1,5, Daniel Spielman^2,3, and Dirk Mayer^1,2
1Neuroscience Program, SRI International, Menlo Park, CA, United States, ²Radiology, Stanford University, Stanford, CA, United States, ³Electrical Engineering, Stanford University, Stanford, CA, United States, ⁴Applied Science Laboratory, GE Healthcare, Menlo Park, CA, United States, ⁵Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States

Hyperpolarized [1-¹³C]-pyruvate MRS has been used to measure changes in cardiac pyruvate dehydrogenase (PDH) flux, with up-regulation by dichloroacetate demonstrating an increase in ¹³C-bicarbonate production. This work investigates the metabolic fate of the corresponding increase in acetyl-CoA generated by the up-regulated PDH flux, using [2-¹³C]-pyruvate to follow the ¹³C label into the Krebs cycle. The increase in bicarbonate from [1-¹³C]-pyruvate was compared to the increase in [5-¹³C]-glutamate from [2-¹³C]-pyruvate and provides information about the relative fraction of pyruvate going through PDH that enters the Krebs cycle vs. other metabolic pathways.

Jae Mo Park^1,2, Sonal Josan^2,3, Yi-Fen Yen⁴, Ralph E Hurd⁴, Daniel M Spielman^1,2, and Dirk Mayer^2,3
1Electrical Engineering, Stanford University, Stanford, CA - California, United States, ²Radiology, Stanford University, Stanford, CA - California, United States, ³Neuroscience Program, SRI International, Menlo Park, CA - California, United States, ⁴Applied Science Laboratory, GE Healthcare, Menlo Park, CA - California, United States

Although both [2-13C]Pyr and [1, 2-13C]Pyr have been successfully used as substrates to assess mitochondrial function in cardiac metabolism by measuring products such as [5-13C]glutamate (Glu), which is generated from the tricarboxylic acid (TCA) cycle intermediate alpha-ketoglutarate, the application of [2-13C]Pyr in studies of brain metabolism has been limited as Lac was the only metabolic product that could be detected so far. The aim of this work was to exploit the unsaturable component of Pyr transport into the brain by using a high [2-13C]Pyr concentration and measure the effects on brain metabolism when the Pyr dehydrogenase (PDH) flux is up-regulated by dichloroacetate (DCA), a Pyr dehydrogenase kinase (PDK) inhibitor.

Jessica A M Bastiaansen¹, Tian Cheng¹, Rolf Gruetter^1,2, and Arnaud Comment^3
1Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland, ²Department of Radiology, Universite de Lausanne and Geneva, Lausanne and Geneva, Switzerland, ³Institute of Physics of Biological Systems, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland

Following the infusion of hyperpolarized [1-13C]acetate, we measured the real-time metabolic conversion of acetate to acetylcarnitine and citrate in vivo in rat hearts. A kinetic model allowed us to determine quantitative conversion rates inside the myocardium. Our study supports the role of acetylcarnitine as a shuttle for acetyl groups across the mitochondrial membrane.

Lydia M Le Page¹, Michael S Dodd¹, Daniel R Ball¹, Vicky Ball¹, Huw B Jones², Edvin Johansson³, and Damian J Tyler^1
1University of Oxford, Oxford, United Kingdom, ²AstraZeneca, Alderley Park, Macclesfield, United Kingdom, ³AstraZeneca, Mölndal, Sweden

Increasing flux through the pyruvate dehydrogenase (PDH) enzyme has been considered as a potential treatment for type 2 diabetes, as it should lead to reduced blood glucose levels. In this study the ability to assess pharmacologically stimulated increases in PDH flux, both in vivo and ex vivo, has been demonstrated using hyperpolarized [1-¹³C]pyruvate in combination with magnetic resonance spectroscopy. The generic PDH kinase inhibitor, dichloroacetate, was seen to significantly increase PDH flux both in vivo and ex vivo, whilst the PDH kinase 2 specific inhibitor, AZD7545, did not result in changes to PDH flux in either situation.

Brett William Clive Kennedy^1,2, Mikko Iivari Kettunen^1,2, De-En Hu^1,2, Sarah Elizabeth Bohndiek^1,2, and Kevin Michael Brindle^1,2
1Department of Biochemistry, University of Cambridge, Cambridge, England, United Kingdom, ²Cambridge Research Institute, Cancer Research UK, Cambridge, England, United Kingdom

The aim of this study was to use hyperpolarized 13C labeled ketone bodies to examine metabolism in vivo. Despite high polarization (~25%) and long T1 values (~35s), little in vivo metabolism was observed in our current models. Nevertheless, we hope these molecules may still have important roles to play in our understanding of mitochondrial redox state in vivo.

Jessica A M Bastiaansen¹, Tian Cheng¹, Mor Mishkovsky^1,2, Arnaud Comment³, and Rolf Gruetter^1,4
1Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland, ²Department of Radiology, Universite de Lausanne, Lausanne, Switzerland, ³Institute of Physics of Biological Systems, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland, ⁴Department of Radiology, Universite de Lausanne and Geneva, Lausanne and Geneva, Switzerland

Sonal Josan^1,2, Tao Xu³, Yi-Fen Yen⁴, Ralph Hurd⁴, Julio Ferreira⁵, Che-Hong Chen⁵, Adolf Pfefferbaum^1,6, Dirk Mayer^1,2, and Daniel Spielman^2,3
1Neuroscience Program, SRI International, Menlo Park, CA, United States, ²Radiology, Stanford University, Stanford, CA, United States, ³Electrical Engineering, Stanford University, Stanford, CA, United States, ⁴Applied Science Laboratory, GE Healthcare, Menlo Park, CA, United States, ⁵Chemical and Systems Biology, Stanford University, Stanford, CA, United States, ⁶Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States

Aldehyde dehydrogenase-2 (ALDH2) enzyme is important for eliminating toxic aldehydes that accumulate in several diseases. It is also used in ethanol metabolism in the liver, producing NADH in the process. This work investigates using hyperpolarized [1-¹³C]-pyruvate MRSI for in vivo measurement of ALDH2 activity. Two different doses of ALDH2 inhibitor disulfiram were used to reduce ALDH2 activity in two groups with another group acting as control. Using ethanol metabolism to modulate the NADH availability in rat liver, the resulting change in pyruvate-to-lactate conversion was measured with ¹³C MRSI and correlated with ALDH2 enzyme activity.

Justin Yat Cheong Lau^1,2, Albert P. Chen³, William Dominguez-Viqueira², Gang Wu⁴, and Charles H. Cunningham^1,2
1Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, ²Imaging Research, Sunnybrook Research Institute, Toronto, Ontario, Canada, ³GE Healthcare, Toronto, Ontario, Canada, ⁴Department of Chemistry, Queen's University, Kingston, Ontario, Canada

In this work, we characterize longitudinal relaxation of hyperpolarized [1-¹³C], [2-¹³C], and [1,2-¹³C₂] pyruvate in solution and in pig blood at 7 T. We show that single-labelled pyruvate in solution exhibits shorter T₁ at 7 T as compared to 3 T while dual-labelled pyruvate exhibits comparable T₁ at 3 T and 7 T in solution and in blood. We argue that experiments with dual-labelled pyruvate may benefit from a greater chemical shift dispersion at 7 T with minimal T₁ penalty. Results from this work may further the understanding of relaxation mechanisms that affect hyperpolarized pyruvate.

Christoffer Laustsen^1,2, Jakob Appel Østergaard³, Rikke Nørregaard⁴, Steffen Ringaard¹, Niels Chr. Nielsen⁵, Allan Flyvbjerg³, Michael Pedersen¹, Per Åkeson², and Jan Henrik Ardenkjaer-Larsen^6,7
1The MR Research Centre, Institute of clinical Medicine, Aarhus University, Aarhus N, Denmark, ²DRCMR, Hvidovre Hospital, Hvidovre, Denmark,³Department of Endocrinology and Internal Medicine, Aarhus University, Aarhus, Denmark, ⁴Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark, ⁵Center for Insoluble Protein Structures (inSPIN), Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark, ⁶GE Healthcare, Denmark, ⁷Department of Electrical Engineering, Technical University of Denmark, Kgs Lyngby, Denmark

A type-1 STZ induced diabetic nephropathy rat model is investigated with hyperpolarized [1- ¹³C]pyruvate, to allow early diagnosis and monitoring of decreased kidney function, with increased diabetes. We here show the metablic profile of the type 1 diabetic rat, from early diabetes to late diabetes, with a significant altered profile over the time course, showing the decreasing kidney function. The method show great promise for accurate non-invasive metabolic profiling of diabetic patients, with different stages of reduced kidney function.

Simon Hu¹, Hikari Yoshihara¹, Robert A Bok¹, John Kurhanewicz¹, and Daniel B Vigneron^1
1Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States

Development of hyperpolarized technology utilizing dynamic nuclear polarization has enabled the measurement of ¹³C metabolism in vivo at very high SNR. In vivo mitochondrial metabolism can, in principle, be monitored with pyruvate, which is catalyzed to acetyl-CoA via pyruvate dehydrogenase (PDH). The purpose of this work was to determine if the compound sodium dichloroacetate (DCA) could aid the study of mitochondrial metabolism with hyperpolarized pyruvate. DCA stimulates PDH by inhibiting its inhibitor, pyruvate dehydrogenase kinase (PDK). In this work, hyperpolarized [1-¹³C]pyruvate and [2-¹³C]pyruvate were used to probe mitochondrial metabolism in normal rats. In the case of [1-¹³C]pyruvate, increased bicarbonate was observed after DCA was given. In the case of [2-¹³C]pyruvate, increased acetoacetate and acetylcarnitine were detected.

Daniel Ball¹, Ben Rowlands¹, Rhys Evans¹, Kieran Clarke¹, and Damian Tyler^1
1Physiology, Anatomy and Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom

The isolated perfused heart, in combination with dynamic nuclear polarization, has proven to be an excellent model for the study of cardiac metabolism. However this model ideally requires the use of fatty acids to achieve a more physiological preparation. Previous work has shown that using bovine serum albumin to solubilise long chain fatty acids reduces the signal observed from hyperpolarized metabolites. The aim of this study was therefore to find alternative ways of providing the heart with fatty acids without compromising hyperpolarized signal intensity.

James A Bankson¹, Vlad C Sandulache², Matthew E Merritt³, Andrew M Elliott¹, Yunyun Chen⁴, Waldemar Priebe⁵, Dawid Schellingerhout⁶, Stephen Y Lai⁴, Charles A Conrad⁷, and John D Hazle^1
1Department of Imaging Physics, UT MD Anderson Cancer Center, Houston, TX, United States, ²Bobby R. Alford Department of Otolaryngology, Baylor College of Medicine, Houston, TX, United States, ³Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States,⁴Derpatment of Head & Neck Surgery, UT MD Anderson Cancer Center, Houston, TX, United States, ⁵Department of Experimental Therapeutics, UT MD Anderson Cancer Center, Houston, TX, United States, ⁶Department of Diagnostic Radiology, UT MD Anderson Cancer Center, Houston, TX, United States, ⁷Department of Neuro-Oncology, UT MD Anderson Cancer Center, Houston, TX, United States

Metabolic imaging using hyperpolarized [1-13C]pyruvate can provide new insights into cancer and therapies that target or affect metabolism. Strategies for acquisition, reconstruction, and analysis must be designed to extract reproducible quantitative biomarkers within a limited window of time. We have dynamically monitored the chemical fate of hyperpolarized pyruvate in murine models of cancer to investigate temporal dynamics and inform on the design of robust acquisition and analysis strategies. Preliminary results indicate, as expected, that multiple processes can modulate the behavior of hyperpolarized tracers in vivo, and that the effects of these processes can be modeled to clarify data interpretation.

Georgios Batsios¹, Catherine Germanier¹, Marcin Krajewski¹, Michael Batel², Kilian Weiss¹, Andreas Sigfridsson¹, and Markus Rudin^1,3
1Instute for Biomedical Enginnering, ETH and University of Zurich, Zurich, Switzerland, ²Laboratory of Physical Chemistry, ETH, Zurich, Switzerland,³Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

Hyperpolarized 13C magnetic resonance spectroscopy and imaging is a rapidly expanding field with many applications, in particular in the field of cancer. Due to a variety of reasons preclinical cancer studies are commonly carried out in nude mice, which put limits to the total amount of solution that can be administered intravenously. However, the amount of compounds polarized by commonly used polarizers is significantly larger. To make efficient use of this amount, in the present work we demonstrate the feasibility of parallel monitoring pyruvate metabolism in two animals using a single MR transceiver coil in combination with slice selective excitation.

Jyothi Menon^1,2, Praveen Gulaka¹, Madalyn McKay², Sairam Geethanath¹, and Vikram D Kodibagkar^1,3
1Joint program in biomedical engineering, UT Arlington/UT Southwestern Medical Center, Dallas, Texas, United States, ²Radiology, UT Southwestern medical center, Dallas, Texas, United States, ³School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona, United States

An emerging need for evaluation of promising cellular therapies is a non-invasive method to track and image the movement and health of cells following transplantation into the subject. Multi-modal imaging strategies are becoming more popular in recent times because of their improved sensitivity, higher resolution and structural/functional visualization. This study aims at formulating hexamethyldisiloxane (HMDSO) based dual modality (MRI / Fluorescence), dual-functional (oximetry/detection) nanoprobes for cellular and molecular imaging. Studies using CRI Maestro and PISTOL imaging confirmed that these nanoprobes could be used to detect changes in oxygen tension and for fluorescence imaging.

Talaignair N Venkatraman¹, Haichen Wang^2,3, Artak G Tovmasyan⁴, Ines Batinic-Haberle⁴, and Chris D Lascola^1
1Radiology, Duke University Medical Center, Durham, North Carolina, United States, ²Neurology, Duke University Medical Center, ³Duke University Medical Center, ⁴Radiation Oncology, Duke University Medical Center

In this study, we present initial results investigating the use of two novel, water-soluble, lipophilic manganese-based porphyrins with remarkably high T1 relaxation properties and strong avidity for cardiac mitochondria. We present initial results investigating the use of two novel, water-soluble, lipophilic manganese-based porphyrins (MnTMOHex-PyP and MnTButOE-PyP) with remarkably high T1 relaxation properties and strong avidity for cardiac mitochondria. In vitro and in vivo quantitative MR imaging experiments demonstrate the potential of a novel class of manganese-based porphyrins for diagnostic characterization of myocardial perfusion and viability. The time course of myocardial enhancement and washout, as determined both qualitatively and quantitatively using a novel 3D variable flip angle steady state acquisition technique, would allow for the use of physiological rather than pharmaceutical stress, and also offer the possibility of quantitation at high isotropic resolution.

Mohammed Salman Shazeeb¹, Giancarlo Feula^1,2, and Alexei Bogdanov^1,3
1Department of Radiology, University of Massachusetts Medical School, Worcester, MA, United States, ²Worcester Polytechnic Institute, Worcester, MA, United States, ³Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, United States

M40403 is a synthetic manganese based superoxide dismutase (SOD) mimetic that has been extensively studied in vivo and found to have a catalytic activity rate which approaches that of the native Mn SOD enzyme. Here we compared the kinetics of liposome encapsulated M40403 and found that in addition to catalyzing superoxide dismutation in vitro, M40403 also doubled as a paramagnetic contrast agent in vivo, causing enhancement of mouse brain after systemic administration. Thus liposome encapsulated M40403 is an ideal candidate for development as a theranostic compound useful for MR imaging of SOD activity and disease treatment.

Benjamin Marty¹, Nicolas Ginet², Christopher Lefevre², Daniel Garcia², Franck Lethimonnier¹, Denis Le Bihan¹, Sébastien Mériaux¹, and David Pignol^2
1CEA/DSV/I2BM/NeuroSpin, Gif sur Yvette, France, ²CEA/DSV/IBEB/Laboratoire de Bioénergétique Cellulaire, Saint-Paul-lez-Durance, France

In this study we present a new class of superparamagnetic nano-particles, produced naturally by magnetotactic bacteria, and which regroup different characteristics of interest for biomedical applications: a perfectly crystalline and regular nanocrystal of magnetite, a natural lipid bilayer coating the nanoparticles, ensuring their solubilization and a possible functionalization of the lipid surface with biological functions for cellular targeting or in situ enzymatic catalysis. Transverse relaxivity of magnetosomes was measured at high magnetic field (17.2T) and preliminary experiments were performed on mice demonstrating the high in vivo sensivity of such contrast agents.

Krishna Kattel¹, Ja Young Park¹, Wenlong Xu¹, Badrul Alam Bony¹, Woo Choul Heo¹, Tirusew Tegafaw Mengesha¹, and Gang Ho Lee^1
1Department of Chemistry, Kyungpook National University, Daegu, Korea

Dy-compounds are promising candidates for MRI contrast agent. Dy³⁺ has the shortest electronic relaxation time and highest magnetic moment (10.6 ¥ì_B) which induce water proton relaxation that primarily affect T₂. It increases significantly with the external magnetic field, and is proportional to the square of the magnetic moment of the Dy³⁺ ion. Dy(OH)₃ nanostructures were examined for their possible use in MR imaging and tracking of cells by investigating their cytotoxic behaviors.

Mangala Srinivas¹, Houshang Amiri², Fernando Bonetto³, Javier L Cruz⁴, Eric van Dinther², Jeanette Pots², Arend Heerschap⁵, Carl Figdor¹, and Jolanda de Vries^1
1Tumor Immunology, RUNMC, Nijmegen, Gelderland, Netherlands, ²Tumor Immunology, RUNMC, Netherlands, ³INTEC-CONICET, Argentina, ⁴Molecular Imaging, UMC Leiden, Leiden, Netherlands, ⁵Radiology, RUNMC, Nijmegen, Gelderland, Netherlands

Gadolinium has previously been used to enhance the relaxativity of perfluorocarbons for more efficient 19F MRI. However, the poor interaction between hydrophilic Gd chelates and hydrophobic perfluorocarbons is problematic. We overcome this issue using polymeric nanoparticles encapsulating both Gd chelates and perfluorocarbon, thereby forcing close interaction. These particles are synthesized using clinically-approved components, and are stable for at least 6 months. We demonstrate frequency and concentration dependence of the 19F longitudinal relaxation time. Finally, we show that labeling has minimal effect on cell function and viability when used to label primary human dendritic cells, as currently used in cancer vaccines.

Bashar Issa^1,2, Ihab Obaidat¹, Shahnaz Qadri², and Yousef Haik^2,3
1Physics, UAE University, Al-Ain, AD, United Arab Emirates, ²CREN, UNCG, Greensboro, NC, United States, ³Mech Eng, UAE University, Al-Ain, AD, United Arab Emirates

The magnetic and NMR relaxation properties of Gd-substituted Mn-Zn ferrite nanoparticles are studied at different temperatures. Magnetization data yielded a decrease in the saturation magnetization with temperature while the average magnetic moment of the particle increased. We propose that heating the particles increased the particle volume and hence its magnetic moment, with larger expansion at the surface shell layer than at the core of the particle. Only when temperature dependent particle size and magnetization are taken into account a close agreement between T2 data and model can be obtained. This enables correct characterization of contrast agent effect on MR images.

Jesse Trekker^1,2, Michel Hodenius³, Stefaan Soenen³, Wim Van Roy², Marcel De Cuyper³, Liesbet Lagae^2,4, and Uwe Himmelreich^1
1Radiology / BioNMR unit, K.U.Leuven, Leuven, Belgium, ²imec, Leuven, Belgium, ³Lab of BioNanoColloids, IRC, K.U.Leuven Campus Kortrijk, Kortrijk, Belgium, ⁴Solid State Physics and Magnetism, K.U.Leuven, Leuven, Belgium

To study the effect of intracellular clustering on the stability and contrast generation properties of SPIOs we prepared non-clustering PEGylated-SPIOs and clustering liposome-SPIOs. Both SPIOs were taken up by mesenchymale stem cells and showed no to limited toxicity. Intracellular studies showed a difference in clustering between both SPIOs, however no difference in contrast could be detected. On the other hand the intracellular stability of the clustered SPIOs seemed to increase.

Naira P. Martínez Vera¹, Klaus Langer², Lavor Zlatev², Robert Wronsky³, Manfred Windisch³, Hagen von Briesen⁴, Sylvia Wagner⁴, Motti Deutsch⁵, Claus Pietrzik⁶, Reinhold Schmidt¹, and Stefan Ropele^1
1Department of Neurology, Medical University of Graz, Graz, Styria, Austria, ²Institut für Pharmazeutische Technologie und Biopharmazie,WWU Münster, Germany, ³JSW Life Sciences GmbH, Grambach, Austria, ⁴Department of Cell Biology & Applied Virology, Fraunhofer-Institute for Biomedical Engineering, St. Ingbert, Germany, ⁵Physics Department, Schottenstein Center for the Research and Technology of the Cellome, Bar llan University, Israel, ⁶Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

Nanoparticles (NP) are expected to allow a more effective application of therapy by facilitating transport of drugs over the blood brain barrier (BBB). This experimental study focused on the development and in vivo testing of magnetite labeled NP. Following the optimization of the R1 relaxivity of different NP formulas in phantoms, the NP were administered intravenously in rats. The distribution and uptake then was assessed by T1 mapping and T1 weighted sequences. Most pronounced NP accumulations were observed in the liver and spleen. Using a histogram analysis, also a small but significant uptake was observed in the brain

Andreas Pohlmann¹, Babette Wagenhaus¹, and Thoralf Niendorf^1,2
1Berlin Ultrahigh Field Facility, Max Delbrueck Center for Molecular Medicine, Berlin, Berlin, Germany, ²Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center, Berlin, Berlin, Germany

Monitoring changes in blood volume with the use of intravascular contrast agents is of great interest for rodent studies of cerebrovascular diseases, fMRI and cerebrovascular reactivity. Ferumoxytol is a new intravenous iron preparation for treatment of the anemia of chronic kidney disease. It is a carbohydrate-coated USPIO and can also be used as a MRI contrast agent. In this study we investigated the use of ferumoxytol as a T2/T2* based MRI contrast reagent in rats at 9.4T. Its very slow wash-out and narrow, unvarying particle size distribution suggest that it may be well suited for rCBV quantification and rCBV-based fMRI.

Xiao-Ming Zhu¹, Ken Cham-Fai Leung², Siu-Fung Lee³, Da-Wei Wang³, Feng Zhao¹, Josie M. Y. Lai⁴, Chao Wan⁴, Christopher H. K. Cheng⁴, and Yi-Xiang Wang^1
1Dept Imaging & Interventional Radiology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, ²Institute of Creativity and Department of Chemistry, The Hong Kong Baptist University, Kowloon Tong, KL, Hong Kong, ³Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, ⁴School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong

It was shown aminosilane (SiO2-NH2) coated SPIO (SPIO@SiO2-NH2) had higher labeling efficiency for rabbit mesenchymal stem cells (MSCs) than SiO2 coated SPIO (SPIO@SiO2). This study compared the intracellular uptake of SPIO@SiO2-NH2 with SPIO@SiO2, bare SPIO, and dextran coated SPIO (SPIO@dextran) in RAW 264.7, L929, HepG2, PC-3, U-87 MG cells, and mouse MSCs. All these six mammalian cell lines showed the highest cellular uptake for SPIO@SiO2-NH2. For SPIO@SiO2, bare SPIO and SPIO@dextran, there were variations of labeling efficiency among different cell lines, with SPIO@SiO2 tended to rank as the second, and bare SPIO and SPIO@dextran tended to have lower labeling efficiency.

Andrea Protti¹, Xuebin Dong², Marcelo E. Andia³, Bin Yu², Kate Dokukina², Sanjay Chaubey², Maria G. Vizcay-Barrena³, Alkystis Phinikaridou³, Matthias Taupitz⁴, Ajay M. Shah², and Rene Botnar^3
1Cardiovascular Division and Division of Imaging Sciences and Biomedical Engineering, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom, ²Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom, ³Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, United Kingdom, ⁴Charite Berlin, Department of Radiology, Berlin, Germany

 

Céline Giraudeau¹, Benjamin Marty¹, Julien Flament¹, Françoise Geffroy¹, Christelle Médina², Philippe Robert², Caroline Robic², Marc Port², Denis Le Bihan¹, Julien Valette¹, Sébastien Mériaux¹, Fawzi Boumezbeur¹, and Franck Lethimonnier^1
1NeuroSpin, I2BM, Commissariat à l'Energie Atomique, Gif-sur-Yvette, France, ²Guerbet, Research Division, Roissy-Charles de Gaulle, France

In the present work, three different contrast agents (CA) are evaluated: Gd-based emulsion, LipoCEST and fluorine emulsion. A comparison of the three modalities sensitivity and specificity is performed on a mouse model of brain tumor using CA grafted with RGD peptides to specifically target ₃ integrins over-expressed in angiogenic vessels. CA are detected with a sub-nanomolar sensitivity by the three modalities. A higher contrast is systematically observed for RGD contrast agents inside the tumor. Each modality provides additional information, promising for multimodal investigation of brain diseases.

Lindsey A Crowe¹, Eline A Vermeij², Marije I Koenders², Fons A J van de Loo², Frank Tobalem¹, Thomas Goget¹, Azza Gramoun¹, Wim B Van den Berg², and Jean-Paul Vallée^1
1Faculty of Medicine/Department of Radiology, University of Geneva, Geneva, Switzerland, ²Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmengen, Netherlands

We investigate a ‘MultiPaw’ imaging protocol for optimizing small sample scanning at high-resolution in a clinical MRI. An antigen induced mono-arthritis model in mouse knees with/without intra-venous or intra-articular SPION injection is presented to show the diagnostic potential. Pre-clinical studies may use clinical MRI systems due to translational possibilities and availability of the technology. For small sample sizes, an adapted coil to give high signal intensity is needed, though the initial obvious choice of the smallest coil may not be the best. Signal-to-noise is optimized with small, adapted coils, but a longer scan using a larger coil with greater signal homogeneity can be efficient.

Benjamin Schmitt¹, Pavol Szomolanyi², Toshiyuki Shiomi³, and Siegfried Trattnig^2
1Centre for High-Field MR, Medical University of Vienna, Vienna, Austria, ²Medical University of Vienna, ³Osaka University Graduate School of Medicine

The study was performed to assess if the ionic X-ray contrast agent Hexabrix® can be used as an agent for CEST MRI. In-vitro solutions with different concentrations of Hexabrix® were examined with CEST imaging on 3 T and 7 T whole-body MR scanners. Results showed signals, which are attributed to exchangeable amide protons of Hexabrix®. These signal seem to be well suited for CEST imaging as they showed dependency on agent concentration. Using an approved X-ray contrast agent could facilitate the usage as a designated agent for CEST MRI targeting, e.g., biomolecules with surface charge

Ashwini A. Ketkar-Atre¹, Tom Struys², Tineke Notelaers³, Michel Hodenius⁴, Philip Roelandt³, Tom Dresselaers², Marcel De Cuyper⁴, Catherine Verfaillie³, and Uwe Himmelreich^1
1Biomedical NMR unit, KU Leuven, Leuven, Vlaams Brabant, Belgium, ²Biomedical NMR unit, KU Leuven, Leuven, Belgium, ³Interdepartmental Stem Cell Institute, Leuven, Belgium, ⁴Lab Of BioNano Colloids, KULeuven, Leuven, Belgium

In diseases like liver cirrhosis or hepatitis where hepatocytes are damaged and healing is difficult, it is necessary to isolate hepatocytes from mixed population of endo- and mesodermal cells differentiated from stem cells. We labelled differentiated mESCs into hepatocyte like cells with Cationic MLs (unspecific uptake), Anionic MLs (negative control) and Lac MLs (specific uptake) with galactose-terminal entities which are recognized by asialoglycoprotein receptors (ASGPR)present on hepatocytes. Higher specificity in uptake was observed with Lac MLs. And In vivo experiments revealed the potential use of Lac MLs as a contrast agent for non-invasive evaluation of liver function.

Lindsey A Crowe¹, Frank Tobalem¹, Wolfgang Wirth², Azza Gramoun¹, Benedicte M A Delattre¹, Kerstin Grosdemange¹, Jatuporn Salaklang³, Anthony Redjem³, Alke Petri-Fink³, Felix Eckstein², Heinrich Hofmann⁴, and Jean-Paul Vallée^1
1Faculty of Medicine/Department of Radiology, University of Geneva, Geneva, Switzerland, ²Institute of Anatomy & Musculoskeletal Research, Paracelsus Medical University, Salzburg, Austria, ³Adolphe Merkle Institute, University of Fribourg, Fribourg, Switzerland, ⁴Powder Technology Laboratory, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Nanoparticle technology, including SPIONs, is of emerging importance for monitoring onset, progression and treatment of inflammatory diseases such as arthritis and drives quantitative imaging. Conventional signal loss in SPION-containing tissues saturate at medium concentrations and show non-linear/non-proportional intensity/concentration profiles due to competing T1/T2 effects. Intra-articular injected SPIONs were compared to phantom calibrations using dUTE (difference-Ultrashort TE) with positive, unambiguous signal characteristics and monotonic increasing concentration response over a wide range in a phantom and a rat model, opening possibilities for quantification. A further advantage of dUTE is the distinction of synovial iron signal intensity from tissues (muscle, bone) and noise.

Yung-Ya Lin¹, Chaohsiung Hsu¹, Zhao Li¹, and Lian-Ping Hwang^2
1Chemistry and Biochemistry, UCLA, Los Angeles, CA, United States, ²Chemistry, National Taiwan University, Taipei, Taiwan

Sensitive in vivo MR imaging of virus (especially the ability to quantify virus concentrations and type/subtype) and tumors (especially at early stages) are important and challenging for medical development and clinical applications. For this purpose, synergistic targeting-imaging approaches were developed and demonstrated. Computer simulations and in vitro H5N2 images suggest 4-10 times of improvements in imaging sensitivity to virus concentrations can be achieved by this this targeting-imaging approach over conventional methods. (ii) In vivo mouse images of colon cancers targeted by SPIO suggest this targeting-imaging approach can provide enhanced, robust, and positive contrast for sensitive tumor detection.

Julien Flament¹, Françoise Geffroy¹, Christelle Médina², Caroline Robic², Philippe Robert², Marc Port², Gilles Bloch¹, Denis Le Bihan¹, Franck Lethimonnier¹, and Fawzi Boumezbeur^1
1CEA/DSV/I²BM/NeuroSpin, Gif-sur-Yvette, France, ²Guerbet Research, Roissy-Charles de Gaulle, France

LipoCEST are promising contrast agents for molecular imaging which can be functionalized to target specific biomarkers. Although in vivo detection is complicated by to endogenous MT effects, several studies have already shown feasibility. Still, quantification remains very challenging. Here, we used a 4-pools model which takes into account both endogenous and exogenous MTRasym effects as well as field inhomogeneities in order to establish in vivoquantitative maps. This model was evaluated in a tumor mouse brain model with a functionalized RGD-lipoCEST which targets ₃ integrins expressed during tumor angiogenesis.

Rolf Lamerichs^1,2, Marije van der Paardt², Aart Nederveen², Jaap Stoker², and Raquel Diaz-Lopez^1,3
1Philips Research, Eindhoven, Netherlands, ²Academic Medical Center, Amsterdam, Netherlands, ³VU University Medical Center, Amsterdam, Netherlands

Contrast agents based on fluorine (19F) compounds have several advantages over T1 or T2 based contrast agents. Here we show the use of non-targeted polymeric microcapsules for bowel imaging. These microcapsules contain perfluoro-octylbromide (PFOB). For the detection of the fluorine signal we used the Fluorine ultrafast Turbo Spectroscopic Imaging (F-uTSI) sequence. This sequence can be applied to any PFC compound. The data show that the polymeric microcapsules can be developed into promising 19F-MRI contrast agents for bowel imaging using 19F spectroscopic imaging methods. The bowel transit time of these agents is around 10 hrs in black mice.

Nicolas Gargam¹, Marie Poirier-Quinot¹, Caroline Robic², Jean-Frédéric Salazar², Jean-Sébastien Raynaud², Philippe Robert², and Luc Darrasse^1
1IR4M - UMR 8081 - CNRS - Université Paris Sud XI, Orsay, France, ²Guerbet Research, Paris, France

In this work, we demonstrate by micro-MRI the dynamic uptake of a RGD-targeted Gd-loaded emulsion by a HUVEC cell monolayer expressing the áíâ3 integrin, which is a promising target for molecular imaging due to its high level of expression during tumor angiogenesis. The signal enhancement observed on the cell monolayer indicates a 3-fold higher uptake of the targeted emulsion by the HUVEC cells when compared to the control emulsion. This in vitro molecular imaging model approach can be useful prior to in vivo experiments on animals, particularly to assess the specificity and characterize the binding kinetics of targeted CAs.

Brigit den Adel¹, Carmen Burtea², Sophie Laurent², Ernst Suidgeest³, Robert E. Poelmann¹, Robert N. Muller², and Louise van der Weerd^3,4
1Anatomy & Embryology, Leiden University Medical Center, Leiden, Netherlands, ²Université de Mons-Hainaut, Mons, Belgium, ³Radiology, Leiden University Medical Center, Leiden, Netherlands, ⁴Human Genetics, Leiden University Medical Center, Leiden, Netherlands

We identified a highly specific peptide with nanomolar affinity for human VCAM-1. High resolution MRI performed 1.5 hours after i.v. injection of VCAM-1 targeted USPIOs in aged ApoE-/- mice with advanced plaques showed enhanced uptake of the contrast agent. Young ApoE-/- mice with a collar around the carotid artery, showed an increased uptake of the iron particles, particularly in early plaque stages when VCAM-1 expression is highest. Histology showed co-localisation of VCAM-1 positive endothelial cells and iron deposits in the vessel wall.

Jesús Agulla¹, David Brea¹, Barbara Argibay¹, Miguel Blanco¹, José Castillo¹, and Pedro Ramos-Cabrer^1
1Clinical Neuriosciences Research Laboratory, Department of Neurology, University Clinical Hospital, University of Santiago de Compostela, Santiago de Compostela, Spain

In this work we report the development of a theranostic molecule containing Gadolinium based imaging probes, targeted to cells of the peri-infarct region in stroke. The molecular marker used as target for peri-infarct tissue was found by proteomic and immunohistological studies. Fluorescence microscopy and MRI were used to test the diagnostic capacity of the theranostic molecule, allowing the identification of cells of the peri-infarct region.

Rajesh Dash¹, Justin Lam¹, Ildiko Toma¹, Yongquan Gong², Robert C. Robbins², Paul C. Simpson^3,4, and Phillip C. Yang^1
1Cardiovascular Medicine, Stanford University Medical Center, San Francisco, CA, United States, ²Cardiac Surgery, Stanford University Medical Center,³Medicine / Cardiology, UCSF Medical Center, San Francisco, CA, United States, ⁴Cardiology, San Francisco VA Medical Center, San Francisco, CA, United States

A novel anti-apoptotic alpha-adrenergic agonist preserves left ventricular ejection fraction in mice following myocardial infarction. This therapeutic effect is able to be detected and quantified non-invasively, using T2* signal loss assessment of an Annexin-SPIO molecular apoptosis probe.

Rajesh Dash¹, Ildiko Toma¹, Fumiaki Ikeno¹, Jennifer K. Lyons¹, Shahriar Heidary¹, Marie-Claude Parent¹, I-Ning E. Wang¹, Xiaohu Ge¹, Justin Lam¹, Jaehoon Chung², Paul J. Kim¹, Kaori Nakagawa¹, Svetlana Lyalina¹, Grace Do¹, Robert C. Robbins³, Michael V. McConnell^1,4, Alan C. Yeung¹, Phillip Harnish⁵, and Phillip C. Yang^1
1Cardiovascular Medicine, Stanford University Medical Center, STANFORD, CA- CALIFORNIA, United States, ²Medicine / Cardiology, University of Illinois-Chicago, Chicago, IL, United States, ³Cardiac Surgery, Stanford University Medical Center, ⁴Electrical Engineering, Stanford University, ⁵Eagle Vision Pharmaceutical Corporation, Downington, PA, United States

Human Amnion-derived Mesenchymal Stem Cells (hAMSCs) were transplanted into the infarct and peri-infarct regions of a pig ischemia-reperfusion model. The hAMSC therapy improved cardiac systolic function post-MI, compared to control animals, and Cardiac MRI with Manganese-Enhanced MRI (MEMRI) was able to detect increased CNR from live populations of hAMSCs within infarct and peri-infarct zones, as confirmed by human nuclear antigen (hNA) immunostaining.

Anna V Naumova^1,2, Vasily L Yarnykh^1,2, Niranjan Balu^1,2, Hans Reinecke^2,3, Charles E Murry^2,3, and Chun Yuan^1,2
1Radiology, University of Washington, Seattle, WA, United States, ²Center for Cardiovascular Biology, University of Washington, Seattle, WA, United States, ³Pathology, University of Washington, Seattle, WA, United States

Mouse skeletal myoblasts were genetically modified to overexpress ferritin, a natural iron storage protein. T2 relaxivity of ferritin-tagged cells dramatically increased with increase of the magnetic field strength; thus improves MRI graft identification and assessment of the graft size. Transgenic grafts overexpressing ferritin decreased MRI signal intensity by 30% at the 3T magnetic field strength and by 50% at the 14T magnetic field strength. Unlabeled cells transplanted to the mouse heart did not cause MRI signal intensity change and were indistinguishable from host tissue.

Ethel Ngen¹, Yoshinori Kato¹, Wenlian Zhu¹, and Dmitri Artemov^1
1Russell H. Morgan Department of Radiology and Radiological Sciences, ICMIC Program, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States

Given the current need to non-invasively monitor transplanted stem cell viability and integration in vivo, we evaluated the ability of a novel MRI stem cell tracking technique to monitor cell viability in vivo. Stem cells were labeled with both high molecular weight negative and low molecular weight positive contrast agents, then implanted contra-laterally to a cerebral lesion in both immunodeficient and immunocompetent mice. Following graft rejection in immunocompetent mice, T1 enhancement was observed in the surrounding site. These results suggest that T1 changes in the surroundings of transplanted stem cells could be used to track, their viability in vivo.

Yanfeng Meng¹, Jinnan Wang², Jihong Sun¹, Feng Zhang¹, Patrick Willis¹, Jiakai Li¹, Han Wang¹, Tong Zhang¹, Stephanie Soriano¹, Bensheng Qiu¹, and Xiaoming Yang^1
1Radiology, University of Washington, Seattle, WA, United States, ²Clinical Sites Research Program, Philips Research North America

This study was to develop a new technique, using molecular MRI to monitor local agent delivery to coronary artery walls for potential MRI-guided prevention of in-stent restenosis. The study was divided into three phases. For the in vitro confirmation, we determined the optimum dose of Motexafin Gadolinium (MGd), a multifunctional intracellular T1 MR contrast/anti-atherosclerotic agent. For ex vivo and in vivo study, we infused MGd/trypan blue the coronary arterial walls under MRI, which were correlated with histology confirmation. This study initially demonstrates the possibility of using MRI to monitor the local agent delivery and distribution in the coronary arterial walls.

lin Gao¹, zhiyong Wang¹, lisi Xie², xiaojing Long¹, zhiying Chen³, and bensheng Qiu^1,4
1Paul C Lauterbur Research Center for Biomedical Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China, ²Faculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Gaungzhou, Guangdong, China, ³Gene and Cell Engineering Center, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China, ⁴Department of Radiology, University of Washington School of Medicine, Seattle, Washington, United States

An amphiphilic polymer, stearic-polyethylenimine (PEI600) was synthesized and used for modified hydrophobic supermagnetic iron oxide (SPIO) nanocrystals via self-assemble progress in aqueous phase. The nanocomposite system is novel magnetic imaging contrast agents and capable to bind and deliver plasmid DNA for gene transfection. In vivo, it was observed that MR signal decreased significantly via a clinical 3.0T MRI scanner. The histochemistry of tissue sections of liver results showed that this nanoparticle gene delivery system provided a safe and efficient method for gene delivery with non-invasive imaging monitoring capability.

Jens T Rosenberg^1,2, Megan Muroski³, Tom Morgan⁴, Cathy Levenson⁴, Geoffrey Strouse³, and Samuel Colles Grant^1,2
1Center for Interdisciplinary Magnetic Resonance, The National High Magnetic Field Laboratory, Tallahassee, FL, United States, ²Chemical & Biomedical Engineering, The Florida State University, Tallahassee, FL, United States, ³Chemistry and Biochemistry, The Florida State University, Tallahassee, FL, United States, ⁴Biomedical Sciences, The Florida State University, Tallahassee, FL, United States

Mesenchymal stem cells (MSCs) have demonstrated significant potential for use in the treatment of nervous system injuries, mainly through the secretion of protective proteins rather than direct regeneration. The transport, secretory profile and ultimate fate of MSCs are still areas of active research. The current study reports on a fluorescein and DNA plasmid functionalized iron oxide nanoparticle that has been instituted successfully in MSCs. Used in an animal stroke model, the nanoparticle imparts multimodal MR and optical imaging capabilities as well as genetically modifies MSCs to express in vivo mCherry fluorescence, a precursor to other manipulations of MSC protein expression.

Jens T Rosenberg^1,2, Katelyn Sellgren², Michelle A Baird³, Micheal W Davidson^3,4, Teng Ma², and Samuel Colles Grant^1,2
1Center for Interdisciplinary Magnetic Resonance, The National High Magnetic Field Laboratory, Tallahassee, FL, United States, ²Chemical & Biomedical Engineering, The Florida State University, Tallahassee, FL, United States, ³The National High Magnetic Field Laboratory, Tallahassee, FL, United States,⁴Department of Biological Science, The Florida State University, Tallahassee, FL, United States

Labeling of human mesenchymal stem cells (hMSCs) with superparamagnetic iron oxides (SPIOs) have been demonstrated but few studies have investigated biological impacts or long term tracking capability, especially under stroke conditions. This study shows that hMSCs display dose dependent SPIO uptake and progressive decreases in contrast over extended culture mimicking the maximum expected transplant duration. Though other biological effects were impacted minimally by SPIOs, hypoxic ischemic conditions increased cytotoxicity significantly, with vulnerability related to SPIO exposure. This finding needs to be considered when introducing intracellular contrast agents for cellular based regenerative therapies in an ischemic, low oxygen environment.

Ina Vernikouskaya^1,2, Natalie Fekete³, Alexander Erle³, Hubert Schrezenmeier³, and Volker Rasche^1,2
1Internal Medicine II, University Hospital of Ulm, Ulm, Baden-Wuerttemberg, Germany, ²Small Animal MRI, University of Ulm, Ulm, Baden-Wuerttemberg, Germany, ³Institute of Clinical Transfusion Medicine and Immunogenetics, University Hospital of Ulm, Ulm, Baden-Wuerttemberg, Germany

The objective of this study was to use chemically defined silicone carrier as an delivery aid of the iPLLA-labeled MSCs to the skin wounds for further monitoring of the cell trafficking using MRI. The magnetic properties of iPLLA nanoparticles were investigated at 3T and at 11.7T. In vitro imaging of a silicone carrier with attached labeled MSCs allowed to determine the amount of cells which could be good visualize and still remains attached to the carrier. In vivo imaging showed the attraction of the labeled MSCs to the skin wound and demonstrated that silicone carriers could be used as a vehicle for the application of MSCs to surface wounds.

Zhengyi Yang¹, Viktor Vegh¹, Ian Turner², and David Reutens^1
1Center for Advanced imaging, The University of Queensland, Brisbane, Queensland, Australia, ²School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia

Attenuation correction in PET/MRI imaging is a challenging task because the attenuation map is difficult to be calculated due to the lack of information on tissue classification in MRI image. Consistency conditions on PET emission data contain useful information on the attenuation map and can be employed to regularize the creation of MRI-based attenuation map. In this study, the efficacy of consistency conditions were validated on simulated images of normal brain and brain with lesion. The results indicated these conditions are insensitive to brain lesions in finding the attenuation coefficients of each tissue class.

Ryan Chamberlain¹, Michael Etheridge², Djaudat Idiyatullin¹, Curt Corum¹, John Bischof², and Michael Garwood^1
1Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States, ²Department of Mechanical Engineering, University of Minnesota, Minneapolis, MN, United States

Iron oxide magnetic nanoparticles (MNPs) are widely used in MRI as a T2- and T2*-shortening contrast agent. Quantifying high concentrations of MNPs is crucial in magnetic fluid hyperthermia for cancer therapy. Efforts to quantify MNP concentration have relied on T2* mapping; however, signal loss is a severe obstacle to quantifying high concentrations of MNPs based on traditional MRI methods. Here we use the SWIFT pulse sequence to accomplish T1 measurement of solutions with very high iron concentration and show how the measured T1 value may be used in place of T2* to quantify high concentrations of MNPs.

Eliana Gianolio¹, Enza Di Gregorio¹, Rachele Stefania¹, and Silvio Aime^1
1Chemistry IFM & Molecular Imaging Center, University of Torino, Torino, Italy, Italy

Herein we report a mass spectrometric method for accurate detection and quantification of a Gd-complex after its internalization in living cells. This method allowed to determine if, and how Gd-complexes endowed with different thermodynamic stability can be transformed once entrapped into living cells.

Mangala Srinivas¹, Fernando Bonetto², Jurjen Tel¹, Gerty Schreibelt¹, Javier Cruz³, Arend Heerschap⁴, Carl Figdor¹, and Jolanda de Vries^1
1Tumor Immunology, RUNMC, Nijmegen, Gelderland, Netherlands, ²INTEC-CONICET, Argentina, ³Molecular Imaging, UMC Leiden, Leiden, Netherlands,⁴Radiology, RUNMC, Nijmegen, Gelderland, Netherlands

The use of 19F MRI for cell tracking is a relatively new field. We demonstrate the tracking of two distinct primary human dendritic cell subsets, as used in clinical trials, using distinct 19F resonances. Typically, such multispectral analyses are done using chemical shift imaging (CSI); here we use a modified gradient echo sequence to image both cell populations simultaneously, quantitatively and efficiently (several fold faster than CSI). We use clinically applicable nanoparticle labels, with distinct fluorescent dyes to enable multimodal imaging. We find that labeling has minimal effect on cells, in terms of viability, maturation and migration.

Dattesh D Shanbhag¹, Sheshadri Thiruvenkadam¹, Sandeep Kaushik¹, Rakesh Mullick², Scott D Wollenweber³, and Florian Wiesinger^4
1Medical Image Analysis Laboratory, GE Global Research, Bangalore, Karnataka, India, ²GE Global Research, Biosignatures & Signal Processing, Bangalore, Karnataka, India, ³GE Healthcare, PET Clinical Science, Waukesha, WI, United States, ⁴Diagnostics & Biomedical Tech Laboratory, GE Global Research, Garching b. Munchen, Germany

We have demonstrated an automated workflow for generation of the attenuation map for body Dixon-based MRI for PET attenuation correction. The use of a tri-modality system with dedicated patient transporter results in minimal degree of motion between PET-CT and MRI scans and thereby improves the validation accuracy of attenuation correction of MR-PET system with gold standard PET-CT system.

Peter Linz¹, Davide Santoro², Wolfgang Renz³, Jan Ruff³, Michael Deimling³, Dominik N. Müller^4,5, Jens Titze^1,4, Friedrich C Luft⁵, and Thoralf Niendorf^2
1Department of Nephrology and Hypertension, University Clinic Erlangen, Erlangen, Germany, ²Berlin Ultrahigh Field Facility, Max-Delbrueck Center for Molecular Medicine, Berlin, Germany, ³Siemens Healthcare, Erlangen, Germany, ⁴Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nuernberg, Erlangen, Germany, ⁵Experimental and Clinical Research Center (ECRC), Max-Delbrueck Center for Molecular Medicine, Berlin, Germany

Intake of sodiumchloride (NaCl) contributes to hypertension and target-organ damage. Na is stored in the interstitial compartment of the skin but little is known about Na-metabolism in humans. Skin-Na contents in nine healthy men (25-68 years) were measured with 0.9mm X 0.9mm in-plane resolution 23Na-MRI at 7.0T using an optimized surface-coil and a 10min gradient-echo sequence. Intra-subject variability was found to be below 6%. High tissue concentrations up to 60mmol/L were measured. Skin-Na content increased with age comparable to the probability of becoming hypertensive. Best correlations were achieved with a Boltzmann-fit and a maximum slope at 38±5 years.

Kim Kangasniemi¹, Koji Sagiyama¹, Boning Gao², Chunxian Huang², John Minna³, and Masaya Takahashi^1
1Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States, ²Hamon Center for Therapeutic Oncology, Pharmacology, University of Texas Southwestern Medical Center, UT Southwestern Medical Center, Dallas, TX, United States, ³Hamon Center for Therapeutic Oncology, Internal Medicine, Pharmacology, UT Southwestern Medical Center, Dallas, TX, United States

The proton exchange between amide groups in mobile proteins/peptides and free water in two different human cancer cell lines and normal cell line were studied. Amide proton transfer (APT) imaging is one of the chemical exchange saturation transfer (CEST) imaging methods was utilized to differentiate between the tumors. A comparison in magnetization transfer between cell tumor lines showed a difference in APT signal, suggesting that tumor type characterization can be done by in-vivo APT imaging.

Lindsey A Crowe¹, Sophie Borot², Sonia Nielles-Vallespin³, Christian Toso², Domenico Bosco², Thierry Berney², and Jean-Paul Vallée^1
1Faculty of Medicine/Department of Radiology, University of Geneva, Geneva, Switzerland, ²Islet Isolation and Transplantation Center, Visceral Surgery Department, Geneva University Hospital, Geneva, Switzerland, ³Royal Brompton Hospital, London, United Kingdom

dUTE positive contrast MRI images can be further improved using susceptibility-weighting information from the long echo phase image to enhance contrast and further suppress background to homogeneous near-zero values for the UTE-TE(2) difference image. In-vivo MR imaging of iron-labelled islet cells in the liver are used to illustrate the technique.

Koji Sagiyama¹, Osamu Togao¹, Tomoyuki Mashimo^2,3, Kim Kangasniemi¹, Vamsidhara Vemireddy^3,4, Kimmo J. Hatanpaa⁵, Melissa A. Maddie^3,4, Robert M. Bachoo^3,4, Elizabeth A. Maher^2,3, A. Dean Sherry¹, and Masaya Takahashi^1
1Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, Texas, United States, ²Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, United States, ³Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, United States, ⁴Department of Neurology, UT Southwestern Medical Center, Dallas, Texas, United States, ⁵Departement of Pathology, UT Southwestern Medical Center, Dallas, Texas, United States

Amide proton transfer (APT) imaging shows increasing interest in characterization of the brain tumor. The objective of our study is to investigate whether APT imaging can be used for monitoring treatment responses of the brain tumor in chemotherapy. In the present study, we compared the temporal changes of APT ratio in glioblastoma multiforme (GBM) in a mouse model with and without chemotherapy by Temozolomide which is widely used for the treatment of GBMs.

Guanshu Liu^1,2, Kannie WY Chan^2,3, Xiaolei Song^2,3, Jiangyang Zhang^2,4, Assaf A Gilad^2,3, Jeff WM Bulte^2,3, Peter CM van Zijl^2,4, and Michael T McMahon^2,4
1F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Instittute, Baltimore, Maryland, United States, ²Department of Radiology, Johns Hopkins University School of Medicine, baltimore, maryland, United States, ³Cellular Imaging Section, Institute for Cell Engineering, Johns Hopkins University School of Medicine, baltimore, maryland, United States, ⁴F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, baltimore, maryland, United States

Signal contamination and partial volume effects significantly influence in vivo CEST quantification. To improve upon this, we propose a simple magnetization transfer (MT) based segmentation method based on adding two MT weighted images at offsets of -12.5 and -50 ppm to CEST acquisitions. These are used to calculate a NOrmalizedMAgnetization Ratio (NOMAR) allowing pixels containing fat or fluids to be separated from target tissues using a global threshold determined by histogram analysis. As a first application, we demonstrate that this technique can significantly improve the detection of DIACEST liposomes injected into live mice.

H. Douglas Morris¹, and J. Andrew Derbyshire^2
1NIH Mouse Imaging Facility, National Institutes of Health, Bethesda, MD, United States, ²Laboratory for Cardiac Energetics, National Institues of Health, Bethesda, MD, United States

Rapid individual cell tracking of endogenously labeled stem cells is shown using high-field MRI and balanced Steady-State Free Procession sequences. We present a field artifact suppression technique based on the Golden Angle progression for the RF phase cycle as a modification to Linear Combination SSFP (LCSSFP). The use of golden-angle LCSSFP yields a temporally flexible acquisition scheme that can yield continuous progression of resulting images that do not overlap in pulse-band artifacts. This resulting method can yield very high resolution images quickly with few global artifacts while still tracking magnetic particles.

Jia Zhong^1,2, Parker H Mills^1,2, T Kevin Hitchens^1,2, and Eric T Ahrens^1,2
1Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States, ²The Pittsburgh NMR Center for Biomedical Research, Carnegie Mellon University, Pittsburgh, PA, United States

Compressed sensing (CS) has been used to significantly reduce acquisition times in a variety of MRI applications. In the current study, we describe a 3D CS method for accelerated 19F MRI and signal quantification that is suitable for cell tracking using perfluorocarbon (PFC) labels. The method’s utility was demonstrated in a localized inflammation mouse model, where the quantification of PFC 19F spins in macrophages was performed at the inflammatory site. The 3D CS method displays great potential in advancing in vivo 19F MRI cell tracking to different applications including longitudinal tracking of 19F-labeled cells and in vivo cytometry.

Bart Cornelissen¹, Veerle Kersemans¹, Philip Allen¹, Sarah Able¹, Sean Smart¹, and Katherine Vallis^1
1Department of Oncology, University of Oxford, Oxford, OXON, United Kingdom

A poly-ethylene-glycol conjugated (PEGylated) form of nano-graphene oxide (NGO) was shown to target tumour xenografts, but its mechanism of tumour targeting is not elucidated yet. Here, we show that DCE-MRI proved a valuable tool to study the biodistribution and tumour delivery characteristics of radiolabelled nano-graphene oxide. Taken together, these results suggest that the tumour uptake of NGO-PEG depends heavily on tumour vascular density and permeability.

Houshang Amiri^1,2, Morteza Mahmoudi³, Valerio Zerbi^1,4, and Arend Heerschap^1
1Department of Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ²Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ³National Cell Bank, Pasteur Institute of Iran, Tehran, Iran, ⁴Department of Anatomy, Donders Centre for Neurosciences, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

We have given a comprehensive overview of the current developments in Alzheimer's disease (AD) and focused on the most recent advances in the theranosis strategies using magnetic nanoparticles (MNPs). Functionalized MNPs also have been introduced as smart drug delivery systems. Finally we have discussed state-of-the-art in MRI to track MNPs over time with a special emphasis on the molecular/cellular imaging technique.

Houshang Amiri^1,2, Mangala Srinivas², Carl Figdor², Jolanda de Vries², and Arend Heerschap^1
1Department of Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ²Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

We introduce 19F MRI and its advantages. We focus on the use of 19F MRI for molecular and cellular imaging and 19F signal quantification. The effect of hardware and RF coils; software, acquisition sequences and imaging parameters, on sensitivity are discussed. In particular we focus on the optimization of signal to noise acquired per unit time. The possible clinical application of 19F MRI will be addressed, together with safety concerns. This educational review endeavours to make the technical aspects of MRI, particularly 19F MRI, understandable to biologists and medical researchers.
 

Jelena Kolosnjaj-Tabi^1,2, Jose Vilar², Nathalie Luciani¹, Claire Wilhelm¹, Gwennhael Autret², Daniel Balvay², Jean-Sebastien Silvestre², Florence Gazeau¹, and Olivier Clément^2
1Paris-Diderot University, Laboratoire Matière et Systèmes Complexes, Paris, Ile de France, France, ²Paris Cardiovascular Research Center-PARCC / Paris-Descartes University, Paris, Ile de France, France

The effects of cellular therapy have been recognized long ago. However only recent advances in molecular imaging allow approaches that enable assessment of distribution and evaluation of regenerative effects of cells in vivo in real time. Here we describe a high-resolution MRI method performed at 4.7 T with a cryogenic probe, that allows detection and concomitant quantification of infiltration of magnetically labelled monocytes to ischemic murine paws and quantification of pro-angiogenic action of administered cells.