Erica Marie Andreozzi¹, Marc Dhenain², and Angelique Louie^1
1Biomedical Engineering, University of California, Davis, Davis, CA, United States, ²MIRCen, URA CEA CNRS 2210, Fontenay aux Roses, France

Herein, we report the encapsulation of Gadolinium-DOTA (Gd-DOTA) into solid lipid nanoparticles (SLNs) for use as a stable, long-circulating, biocompatible T1-weighted agent. We have confirmed that these Gd-loaded SLNs are stable in size and Gd content over time, and have previously shown that they have a longer blood half-life in mice compared to free Gd-DOTA. Relaxivity measurements (1.4 T, 37°C) of these Gd-loaded SLNs indicate an r1 value of ~2.5 mM-1sec-1 in vitro, and intracerebral ventricular (ICV) injection of the Gd-loaded SLNs in mice confirms the ability for these particles to provide positive contrast enhancement in vivo using T1-weighted imaging.

Zhen Ye^1,2, Xueming Wu², and Zheng-Rong Lu^2
1Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, United States, ²Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States

A neutral biodegradable polymeric MRI contrast agent containing macrocyclic Gd chelates, GOLS, were synthesized and evaluated for clinical contrast-enhanced MR imaging. The agent had higher relaxivity than clinical agents, and can be readily degraded. Kinetic stability study showed that this agent had significantly higher stability against transmetallation than polymer based on linear chelates. The contrast-enhancing efficacy of GOLS was evaluated on mice bearing orthotopic 4T1 breast tumor. Significantly higher tumor enhancement was generated by GOLS than clinical agents. This new agent is of great potential as a safe and effective contrast agent in contrast enhanced MRI.

Erik C. Wiener¹, Raghvendra Sengar², Luce Vander Elst³, Marie-Caline Abadjian⁴, Curtis E Moore⁵, Arnold L Rheingold⁵, and Douglas Grotjahn^6
1University of Pittsburgh, Pittsburgh, PA, United States, ²University of Pittsburgh, Johnstown, United States, ³General, Organic and Biomedical Chemistry, University of Mons, Mons, Belgium, ⁴San Diego State University, United States, ⁵University of California, San Diego, California, United States, ⁶San Diego State University, San Diego, California, United States

MRI offers the promise of molecular and cellular imaging by using exogenous or endogenous markers. Using exogenous stains requires suitable concentrations at the desired target by delivery of large numbers of paramagnetic or super paramagnetic ions, or a smaller number of more highly efficient agents. This report presents the syntheses of two new bifunctional Gd(III) chelates, with optimal water exchange rates, that can be coupled to other molecules using either click or peptide coupling chemistry. Nuclear magnetic relaxation dispersion experiments demonstrate 100% higher relaxivities then their slower exchange rate controls. Water residence times are measured using 17O NMR.

Klaus Kruttwig¹, Diego R. Yankelevich², Chantal Brueggemann³, Chuqiao Tu¹, Erica Andreozzi¹, Noelle L'Etoile³, André Knoesen², and Angelique Y. Louie^1
1Department of Biomedical Engineering, University of California Davis, Davis, CA, United States, ²Department of Electrical and Computer Engineering, University of California Davis, Davis, CA, United States, ³Center for Neuroscience, University of California Davis, Davis, CA, United States

The work performed here describes as a long term goal a method to noninvasively map gene expression in deep tissues in vivo by developing magnetic resonance contrast agents (MRI CA) that are responsive to commonly employed luminescent biomarker systems. Photoswitchable spiropyran has been conjugated to the crowned ring system DO3A complexed with the lanthanide ion Gadolinium(III). This leads to a photoresponsive MRI CA that displays an increased spin-lattice relaxation time (T1) upon visible light stimulation. The photo response of this contrast agent to weak light illumination using light emitting diodes was investigated, simulating the emission spectra from Gaussia princeps luciferase.

Jens T Rosenberg^1,2, Micheal L Matson^3,4, Brandon T Cisneros³, Michelle Sokoll², Fabian Calixo-Bejarano¹, Lon J Wilson³, 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, ³Department of Chemistry and The Smalley Institute for Nanoscale Science and Technology, Rice University, Houston, TX, United States, ⁴Natural Sciences, University of Houston-Downtown, Houston, TX, United States

Ultra-short, singled walled carbon nanotubes (US-tubes) that encapsulate gadolinium (Gd) have shown MRI cell tracking capabilities. Their biocompatibility together with a hollow interior and potentially beneficial water access are factors of interest especially at high magnetic fields. In this study, Gd-doped US-tubes are compared to a high field optimized, dysprosium (Dy) variant. Results suggest that doped US-tubes in solution follow theoretical field-dependent changes in relaxation for the two lanthanides. Once incorporated into cells, T₁ contrast is quenched while T₂ and T₂* contrast dominates. Dy-doped US-tubes have overall shorter transverse relaxation times and compares favorably to other Dy-based agents.

Maja C. Cassidy¹, Brandon D. Armstrong¹, Henry R. Chan², Brian D. Ross², Pratip K. Bhattacharya², and Charles M. Marcus^1
1Harvard University, Cambridge, MA, United States, ²Huntington Medical Research Institutes, Pasadena, CA, United States

 

Rishi Awasthi¹, Sachidanand Srivastava², Namdeo S Gajbhiye³, Deepak Tripathi⁴, Mohit Kumar Rai⁴, Vikas Agarwal⁴, Vinita Agrawal⁵, and Rakesh Kumar Gupta^1
1Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Lucknow, Uttar Pradesh, India, ²Chemistry, Indian Institute of Technology, Kanpur, Lucknow, Uttar Pradesh, India, ³Chemistry, Indian Institute of Technology, Kanpur, Kanpur, Uttar Pradesh, India, ⁴Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Lucknow, Uttar Pradesh, India, ⁵Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Lucknow, Uttar Pradesh, India

A new type of MR/fluorescence multimodal imaging probe has been developed using fluorescent carbon nanomaterials and Fe3O4 (6 nm) magnetic nanoparticles. The prepared nanocomposite satisfies the primary conditions for both MR as well as fluorescence imaging: i.e (i) superparamagnetic nature; & (ii) wavelength tunable fluorescence properties with high fluorescence quantum yield (QY). The obtained results of in-vivo MR and fluorescence imaging strongly suggest that these multimodal imaging probes can be used as MR contrast agent and equally effective fluorescent biomarker. This novel and facile approach opens up a new route to design carbonaceous based multifunctional nanocomposites for various biomedical applications including various types of multimodal imaging as well as effective drug delivery systems and targeting agents.

Jing Huang¹, Liya Wang¹, Qiqi Yu¹, Andrew Wang², and Hui Mao^1
1Radiology and Imaging Sciences, Emory University, Atlanta, GA, United States, ²Ocean Nanotech LLC, Springdale, Arkansas, United States

Milk protein (casein) coated iron oxide nanoparticles (CSIOs) are fabricated and investigated for potential MRI probes in molecular imaging. Due to the specific protein coating, these CSIOs have been demonstrated to have higher T2-weighted MRI contrast enhancement, as well as a wide range pH stability, compared with that of conventional polymer coated iron oxide nanoparticles.

Cyril Lorenzato¹, Alexandru Cernicanu², Baudouin Denis de Senneville¹, Pierre Smirnov¹, Marie-Edith Meyre³, Matthieu Germain³, Mario Ries¹, and Chrit Moonen^1
1Molecular and Functional Imaging: from Physiology to Therapy (IMF), Bordeaux, France, ²Philips Healthcare, Suresnes, France, ³Nanobiotix, Paris, France

Thermosensitive magnetoliposomes (TSM) can be prepared to contain drugs as well as super paramagnetic contrast agent. This would allow heat induced drug release, while detecting the release by simultaneously imaging relaxivity changes. Here, we propose a fast dynamic MRI method to simultaneously monitor temperature, T2*, and T1-changes in a gel doped with USPIO-charged TSM during heating. From a sigmoidal fit to the ∆T1 evolution the half-time of release at each voxel is obtained as well as estimate of the temperature of release, effectively characterizing the heat-induced release of USPIO from the TSM.

James S Ratnakar¹, Subha Viswanathan¹, Matthew E. Merritt¹, Chien-Yuan Lin¹, A. Dean Sherry¹, and Zoltan Kovacs^1
1Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, Texas, United States

The CEST properties of a Eu(III)-DOTA-tetraamide complex having two covalently appended TEMPO (2,2,6,6-(tetramethylpiperidin-1-yl)oxyl) units can be turned on under reducing conditions due to the reduction of the paramagnetic TEMPO moieties to its diamagnetic hydroxylamine derivative.

Federica Rossella¹, Christopher Witte¹, and Leif Schröder^1
1Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany

Xenon biosensors are currently under development as a new type of contrast agent. They contain a molecular cage to temporarily trap the detected hyperpolarized 129Xe. To improve our understanding of their interaction with cells, fluorophore-labelled cages have been proposed. However, attachment of functional units like dyes may influence exchange dynamics and accessibility of the noble gas to its host, thereby potentially hampering the Hyper-CEST signal amplification technique that has been successfully applied to biosensor detection. Here, we present proof that a flexible linker between the cage and the dye ensures full Hyper-CEST performance as a prerequisite for future NMR studies.

Xueming Wu¹, Niranjan Balu², Wen Li¹, Yong Chen¹, Xin Yu¹, Chun Yuan², and Zheng-Rong Lu^1
1Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States, ²Department of Radiology, University of Washington, Seatle, Washington, United States

This study designed, synthesized and evaluated a peptide-based low molecular weight MRI contrast agent specific to clotted plasma proteins for molecular imaging of atherosclerotic plaques with MRI. The atherosclerotic plaque imaging effectiveness of the targeted agent was demonstrated by using an atherosclerotic apolipoprotein E–deficient mouse model. Our preliminary results demonstrate that the newly developed targeted MRI contrast agent is promising for noninvasive assessment of plaque progression in an atherosclerotic mouse model.

Jacob Wheatley Myerson¹, Li He², John Stacy Allen², Todd A Williams², Douglas M Tollefsen², Gregory M Lanza^1,2, Shelton D Caruthers¹, and Samuel A Wickline^1,2
1Biomedical Engineering, Washington University in Saint Louis, Saint Louis, Missouri, United States, ²Medicine, Washington University in Saint Louis, Saint Louis, Missouri, United States

Perfluorocarbon nanoparticles functionalized for thombin inhibition with Bivalirudin or PPACK were tested as an inhibitor of thrombin in vitro and in acute thrombosis models. The particles significantly inhibited occlusive arterial thrombi. Via specific polyvalent binding to activated thrombin, the particles also manifested binding providing magnetic resonance contrast highlighting thrombi.

Maxim Terekhov¹, Kurt Reifenberg², Alexander Scholz¹, Stefan Weber¹, Stefan Fischer¹, Vasilyi Sen'³, Valery Golubev³, Thomas Münzel⁴, Andrei L Kleschyov⁴, and Laura Maria Schreiber^1
1Section of Medical Physics, Radiology Department, University Medical Center Mainz, Mainz, Germany, ²Central Animal House, University Medical Center Mainz, Mainz, Germany, ³. Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Russian Federation, ⁴II-Department of Medicine, University Medical Center Mainz, Mainz, Germany

Cyclic nitroxides (CNR) are stable free radicals with multiple applications in MRI. Heparin is known to have a high affinity for the vascular extracellular structures. We propose that CNR could be delivered to the vascular wall by means of heparin-polynitroxide (HPR) derivatives where the nitroxide is linked with the heparin macromolecule. The first in-vivo studies show that high molecular HPN exhibits the long-lasting in-vivo life time and bind irreversibly to the inner layer of vascular wall, where they can be visualized both by EPR and MR techniques.

Lisette H. Deddens¹, Geralda A. F. Van Tilborg¹, Annette Van der Toorn¹, Willem J. M. Mulder², Helga E. De Vries³, and Rick M. Dijkhuizen^1
1Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, Netherlands, ²Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, New York, United States, ³Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands

Vascular remodeling is a key process in stroke pathophysiology and plasticity. This abstract reports on a novel targeted contrast agent for MRI-based detection of the expression of the vascular marker PECAM-1. PECAM-1 is constitutively expressed on endothelium and regularly used as a target for histological vessel staining. We demonstrate that PECAM-1 mRNA and protein expression were highly increased in ipsilesional vessels as early as 24h after stroke in mice. MPIO targeted to PECAM-1 bound specifically to murine endothelial cells and significantly shortened the T2 of these cell samples compared to cells incubated with IgG-MPIO. PECAM-1-targeted MPIO may therefore provide a promising molecular MRI contrast agent to detect early stage vascular modifications after stroke.

Lisette H. Deddens¹, Geralda A. F. Van Tilborg¹, Annette Van der Toorn¹, Leonie E.M. Paulis², Gustav J. Strijkers², Gert Storm³, Willem J. M. Mulder⁴, Helga E. De Vries⁵, and Rick M. Dijkhuizen^1
1Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, Netherlands, ²Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands, ³Biopharmacy and Pharmaceutical Technology, Utrecht University, Utrecht, Netherlands, ⁴Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, New York, United States, ⁵Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands

Molecular imaging of neuroinflammation after stroke is a challenging field. In this abstract we describe the comparison between two multivalent contrast agent platforms targeted to ICAM-1, i.e. gadolinium-loaded liposomes and micron-sized particles of iron oxide. Particles were injected 24h after experimental stroke in mice, and MRI was performed directly after injection and 24h thereafter. Both types of particles effectively targeted ICAM-1 under in vitro and in vivo conditions, but significant in vivo detection with MRI in post-stroke mouse brain was only achieved with ICAM-1-targeted MPIO. Our data advocate the use of targeted MPIO as most effective contrast agent platform for in vivo molecular MRI after stroke.

Jang Woo Park¹, Hui-jin Song¹, Hee-Kyung Kim¹, Jee Hye Seo¹, Seong-Uk Jin¹, Jong Su Baeck¹, Moon Han¹, Ji-Young Kim², and Yongmin Chang^3,4
1Department of Medical & Biological Engineering, Kyungpook National University, daegu, Korea, ²Department of School of Medicine, Kyungpook National University, daegu, Korea, ³Department of Diagnostic Radiology, Kyungpook National University, daegu, Korea, ⁴Kyungpook National University, Department of Molecular Medicine, daegu, Korea

Magnetic resonance imaging (MRI) allows the direct visualization of the bone and soft tissues and inflammatory activity. Angiogenesis is known to play a significant role in RA. We researched the inflammatory angiogenesis in RA using angiogenesis specific MR contrast agent, Gd-DOTA-RGD. Arginine-glycine-aspartic (RGD) peptide is well known to have a high specific affinity for ¥áv¥â3-integrin, which is over-expressed in endothelial cells during angiogenesis. Targeting and blocking experiments about ¥áv¥â3-integrin receptors were used to confirm integrin specific contrast enhancement of Gd-DOTA-RG. This study demonstrates the successful application of Gd-DOTA-RGD as a potential molecular MR agent for inflammatory disease such as RA with specificity to ¥áv¥â3-integrin receptor in the inflammatory angiogenesis.

Gavin D Kenny^1,2, Alison Bienemann³, Katharina Welser⁴, Frederick Campbell⁴, Aristides D Tagalakis¹, Mauro Botta⁵, Alethea B Tabor⁴, Ed White³, Mark F Lythgoe², and Stephen L Hart^1
1Molecular Immunology Unit ICH, UCL, London, United Kingdom, ²Centre for Advanced Biomedical Imaging, UCL, London, United Kingdom, ³Functional Neurosurgery Group, University of Bristol, Bristol, United Kingdom, ⁴Department of Chemistry, UCL, London, United Kingdom, ⁵Dipartimento di Scienze dell 'Ambiente e della Vita, Università del Piemonte Orientale "Amedeo Avogadro", Alessandria, Italy

Genetic therapies offer great promise for the development of new therapeutics in the CNS. One of the major obstacles to overcome is the inability to effectively bypass the BBB and deliver the therapeutic nucleic acids to the affected region. Nanoparticles are extensively used as delivery vectors for genes due to their biocompatibility and the protection they afford the gene and if administered using convection enhanced delivery the BBB can be circumvented. Here we have investigated the use of anionic nanoparticles, that are MR sensitive, contain labels for fluorescence microscopy/histology, in combination with a targeting peptide to mediate the functional delivery.

Hyunseung Lee¹, Hyeyoung Moon¹, Sankarprasad Bhuniya², Jong Seung Kim², and Kwan Soo Hong^1,3
1Division of MR Research, Korea Basic Science Institute, Cheongwon-gun, Chungcheongbuk-Do, Korea, ²Department of Chemistry, Korea University, Seoul, Korea, ³Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea

The chelated Gd3+ metal ion improves imaging contrast by increasing the longitudinal relaxation time (T1) of proximal water protons, which appear brighter in the T1-weighted image. Current advanced medical diagnosis techniques stipulate high-resolution images with a high magnetic field scanner; however, current Gd3+-based contrast agents (CAs) ligated with polyamino carboxylate are incapable of meeting requirements as they do not have optimal relaxivity profiles at high magnetic fields.

Esmaeel Reza Dadashzadeh^1,2, L. Henry Bryant Jr.³, Dana D. Dean¹, Bobbi Lewis¹, and Joseph A Frank^1,4
1Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, United States, ²Howard Hughes Medical Scholar, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, United States, ³Laboratory of Diagnostic Radiology Research, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, ⁴Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health

A straight-forward method has been developed to label cells with self-assembling nanocomplexes (NC) that form by combining three FDA-approved agents: ferumoxytol (F), heparin (H) or fragmin (Fr), and protamine sulfate (P). HPF or FrPF NC self-assemble and flocculate over time and can be isolated by lyophilization to form solid NC. Lyophilization appears to stabilize NC based on the dynamic polydispersion profile (size and PDI) over the time-course of 24h. Intracerebrally implanted HPFL-labelled neural stem cells migrated to growing metastatic breast cancer in rat brain demonstrating the utility of this family of NC to label cells for use in cellular MRI.

Ilgar Mamedov¹, Joern Engelmann², Gisela Hagberg¹, Oxana Eschenko¹, and Nikos K Logothetis^1,3
1Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Tuebingen, BW, Germany, ²High Field Magnetic Resonance Center, Max Planck Institute for Biological Cybernetics, ³Imaging Science and Biomedical Engineering, University of Manchester, Manchester, United Kingdom

A Gd3+ based paramagnetic dextran conjugate has been developed, which enables the tracking of neuroanatomical connectivity in the brain by both MR and optical imaging. Cell studies demonstrated that the synthesized tracer was efficiently internalized into neuronal cells and transported toward the axons. Furthermore, our preliminary in vivo experiments revealed efficient transportation of the conjugate, thereby proving its applicability for neuroanatomical studies by T1-weighted MRI. Initial in vivo experiments in rodents demonstrated the significant potential of this method.

Xiaoli X. Liu¹, Achuthamangalam B. Madhankumar¹, Patti A. Miller², Kari A. Duck¹, James R. Connor¹, and Qing X. Yang^2
1Neurosurgery, The Pennsylvania State College of Medicine, Hershey, PA, United States, ²Radiology, The Pennsylvania State College of Medicine, Hershey, PA, United States

A formulation liposome has been developed to encapsulate Gd-DTPA (Liposome-Gd) for targeted imaging of glioma. However, it is not clear whether Liposme-Gd is able to cross intact blood brain barrier (BBB) so that it can be used for detecting tumors at early stage when treatment is more effective. Our data obtained from normal mice with intact BBB demonstrated the first and direct evidence that liposome-Gd are capable of crossing BBB, which creates a great potential application in imaging of gliomas.

Robert Zivadinov¹, Sara Hussein¹, Cheryl Kennedy¹, Niels Bergsland¹, Christina Brooks², and Michael G Dwyer^1
1Buffalo Neuroimaging Analysis Center, Buffalo, NY, United States, ²Buffalo Neuroimaging Analysis Center

This was prospective, randomized, cross-over, blinded study that included 86 RRMS patients who underwent brain, 53 spinal cord and 40 optic nerve MRI exams at both 1.5T and 3.0T. The same scanning protocol was applied at two scanner field strengths (1.5T and 3.0T) after administration of MultiHance 0.1 mmol/kg body weight (injection, 529 mg/mL) with 5 min delay between injection and scanning. The use of a high relaxivity contrast agent, such as MultiHance at 3.0T field strength increases the diagnostic benefit in detecting enhancing lesions when compared intra-individually to the application of the same agent at 1.5 T.

Gavin D Kenny¹, Bhavana S Solanky², Italo A Sanhueza³, Nicholas J Mitchell³, Frederick Campbell³, Katharina Welser³, Mauro Botta⁴, Alethea B Tabor³, Helen C Hailes³, and Mark F Lythgoe^1
1Centre for Advanced Biomedical Imaging, UCL, London, United Kingdom, ²Institute of Neurology, UCL, London, United Kingdom, ³Department of Chemistry, UCL, London, United Kingdom, ⁴Dipartimento di Scienze dell 'Ambiente e della Vita, Università del Piemonte Orientale "Amedeo Avogadro", Alessandria, Italy

Nanoparticles are widely used as therapeutic delivery vectors in a wide range of diseases, due to their versatility. However, accurate monitoring of distribution is challenging using current techniques. Here, we have investigated the use of a novel fluorinated peptide incorporated into a nanoparticle for the monitoring of distribution and assessment of therapeutic delivery by taking advantage of the lack of endogenous 19F signal

Hongwei Chen^1,2, Qiqi Yu^1,3, Liya Wang^1,2, Weiping Qian⁴, Zehong Cao⁴, Lily Yang⁴, and Hui Mao^1,2
1Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, United States, ²Center for Systems Imaging, Emory University School of Medicine, Atlanta, Georgia, United States, ³Center for Systems Imaging, Emory University School of Medicine, Atlanta, GA, United States, ⁴Surgery, Emory University, Atlanta, GA, United States

Magnetic iron oxide nanoparticles (IONPs) coated with block copolymer poly(ethylene oxide)-block-poly(¦Ã-methacryloxypropyltrimeth oxysilane) (PEO-b-P¦ÃMPS) that exhibit a long blood circulation time (t1/2 = 12 h) in mice and low accumulation in both the liver and spleen. Conjugation of a HER2 antibody, or a single chain fragment (scFv) of antibody against epidermal growth factor receptor (scFvEGFR) to PEO-b-P¦ÃMPS coated IONPs (anti-HER2-IONPs or scFvEGFR-IONPs) results in HER2 or EGFR-targeted IONPS which specifically bind to HER2 over-expressing breast cancer cell line SK-BR-3 or EGFR positive MDA-MB-231 cells. Both antibody-conjugated and non-conjugated IONPs avoid non-specific uptake by mouse macrophages in vitro. Magnetic resonance imaging (MRI) of the mice bearing EGFR positive human breast cancer xenografts 24 h after systemic administration of scFvEGFR-IONPs led to signal reduction in tumors as the result of accumulation of the targeted IONPs and IONP induced transverse relaxation T2 weighted contrast.

Hyeonjin Kim¹, and Byung-Chul Oh^2
1Radiology, Seoul National University Hospital, Seoul, Seoul, Korea, ²Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea

Tumor-associated macrophages (TAMs) accumulate in various cancers and promote tumor angiogenesis and progression, and thus might be ideal imaging targets for non-invasive detection of tumors with high specificity. Here, we developed an iron-calcium-phytate complex (ICPC) as an MRI agent that specifically targets TAMs. Beyond the capability of current TAM imaging methods, which is limited to visualization of TAMs, an ICPC variant was also developed by combining ICPC with an anticancer drug, Doxorubicin (Dox@ICPC). Our preliminary data strongly support that the novel antitumor MR agent, Dox@ICPC, may potentially achieve both TAM-specific MR imaging and tumor-specific drug delivery simultaneously.

Kannie WY Chan^1,2, Tao Yu³, Guanshu Liu^1,4, Ming Yang⁵, Assaf A Gilad^1,2, Jeff WM Bulte^1,2, Peter CM van Zijl^1,4, Justin Hanes^3,5, and Michael T McMahon^1,4
1Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Baltimore, MD, United States, ³Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ⁴F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, ⁵Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Nanoparticle-based local drug treatment has potential for chemotherapy for cervical tumors, but there is a need for real time in vivo imaging of the particle delivery to monitor therapeutic efficacy. We are interested in using Chemical Exchange Saturation Transfer (CEST), a molecular MRI contrast mechanism, to monitor the vaginal delivery of drug-loaded nanoparticles to treat local cervical tumors by co-encapsulating CEST contrast agents and drugs within liposomes. The goal is to image the distribution of these particles and to indirectly assess the retention of drugs over the course of treatment.

Yun-Ming Wang¹, Shou-Cheng Wu², and Jia-Gong Lin^3
1Department of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan, ²Department of Biological Science and Technology, National Chiao Tung University, Taiwan, ³National Chiao Tung University, Taiwan

In this study, a facile approach for the passive masking of non-conjugated reactive amine groups on the surface of iron oxide nanoparticles is demonstrated. The usefulness of this strategy has been exemplified by EGFR specific MR-optical imaging agent (SPIO-mAb-FITC NPs). The TEM and confocal image shows that the passive masking of reactive groups enhances the targeting efficacy of the imaging agent.

Jonathan Marmurek¹, Elaine Lunsford², Elena Vinogradov^2,3, Khaled Nasr², Fangbing Liu², Ananth J. Madhuranthakam⁴, John V. Frangioni^2,5, and Robert E. Lenkinski^3
1Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, United States, ²Beth Israel Deaconess Medical Center, Boston, MA, ³UT Southwestern Medical Center, Dallas, TX, ⁴Global Applied Science Laboratory, GE Healthcare, Boston, MA, ⁵Harvard Medical School, Boston, MA

Clinical x-ray mammography cannot delineate hydroxyapatite (HA) and calcium oxalate (CO), the respective forms of microcalcification in malignant and benign breast cancer. We present the first in-vivo MRI of an HA-targeted gadolinium contrast agent. Pre- and post-contrast MRI using ultra-short echo times (UTE) showed that the contrast agent had a 4.3-fold relative specificity for HA over CO when delivered systemically to subcutaneous crystal implants in mice. UTE MRI of a breast cancer model in rats showed that the HA-targeted contrast agent produced a signal intensity enhancement greater than 200% in tumor calcifications.

Richard Matthew Ramirez^1,2, Krishnan K Palaniappan¹, David E Wemmer^1,3, Matthew B Francis^1,2, and Alex Pines^1,2
1Department of Chemistry, University of California, Berkeley, CA, United States, ²Materials Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United States, ³Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United States

A hyperpolarized Xe molecular sensor capable of targeting specific cell types is presented. The sensor agent is composed of multiple cage-like cryptophane molecules attached to a bacteriophage which can then be targeted. This particular agent incorporated an anti-EGFR moiety and was successfully bound by EGFR-positive MDA-MB-231 cells, but not by Jurkat cells which do not express the EGF receptor. Presence of the agent is detected using a hyperCEST scheme.

Natalie M Barkey¹, Christian Preihs², Heather H Cornnell¹, Gary Martinez³, Kevin N Sill⁴, Adam Carie⁴, Josef Vagner⁵, Jonathan L Sessler², Robert J Gilles¹, and David L Morse^1
1Molecular and Functional Imaging, Moffitt Cancer Center, Tampa, FL, United States, ²Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX, United States, ³Small Animal Molecular Imaging, Moffitt Cancer Center, Tampa, FL, United States, ⁴Intezyne Technologies, Inc, Tampa, FL, United States, ⁵The Bio5 Institute, University of Arizona, Tuscon, AZ, United States

Rationally-designed, polymer-based micelle carriers offer a promising approach to the delivery of therapeutic and/or diagnostic payloads. We have described the synthesis and characterization of MC1R targeted triblock polymer micelles with encapsulated Gd-texaphyrin and Fe(III) crosslinking for stabilization. These micelles selectively target MC1R-expressing melanoma xenograft tumors in vivo. Tumor uptake is not observed with untargeted or unstabilized control micelles. These agents biodegrade and clear systemically without retention in kidney or liver. To the best of our knowledge, this represents the first report of a targeted micelle system that selectively accumulates in the tumor relative to other tissues.

Sudath Hapuarachchige¹, Wenlian Zhu², Yoshinori Kato², and Dmitri Artemov^3
1Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²The Johns Hopkins University School of Medicine,³Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MARYLAND, United States

The overexpression of Her2/neu leads to the poor prognosis in human breast cancer. The affinity of the cancer therapeutics can be increased by the synergistic drug delivery by controlled internalization. The mouse models were injected with modified herceptin, followed by secondary component. T1 images were and optical images of the mice were obtained. In vivo optical shows the retention of cargo-carrier on tumor-site due to the "click" chemistry (followed by possible internalization) with respect to the control, without PEG4-Az on Herceptin). MRI imaging exhibits the drop of T1, showing the possible non-invasive image-guided prognosis and translational cancer therapy.

Ji-Ae Park¹, Jung Young Kim¹, Wonho Lee¹, In Ok Ko¹, Sang-Keun Woo¹, Jong Guk Kim¹, Joo Hyun Kang¹, Sang Moo Lim², Yongmin Chang³, Tae-Jeong Kim⁴, and Kyeong Min Kim^1
1Molecular Imaging Research Center, Korea Institute of Radiological & Medical Science, Seoul, Nowon-gu, Korea, ²Department of Nuclear Medicine, Korea Institute of Radiological & Medical Science, ³Department of Medical & Biological Engineering, Kyungpook National University, ⁴Department of Applied Chemistry, Kyungpook National University

We report tumor targeting RGD conjugate Gd complex for MRI/SPECT dual imaging based on isostructural I/¹²⁵I-RGD-DOTA-Gd to be a potential multimodal imaging probe. To develop a MR/SPECT dual imaging probe, YKRGD amino acids were modified with iodo-tyrosine, resulting in (iodo)YKRGD. For MR imaging agent, Gd-DOTA conjugates to (iodo)YKRGD of the type I-YKRGD-DOTA-Gd have been prepared. For SPECT imaging radioisotope, I-125, was labeled to tyrosine resulting in ¹²⁵I-YKRGD-DOTA-Gd. The chemical and structural equivalence of I-YKRGD-DOTA-Gd and ¹²⁵I-YKRGD-DOTA-Gd can be confirmed by HPLC. In vivo MR and SPECT imaging of tumor-bearing mice, these complexes show high specificity for ¥á_¥í¥â₃ receptor. These result revealed that the I/¹²⁵I-RGD-DOTA-Gd would be an attractive entry into tumor-targeting dual MRI/SPECT agent.

Yun-Ming Wang¹, Shou-Cheng Wu², and Gyan Singh^3
1Department of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan, ²Department of Biological Science and Technology, National Chiao Tung University, Taiwan, ³National Chiao Tung University, Taiwan

A highly sensitive and specific dual modality T2 weighted MR-optical imaging agents (SPIO-mAb-Cy777 NPs) has been synthesized. The SPIO NPs and Cy777 serves as MR enhancer and NIR optical imaging dye respectively. The anti-MUC4 mAb has been used as targeting moiety to target MUC4 receptor which is exclusively expressed in pancreatic cancer. An ex-vitro and in vitro experiments shows significant negative contrast enhancement in MUC4 positive cell line, on the contrary contrast enhancement was not observed in MUC4 negatively expressed cell. Therefore, we can conclude that the SPIO-mAb-Cy777 NPs can specifically target MUC 4 receptor and can be potentially used as tool for the detection of pancreatic cancer with high specificity and sensitivity.

Raag D. Airan^1,2, Amnon Bar-Shir^1,2, Guanshu Liu^1,3, Michael T. McMahon^1,3, Galit Pelled^1,3, Peter C.M. van Zijl^1,3, Jeff W.M. Bulte^1,2, and Assaf A. Gilad^1,2
1Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States, ²Cellular Imaging Section, Institute for Cell Engineering, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States, ³F.M. Kirby Research Center for Functional Imaging, Kennedy Krieger Institute, Baltimore, Maryland, United States

Protein kinases, such as Protein Kinase A (PKA), underlie myriad clinically important signaling pathways. We developed a genetically encoded molecular MRI biosensor for detecting real-time PKA activity dynamics. This biosensor uses chemical exchange saturation transfer (CEST) MRI and its advantages over traditional molecular imaging techniques for detecting organic metabolite activity dynamics. We find that PKA phosphorylation of the biosensor resulted in a >50% modulation of its baseline CEST contrast, with near 250 µM discrimination sensitivity and minutes temporal resolution in vitro. CEST contrast change with phosphorylation likely results from coordination of CEST-contrast generating residues by the negatively-charged phosphate group.

Henrik Lauridsen¹, Casper Foldager², Mette Hagensen³, Tobias Wang⁴, and Michael Pedersen^5
1MR-Research Centre, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark, Denmark, ²Department of Othopaedics, Aarhus University, Denmark, ³Department of Cardiological Mecicine, Aarhus University, Denmark, ⁴Department of Biological Sciences, Aarhus University, Denmark, ⁵MR-Research Centre, Institut of Clinical Medicine, Aarhus University, Denmark

Tissue regenerative capacity in humans is very limited. However, there exist model animals in zoology expressing impressive regenerative potential inspiring for future breakthroughs in regenerative medicine. One such model organism is the axolotl, capable of regenerating various tissues, organs and even whole appendages. This study incorporates the expanding field of super paramagnetic iron oxide particle (SPIO) guided MRI evaluation of stem cells therapies with an intrinsic regenerative environment, the regenerating axolotl limb. This has the potential both to allow for a better regenerative model for development of SPIO’s for non-invasive use as well as revealing the mechanisms behind axolotl regeneration.

Marina Radoul¹, Batya Cohen¹, Moriel Vandsburger¹, Raz Zarivach², and Michal Neeman^1
1Biological Regulation, Weizmann Institute of Science, Rehovot, Israel, ²Department of Life Sciences, Ben Gurion University, Israel

Ferritin is a main iron storage intracellular protein which has recently proposed as MRI reporter gene due to paramagnetic ferrihydrate in its core. However, it has low R2 relaxivity and thus provides relatively low sensitivity. In this study, we have designed a recombinant fusion ferritin-N6A to facilitate conversion of ferrihydrate into magnetite and by this induce MRI contrast.

Ramon Van der Werf¹, Gerben M. Van Buul¹, Henk Smit¹, Gavin C. Houston², Gabriel P. Krestin¹, Stefan Klein³, Gerjo J.V.M. Van Osch⁴, Monique R. Bernsen¹, and Gyula Kotek^1
1Radiology, Erasmus Medical Centre, Rotterdam, Zuid Holland, Netherlands, ²General Electric Healthcare, Hoevelaken, Gelderland, Netherlands, ³Medical Informatics, Erasmus Medical Centre, Rotterdam, Zuid Holland, Netherlands, ⁴Orthopaedia, Erasmus Medical Centre, Rotterdam, Zuid Holland, Netherlands

Tracking of stem cells is highly desirable to obtain insight into mechanisms of stem cell based therapies. In the region of the knee, tracking of SPIO labeled cells is hampered by low hydrogen spin density. We show a voxel-based R2* mapping method to visualize a single voxel broad layer of stem cells attached to several structures in knee joints (voxelsize: 26 x 26 x 500 m3) that are not detectable by looking at signal voids employing conventional MR methods.

Jee-Hyun Cho^1,2, Janggeun Cho^1,2, Sangdoo Ahn², and Chulhyun Lee^1
1Magnetic Resonance Research, Korea Basic Science Institute, Ochang, Cheongwon, Korea, ²Chemistry, Chung-Ang University, Seoul, Korea

In this study, to numerically evaluate how to change the detectability and image-contrast depending upon the concentration of contrast agents, we systematically compared the fractional signal losses of iDQC, EPI, and GE images of single cells labeled with different iron concentrations. The iDQC images visualized labeled cells more effectively and with a higher contrast-to-noise ratio than conventional EPI and GE images, especially at low resolutions and low iron concentration in cell.

Xiang Nan^1,2, Anna V Naumova³, Jianmin Wei², Qian Wan¹, Lin Gao¹, Xin Liu¹, and Bensheng Qiu^1,3
1Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Enginee, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China, ²Inner Mongolia Agricultural University, Huhhot, Inner Mongolia, China, ³Radiology, University of Washington School of Medicine, United States

In this study, we aimed to develop a reliable method to monitor the gene expression or therapy in vivo, non-invasively. We first utilized optical imaging to assess EP-mediated transgene expression in vitro, and then we next constructed a dual mammalian expression vector also carrying a murine ferritin gene, the vector can provide us to monitor the gene expression in vivo by magnetic resonance imaging scanner. DNA was transfected into mouse muscle by electroporation. We succeeded in imaging transgene expression of marine ferritin reporter gene by MR, and further study is going on.

Daniel Calle¹, Viviana Negri², Arisbel Cerpa³, Pilar López-Larrubia¹, Paloma Ballesteros², and Sebastián Cerdán^1
1Departamento de Modelos Experimentales Humanos, Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC, Madrid, Madrid, Spain, ²Laboratory of Organic Synthesis and Molecular Imaging by Magnetic Resonance, Faculty of Sciences, UNED, Madrid, Madrid, Spain, ³Universidad Europea de Madrid, Madrid, Madrid, Spain

 

Xilin Sun¹, Dan Wang¹, and Baozhong Shen^1
1The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, China

The mechanism of action of Abraxane is complex, and some reports exist that Abraxane triggers reactionary angiogenesis. Our previous studies had shown some alterations of tumor vessels from immature to mature in morphological and molecular characteristics by Abraxane, and the integrin-specific PET tracer 18F-FPPRGD2 (investigational new drug 104150) can noninvasive monitoring the integrin avb3 level. The purpose of this study is to further investigate a comprehensive vascular response (molecular level and functional such as permeability and penetration) during Abraxane therapy with combined dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-FPPRGD2 PET.

Sebastian Temme¹, Christoph Jacoby¹, Zhaoping Ding¹, Florian Bönner¹, Nadine Borg¹, Jürgen Schrader¹, and Ulrich Flögel^1
1Molecular Cardiology, Heinrich Heine University, Düsseldorf, NRW, Germany

In the present study, we developed a standardized matrigel-based LPS-release model of local inflammation suitable for MRI approaches. We demonstrate that matrigel itself can be visualized by conventional 1H MRI and that LPS induced inflammation resulted surprisingly in a decreased T2-relaxation time in the matrigel plug. Furthermore, inflammation in the plug was specifically detected by 19F MRI and the intensity of the 19F signal correlated with the LPS dose. These findings suggest that the matrigel-LPS model is a reproducible and quantitative method for evaluation of specificity and sensitivity of MRI methods used for imaging of inflammation in vivo.

Matthew J Goette¹, Gregory M Lanza¹, Samuel A Wickline¹, and Shelton D Caruthers^1
1School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

This study presents a strategy to more accurately quantify the sparse ¹⁹F signal from perfluorocarbon nanoparticle emulsions through flip angle calibration utilizing the abundant ¹H signal. We hypothesize that the RF power settings optimized for ¹H can be used to determine the correct RF power settings for the ¹⁹F signal acquired with¹⁹F/¹H dual-tuned coils on a 3 T clinical scanner. Flip angle sweep experiments using two types of dual-tuned coils were performed, which showed that a coil-specific, but spatially-independent calibration value can be determined to set the correct ¹⁹F power settings using the ¹H signal.

Daisuke Kokuryo¹, Jun-ichiro Jo¹, Tsuneo Saga¹, and Ichio Aoki^1
1Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba, Japan

A newly developed manganese-nanoprobe (Dextran-DTPA-Mn) and three-dimensional ultra-short echo-time (UTE) imaging was applied to evaluate a lung metastatic tumor model. Comparison was made with a conventional Gd-DTPA contrast-agent as a control. The Dextran-DTPA-Mn signal in the lung parenchyma increased immediately after administration and was thereafter maintained for 24 hours. The tumor region in lung parenchyma was enhanced by the accumulation of Dextran-DTPA-Mn. The Dextran-DTPA-Mn with UTE imaging will allow optimized chemotherapy using tumor-targeting nanoprobes.

Stephen Dodd¹, Gary Zabow¹, and Alan Koretsky^1
1Laboratory of Functional and Molecular Imaging, NINDS, National Insitutes of Health, Bethesda, MD, United States

A method to measure the distance between two magnetic particles at high spatial resolution is presented. Microfabrication is used to make an array of particles at different separations with high precision. Gradient-echo MR images are acquired with 4x higher spatial resolution in the direction of the particle spacing and using phase maps the distance between particles can be measured down to the level of a pixel.

Nicoleta Baxan¹, Stella Maria Carro², Roberto Ferrarese², Dominik von Elverfeldt¹, Markus Bredel^2,3, and Wilfried Reichardt^1
1Department of Radiology, University Medical Center Freiburg, Freiburg, BW, Germany, ²Department of Neurosurgery, University Medical Center Freiburg, Freiburg, BW, Germany, ³Department of Radiation Oncology, University of Alabama, Birmingham, United States

As the brain is composed of a variety of cell type that vary strongly according to their anatomical location, an accurate assessment of the implantation site plays an important role in the investigation of growth characteristics and physiology of tumors. This study was performed to determine to what extend high-resolution MR microscopy enables to accurately determine the early fate of implanted glioma cells and the injection tract under in vivo conditions. The presented approach based on the MR signal phase can be an efficient alternative to replace the need of cell labeling that might potentially alter cellular characteristics.

Philipp Böhm-Sturm¹, Eberhard D. Pracht¹, Markus Aswendt¹, Nadine Henn¹, and Mathias Hoehn^1
1In-Vivo-NMR, Max-Planck-Institute for Neurological Research, Cologne, Germany

19F MRI has recently received much attention, especially in the field of cell tracking. One of the main advantages of 19F MRI is that it is possible to quantify the number of cells. However, this only holds for the use of volume coils with a homogeneous B1 field for both transmission and reception. Here we present a workflow that allows quantitative 19F MRI with surface coils by mapping the B1 field on the 1H channel and subsequent correction of 19F data by post-processing. Our work may resolve an inherent conflict of sensitivity vs. quantification in coil design for 19F MRI.

Klaus Strobel¹, Rabecca Schmidt¹, Carsten Höltke¹, and Cornelius Faber^1
1University Hospital Münster, Münster, Germany

Unambiguous MRI detection of labeled cells often uses ¹⁹F, because fluorine has no natural background in the images. However, ¹⁹F MRI requires dedicated hardware. Alternatively, Tm-DOTMA, which has twelve methyl protons with a chemical shift of 100 ppm, may be used to obtain background free proton images. In this work, we have implemented an ultra-short echo time (UTE) imaging sequences to obtain optimal SNR-efficiency with labeled HT-1080 cells that were injected subcutaneously into the flank of mice. We show that Tm-DOTMA labeled cells can be imaged in vivo without significant water background signal.

Todd C. Soesbe¹, Federico A. Rojas-Quijano¹, and A. Dean Sherry^1,2
1Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States, ²Department of Chemistry, The University of Texas at Dallas, Dallas, TX, United States

We have recently shown for Eu3+-based PARECEST agents that the same water molecule exchange that enables the CEST effect can also facilitate severe bulk water line broadening via the T2-exchange (T2ex) mechanism. T2ex can significantly reduce the bulk water T2 (i.e. negative contrast) even without spin saturation, causing the PARACEST agent to behave like a susceptibility or T2 agent. This makes “Off” minus “On” imaging of PARACEST agents difficult since the regions of uptake appear dark in both images. We have also recently shown that the ultra-short TE times (<10 μs) used in the Sweep Imaging with Fourier Transform (SWIFT) pulse sequence can reclaim the loss in signal due to T2ex to enable fast and sensitive in vivo PARACEST imaging using simple “Off” minus “On” image subtraction. Here, we use the same SWIFT-CEST method to image a Tb3+-based PARACEST agent in vivo.

Cornelius von Morze¹, Subramaniam Sukumar¹, Galen Reed¹, Peder E Larson¹, John Kurhanewicz¹, and Daniel B Vigneron^1
1Department of Radiology and Biomedical Imaging, UCSF, San Francisco, California, United States

The spectral selectivity of SSFP in the low flip angle regime enables frequency-specific imaging of hyperpolarized ¹³C compounds. Through simulations, we optimized the acquisition parameters for dynamic frequency-specific SSFP imaging of co-polarized [1-¹³C]pyruvate and [¹³C]urea, which is useful for studying tumor metabolism and perfusion in vivo. We implemented the methods as a dynamic frequency-cycled bSSFP pulse sequence on a 14.1T animal MRI scanner. We performed thermal and hyperpolarized phantom studies to test the acquisition, and performed in vivo dynamic imaging of a normal mouse kidney.

Rolf F Schulte¹, Jonathan I Sperl¹, Eliane Weidl², Marion I Menzel¹, Martin A Janich^1,3, Oleksandr Khegai^1,3, Markus Durst^1,4, Jan Henrik Ardenkjaer-Larsen^5,6, Steffen J Glaser³, Axel Haase⁴, Markus Schwaiger², and Florian Wiesinger^1
1GE Global Research, Munich, Germany, ²Nuclear Medicine, TU Munich, Germany, ³Chemistry, TU Munich, Germany, ⁴IMETUM, TU Munich, Germany, ⁵GE Healthcare, Copenhagen, Denmark, ⁶Electrical Engineering, Technical University of Denmark, Copenhagen

Hyperpolarised [1-13C]pyruvate is enzymatically converted into lactate, alanine and bicarbonate. In this work, a metabolic exchange rate mapping approach is presented for quantifying metabolic activity. It based on a spectral-spatial excitation of the metabolites combined with a saturation of the downstream metabolites and subsequent recovery due to fresh conversion from pyruvate. Various improvements were made to the spectral-spatial pulse design, the spiral readout and other sequence parameters. The saturation-recovery metabolic exchange rate imaging approach was demonstrated in four rats bearing subcutaneous MAT B III tumours.

Tian Cheng¹, Mor Mishkovsky^2,3, Matthias Junk⁴, Dariush Hinderberger⁴, Kerstin Münnemann⁴, and Arnaud Comment^1
1Institute of Physics of Biological Systems, École Polytechnique Fédérale de Lausanne, Lausanne, VD, Switzerland, ²Department of Radiology, Université de Lausanne, Lausanne, VD, Switzerland, ³Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, VD, Switzerland, ⁴Max Planck Institute for Polymer Research, Mainz, Germany

Dissolution dynamic nuclear polarization allows achieving tremendous gain in signal-to-noise ratio in nuclear magnetic resonance experiments. Once the polarized sample is dissolved, the stable radicals used as polarizing agents become undesirable since their presence is an additional source of nuclear spin relaxation and their toxicity might be an issue. We demonstrate here that by using spin-labeled thermoresponsive hydrophilic polymer networks it is possible to prepare hyperpolarized solutions free of stable radicals immediately after dissolution. We applied this method to hyperpolarize 13C-labeled tert-butanol which has been recently shown to be a promising contrast agent for perfusion imaging.

Markus Durst^1,2, Rolf F. Schulte², Franz Schilling¹, Eliane Weidl³, Oleksandr Khegai^2,4, Martin A. Janich^2,4, Jonathan I. Sperl², Ulrich Koellisch¹, Florian Wiesinger², Markus Schwaiger³, and Axel Haase^1
1IMETUM, Technische Universität München, Munich, Bavaria, Germany, ²GE Global Research, Munich, Bavaria, Germany, ³Department for Nuclear Medicine, Technische Universität München, Munich, Bavaria, Germany, ⁴Department of Chemistry, Technische Universität München, Munich, Bavaria, Germany

Imaging hyperpolarised compounds requires rapid acquisition methods due to irreversible T1 decay of the magnetisation. In this work, parallel imaging is used to improve the spatial resolution and spectral width of spiral chemical shift images of healthy rats in-vivo after injection of hyperpolarised [1-13C]pyruvate. An interleaved spiral PMRI sequence specifically designed for the requirements of hyperpolarised chemical shift imaging is presented. The results are in good agreement with a proton GRE anatomical reference image and the metabolic images show high SNR and similar distribution of metabolites as compared to a fully sampled reference measurement from a second injection.

Nicholas N. Kuzma¹, Huseyin Kara^1,2, Mehrdad Pourfathi¹, Philip Manasseh³, Jan H. Ardenkjær-Larsen⁴, Stephen J. Kadlecek¹, and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²Astronomy and Physics, University of Pennsylvania, Philadelphia, PA, United States, ³Department of Chemistry, Earlham College, Richmond, IN, United States, ⁴GE Healthcare, Brøndby, Denmark

At 1.5K and 5T, ¹²⁹Xe NMR spectra of a homogeneous xenon/1-propanol/trityl-radical mixture exhibit a single ¹H-broadened peak. Another peak appears upon 4-hour annealing at 125K. Its characteristic width and chemical shift indicate spontaneous formation of pure Xe clusters. Microwave irradiation can bring both peaks to either positive or negative polarization. Time evolution of DNP in pure Xe clusters can be understood in terms of spin diffusion and T₁ relaxation. Our data can be used to evaluate major DNP parameters in situ, revealing a severe spin-diffusion bottleneck at the cluster boundaries and a significant sample overheating due to microwave irradiation.

Jörg Döpfert¹, Christopher Witte¹, Martin Kunth¹, Michael Beyermann¹, and Leif Schröder^1
1Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany

Chemical Exchange Saturation Transfer (CEST) is typically quantified by subtracting an on resonant saturation image from an off resonant reference image. When performing single-shot Hyper-CEST imaging with low signal from dissolved xenon this approach has serious problems as the low SNR is further decreased by the image subtraction. Here, we propose two alternative methods based on least squares fitting and principal component analysis, which exploit the information of a series of CEST images with a range of different saturation frequencies. Both presented methods lead to a significant gain in SNR and strongly improve the visualization of the agents.

Rajat K. Ghosh¹, Stephen J. Kadlecek¹, Nicholas N. Kuzma¹, Jan Henrik Ardenkjaer-Larsen^2,3, Giuseppe Pileio⁴, Malcolm H. Levitt⁴, and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States, ²Electrical Engineering, The Technical University of Denmark, Lyngby, Denmark, ³GE Healthcare, Broendby, Denmark, ⁴University of Southampton

The utility of hyperpolarized tracers is limited by polarization lifetime. Transferring spin order to a singlet state can significantly increase polarization lifetimes in nitrous oxide dissolved in a liquid solvent. The longitudinal relaxation of nitrous oxide is largely dominated by the spin-rotation interaction. In this work we formulate a model to describe the relaxation of nitrous oxide dissolved in various solvents, and avenues to lengthen the singlet lifetime by altering the characteristics of the dissolving solvent. We experimentally investigate the effect of altering the temperature of the solvent, as well as the effect of varying viscosity and hydrodynamic radius.

Galen D. Reed¹, Peder E.Z. Larson¹, Cornelius von Morze¹, Robert Bok¹, Michael Lustig², Adam B. Kerr³, John M. Pauly³, John Kurhanewicz¹, and Daniel B. Vigneron^1
1Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States, ²Electrical Engineering and Computer Sciences, University of California Berkeley, ³Electrical Engineering, Stanford University

An echo planar imaging sequence for simultaneous dynamic imaging of multiple hyperpolarized 13C compounds is presented. Frequency separation was achieved by spatial mis-registration in the phase-encoded direction by the appropriate choice of echo spacing. Suppression of the pyruvate-hydrate and alanine resonances was achieved using an optimized spectral-spatial RF waveform. Dynamic imaging was demonstrated in a transgenic mouse cancer model. Images of pyruvate and lactate were acquired after hyperpolarized pyruvate infusion. Images of lactate and HP001 were acquired after simultanous infusion of hyperpolarized pyruvate and HP001.

Markus Durst^1,2, Ulrich Koellisch¹, Jonathan I. Sperl², Eliane Weidl³, Florian Wiesinger², Axel Haase¹, and Rolf F. Schulte^2
1IMETUM, Technische Universität München, Munich, Bavaria, Germany, ²GE Global Research, Munich, Bavaria, Germany, ³Department for Nuclear Medicine, Technische Universität München, Munich, Bavaria, Germany

Due to the irreversible T1-decay of the magnetization, scan time is crucial for hyperpolarized 13C MRI. In contrast to existing autocalibrated parallel MRI algorithms, calibrationless parallel imaging does not require a fully sampled k-space region as used in existing autocalibrated methods, and therefore yields a further reduction of acquisition time. The basic idea is to reconstruct the data with low-rank matrix completion. This existing approach was succesfully adopted to hyperpolarized 13C spiral imaging. Simulations were performed as well as a reconstruction of in-vivo rat data, results were comparable to existing autocalibrated parallel MRI methods, nevertheless allowing a faster acquisition.

Thomas C Booth^1,2, Mikko I Kettunen^1,2, Ferdia A Gallagher^1,2, Brett WC Kennedy^1,2, Tiago B Rodrigues^1,2, Sarah E Bohndiek^1,2, and Kevin M Brindle^1,2
1Biochemistry, University of Cambridge, Cambridge, United Kingdom, ²Cambridge Research Institute, Cancer Research UK, Cambridge, United Kingdom

Tissue pHe can be determined using 13C MRS and hyperpolarized 13C-labelled bicarbonate. Using an assumed pKa, the H13CO3- and 13CO2 signal intensities allow pH determination using the Henderson-Hasselbalch equation. We compared pH derived by DNP NMR with direct potentiometric measurement of H+ activity using a glass electrode. Using pKa’ = pH – log ([H13CO3]/[ 13CO2]), we assigned the pH determined potentiometrically as the standard and determined whether the 13C MRS derived pKa diverges when there is alteration of ionic strength, pH, temperature and protein concentration within a clinically relevant range of values. Additionally, the pKa in human blood was determined.

Nicholas N. Kuzma¹, Huseyin Kara^1,2, Mehrdad Pourfathi¹, Philip Manasseh³, Rajat K. Ghosh¹, Stephen J. Kadlecek¹, Giuseppe Pileio⁴, Pär Håkansson⁴, Malcolm H. Levitt⁴, and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²Astronomy and Physics, University of Pennsylvania, Philadelphia, PA, United States, ³Department of Chemistry, Earlham College, Richmond, IN, United States, ⁴School of Chemistry, Southampton University, Southampton, Hempshire, United Kingdom

This is the first report of dynamic nuclear polarization (DNP) of doubly-labeled ¹⁵N₂O. Sample polarization during DNP at 1.5 K and 5 T was monitored in-situ by solid-state NMR as a function of microwave frequency in the range 140.04 - 140.16 GHz. The fastest initial polarization rate occurred at 140.063 and 140.130 GHz microwave frequencies, corresponding to positive and negative polarizations of the nuclear spin system. Polarization levels of (114)% were achieved in the frozen sample.

Aaron M. Coffey^1,2, Roman V. Shchepin¹, Ken Wilkens¹, Kevin W. Waddell¹, and Eduard Y. Chekmenev^1
1Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN, United States, ²Biomedical Engineering, Vanderbilt University, Nashville, TN, United States

A low field MR imaging system for heteronuclear hyperpolarized contrast agents in vivo is under development to demonstrate utility for human scale. Hyperpolarization reopens examination of low field imaging leveraging multi-turn inductors. A 206 turn ¹³C single layer solenoid coil was used to polarize by PASADENA and detect in situ hyperpolarized 1-¹³C-succinate-d2 (P = 15%, ¹³C SNR = 500, FWHM = 22 Hz). Comparison with identical phantom and polarization yielded SNR = 120 with FWHM = 6 Hz for a Doty volume coil (4.7 T) with the solenoid coil (0.0475 T) yielding SNR = 30 with FWHM = 25 Hz.

Jan-Bernd Hövener¹, Robert Borowiak¹, Sebastien Bär¹, Jochen Leupold¹, Jürgen Hennig¹, and Dominik von Elverfeldt^1
1Medical Physics, Dep. of Radiology, Medical Center, University of Freiburg, Freiburg, BW, Germany

While the methodology of pH2 production is known for decades (flow through catalyst at 20 K), its implementation in a clinical setting is rare (none is known to us), but key if pH2 hyperpolarization is to enter life sciences. Here, we present the safety concept, experimental setup and quality assurance to run a pH2 production unit in hospital.

Andreas Sigfridsson¹, Kilian Weiss¹, and Sebastian Kozerke^1
1Institute for Biomedical Engineering, University and ETH Zurich, Zürich, Switzerland

Cardiac metabolic imaging after injection of hyperpolarized pyruvate is inherently limited by resolution due to the short acquisition time available. The low resolution may result in signal contamination from the blood pools into myocardial regions, which can compromise analysis of metabolic processes. Here, an approach that uses high-resolution spatial information obtained from proton images to constrain the reconstruction of the carbon images is presented. The technique is evaluated both in simulations and in-vivo, and the results indicate that the signal contamination may be reduced.

Matthew Smith¹, Jeremy Gordon¹, Dave Niles¹, Kevin Johnson¹, and Sean Fain^1,2
1Medical Physics, University of Wisconsin, Madison, Wisconsin, United States, ²Radiology, University of Wisconsin, Madison, WI, United States

Dynamic imaging of hyperpolarized ¹³C with MRI provides metabolic kinetics with spatial localization in-vivo but is challenging because both T₁ and RF decay reduce the hyperpolarized signal throughout the experiment. A low flip angle is typically used to mitigate RF decay and enable acquisition of many images by sacrificing image SNR. The simulations presented in this study investigate the kinetic modeling accuracy for a variety of flip angles and number of acquired images using a centric Cartesian trajectory and provides a target SNR for dynamic images.

Martin Kunth¹, Jörg Döpfert¹, Christopher Witte¹, Federica Rossella¹, and Leif Schröder^1
1Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany

Concepts of biosensor detection by MRI are of actual interest, since its non-ionizing radiation property. This study demonstrates single-shot localization of functionalized¹²⁹Xe as used in specific biosensors in low concentration. Cryptophane-A was used in different surroundings to simulate two different types of biosensors at concentrations of 10µM each, seperated by 1.2 ppm. Our technique employs presaturation and EPI encoding on hyperpolarized (HP) ¹²⁹Xe. This fast imaging limits the Hyper-CEST technique to the HP Xe delivery process to the cryptophane-A cages and turns out to be promising for biosensor detection even in the nanomolar range.

Thomas Trantzschel¹, Ute Bommerich², Markus Plaumann¹, Denise Lego², Torsten Gutmann³, Tomasz Ratajczyk³, Sonja Dillenberger³, Gerd Buntkowsky³, Joachim Bargon⁴, and Johannes Bernarding^1
1Dep. for Biometry and medical Informatic, Otto-von-Guericke University Magdeburg, Magdeburg, Germany, ²Leibniz Institute for Neurobiology, Magdeburg, Germany,³Technical University Darmstadt, Germany, ⁴University Bonn, Germany

Parahydrogen Induced Polarization (PHIP) gains much attention as it is already used for metabolic studies in MR. Because of keto-enol tautomerism, molecules with a hydroxyl group next to double or triple bonds are not accessible via PHIP e.g. vinyl alcohol which is precursor for ethanol. Our study presents the first time an approach to generate PHIP hyperpolarized ethanol that is probably the mostly used psychoactive drug. Based on the offered pathway, PHIP could be extended on biological relevant compounds, such as serine, malate, adrenaline, glucose, or related structures.

Sandro Ebert¹, Andrea Amar¹, Christian Bauer¹, Michael Kölzer¹, Peter Blümler², Dariush Hinderberger¹, Hans W. Spiess¹, and Kerstin Münnemann^1
1Max Planck Institute for Polymer Research, Mainz, Germany, ²Johannes Gutenberg University, Mainz, Germany

Despite its wide applicability in natural science, NMR and MRI still suffers from its inherently low sensitivity. This could be overcome by hyperpolarization via dynamic nuclear polarization (DNP) which result in enhanced NMR signals. In DNP, the use of toxic radicals and microwave irradiation becomes crucial with regard to medical applications. We implemented a flow system into a mobile DNP polarizer, which overcomes both obstacles. Acquired images demonstrate, because of enhanced and due to dipolar coupling inverted signals, that hyperpolarized water can be an excellent and authentic MRI contrast agent.

Kerstin Münnemann¹, Björn C Dollmann¹, O Neudert¹, Andrew K Whittaker², and Kristofer J Thurecht^2
1Max Planck Institute for Polymer Research, Mainz, Germany, ²Australian Institute for Bioengineering and Nanotechnology and Centre for Advanced Imaging, The University of Queensland, St Lucia, Queensland, Australia

The first hyperpolarization of biocompatible hyperbranched polymers using parahydrogen induced polarization (PHIP) and Dynamic Nuclear Polarization (DNP) is reported. 1H NMR signal enhancements of 1500-fold could be obtained via PHIP whereas 19F Overhauser DNP resulted in an enhancement of -37 for the fluorine containing moieties in the molecules. These results open up new possibilities for designing dual-modal molecular MR imaging agents that combine highly sensitive PHIP or DNP enhancements for measuring relatively fast biological processes with an additional imaging mechanism that is likely much less sensitive (normal 19F MRI), but which would provide contrast over a longer time-scale.

Dirk Graafen^1,2, Michael Ryan Hansen², Laura Maria Schreiber¹, and Kerstin Münnemann^2
1Section of Medical Physics, Johannes Gutenberg University Medical Center, Mainz, Germany, ²Max Planck Institute for Polymer Research, Mainz, Germany

The aim of the study was to optimize the timing of a PH-INEPT+ sequence for ¹³C₁-Hydroxyethylproprionate (HEP) to enable optimal polarization transfer from hyperpolarized protons using parahydrogen induced polarization (PHIP) to Carbon-13. Spin dynamics simulations showed the different sequence timing behavior of a thermally polarized and a PHIP polarized molecule. In comparison, for this molecule the optimal ₁ delay of the PH-INEPT+ sequence is ~4ms for the thermal polarization whereas it is ~27.5ms for the hyperpolarized state. Experiments in a 7T spectrometer reproduce the simulation results adequately.

Lasitha Senadheera¹, Dirk Mayer^2,3, Sonal Josan^2,3, Yi-Fen Yen⁴, Moses Darpolor³, Jae Mo Park³, Ralph E. Hurd⁴, Richard Luong⁵, Lei Xing¹, and Daniel M. Spielman^3
1Radiation Oncology, Stanford University, Stanford, CA, United States, ²Neuroscience Program, SRI International, Menlo Park, CA, United States, ³Radiology, Stanford University, Stanford, CA, United States, ⁴Global Applied Science Laboratory, GE Healthcare, Menlo Park, CA, United States, ⁵Comparative Medicine, Stanford University, Stanford, CA, United States

Radiation-induced metabolic response of TRAMP prostate tumor was investigated with ¹³C MRSI of hyperpolarized [1-¹³C]Pyruvate. The pyruvate metabolism in the tumors of two groups of mice, x-ray treated and untreated, was assessed in terms of Lactate/Pyruvate ratio. The Lactate/Pyruvate ratio was uncorrelated with the tumor size but was significantly (P < 0.05) lower in the treated group than the untreated. Our preliminary data suggest the feasibility of using ¹³C MRSI for detecting therapeutic response of prostate cancer to radiation in TRAMP mice.

Franz Schilling^1,2, Stephan Düwel^1,2, Markus Durst^1,3, Ulrich Köllisch^1,3, Jan Henrik Ardenkjaer-Larsen⁴, Pedro A. Gómez Damián³, Markus Schwaiger⁵, Rolf F. Schulte³, Steffen J. Glaser², Axel Haase¹, Angela Otto¹, and Marion I. Menzel^3
1Zentralinstitut für Medizintechnik, Technische Universität München, Garching, Germany, ²Department of Chemistry, Technische Universität München, Garching, Germany,³GE Global Research, Munich, Germany, ⁴GE Healthcare, Copenhagen, Denmark, ⁵Department of Nuclear Medicine, Technische Universität München, Munich, Germany

Understanding tumour metabolism is a central issue in diagnosis of tumours. Using magnetic resonance spectroscopy, hyperpolarized [1-13C]pyruvate and its metabolites can be detected to characterise the stage of a tumour. The signal of each metabolite emanates from both extra- and intracellular compartments. In this work, we show for the first time, using real-time direct detection, that diffusion coefficients of [1-13C]pyruvate and its metabolites in tumour cell spheroids can be determined. We foresee many new applications of hyperpolarized 13C diffusion-weighted spectroscopy e.g. to separate intra- and extracellular compartments of tumours, and to separate metabolic conversion from perfusion by large diffusion weightings.

Prasanta Dutta¹, G V Martinez¹, N V Rajeshkumar², A Le², A Maitra², C V Dang², R A Gatenby¹, and R J Gillies^1
1Imaging, Moffitt Cancer Center & Research Institute, Tampa, FL, United States, ²School of Medicine, Johns Hopkins University, Baltimore, MD, United States

In this work, we have evaluated the efficacy of a small molecule drug (a potent LDH-A inhibitor,FX11) treatment to human pancreatic xenograft tumors via assessing the metabolic conversion of lactate from pyruvate using 13C magnetic resonance spectroscopy. Measurement of hyperpolarized 13C label flux between pyruvate and lactate is used to detect early response to therapy before differences in tumor volume were observed.

Keita Saito¹, Shingo Matsumoto¹, H Douglas Morris², Martin J Lizak², Jeeva P Munasinghe², Nallathamby Devasahayam¹, Sankaran Subramanian¹, James B Mitchell¹, and Murali C Krishna^1
1Radiation Biology Branch, National Cancer Institute, Bethesda, Maryland, United States, ²National Institute of Neurological Disorder and Stroke, Bethesda, Maryland, United States

We investigated effects of X-irradiation on pyruvate metabolism in squamous cell carcinoma (SCC) implanted in mice leg using ¹³C-MRI with hyperpolarized [1-¹³C]pyruvate. [1-¹³C]lactate to [1-¹³C]pyruvate ratio (Lac/Pyr) in the SCC tumors increased as tumor grew in non-irradiated control mice. 10 Gy irradiation to SCC tumors slightly suppressed the increase of Lac/Pyr, but there was no significance compared with the control. However, Lac/Pyr significantly droped after three 10 Gy irradiations (10 Gy/day, total dose 30 Gy). So, X-irradiation suppressed increase of LDH activity in SCC tumor, and lactate formation from pyruvate would become a useful marker for tumor response to radiotherapy.

PHILIP LEE¹, EMILIE BARD², and GEORGE RADDA^1
1FUNCTIONAL METABOLISM GROUP, SINGAPORE BIOIMAGING CONSORTIUM, SINGAPORE, SINGAPORE, Singapore, ²INSTITUTE OF MOLECULAR CELL BIOLOGY, AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH, Singapore

By incorporating a human hepatitis-B transgene and inducing mutagenesis via a sleeping-beauty-transposon system, a sophisticated liver cancer model has been created to study human hepatocellular carcinoma in mice. To understand changes in metabolic fuel demand as the disease progresses, hyperpolarized carbon-13 technology was utilized to study pyruvate metabolism in-vivo. We observe a reduction in the oxidative decarboxylation of pyruvate, with slight increases in transamination to alanine and reduction to lactate. Biochemical assay of liver extracts suggests an elevated dependence on glutamine as an anaplerotic carbon source. Metabolic imaging of downstream products such as lactate and alanine provides a map of tumor energetics.

Mehrdad Pourfathi^1,2, Stephen J. Kadlecek¹, Harrilla Profka¹, Hoora Shaghaghi¹, Moses Darpolor¹, Kiarash Emami¹, Nicholas N. Kuzma¹, Jan H. Ardenkjær-Larsen³, Rahim R. Rizi¹, and Janet A. Sawicki^4
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²Electrical and Systems Engineering, University of Pennsylvania, Philadelphia, PA, United States, ³GE Healthcare, Brøndby, Denmark, ⁴Lankenau Institute for Medical Research, Wynnewood, PA, United States

Lactate dehydrogenase (LDH), shown to be unregulated in ovarian cancer, may result in elevated lactate concentrations in the tumors. Using [1–¹³C] pyruvic acid (hyperpolarized via DNP), we sought to infer elevated LDH levels by detecting a more rapid approach to the equilibrium lactate:pyruvate ratio. The data was acquired by slice-selective spectroscopy of ovarian area from six mice and fitted to a simple model incorporating (a) the forward and backward conversion of pyruvate/lactate in steady-state metabolism and (b) spin-lattice relaxation of pyruvate polarization over time. We observed higher levels of LDH activity (in both directions) associated with ovarian-tumor-bearing animals.

Adrianus J. Bakermans¹, Michael S. Dodd², Klaas Nicolay¹, Jeanine J. Prompers¹, Sander M. Houten³, and Damian J. Tyler^2
1Biomedical NMR, Eindhoven University of Technology, Eindhoven, Netherlands, ²Cardiac Metabolism Research Group, University of Oxford, Oxford, United Kingdom,³Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, Netherlands

Glucose oxidation may be unable to compensate sufficiently to maintain myocardial energy homeostasis in patients affected by fatty acid -oxidation disorders. The flux through the pyruvate dehydrogenase (PDH) complex was studied using hyperpolarized ¹³C-MRS of [1-¹³C]pyruvate in the in vivo heart of long-chain acyl-CoA dehydrogenase knock-out (LCAD KO) mice and controls in fed and fasted conditions. PDH flux was normal in fed LCAD KO mice. However, after fasting PDH flux decreased to a lesser extent in LCAD KO mice when compared to controls, suggesting a compensatory role for glucose metabolism in fasted LCAD KO mice to maintain myocardial energy homeostasis.

Michael Dodd^1,2, Vicky Ball¹, Beat Schuler¹, Daniel Ball¹, Houman Ashrafian², Hugh Watkins², Kieran Clarke¹, and Damian Tyler^1
1Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, OXON, United Kingdom, ²Department of Cardiovascular Medicine, Oxford University, Oxford, OXON, United Kingdom

The advent of cardiac hyperpolarized ¹³C-MRS has enabled a greater understanding of the in vivo metabolic changes seen as a consequence of heart disease. This work demonstrates the application of hyperpolarized ¹³C-MRS in the in vivo mouse heart and shows the sensitivity of the technique to detect changes in pyruvate dehydrogenase (PDH) flux caused by fasting and dichloroacetate. Further, the ability of the technique to study transgenic mouse models of cardiac disease is also demonstrated with application in the fumarate hydratase knockout mouse.

Daniel Ball¹, Rachel Cruickshank¹, Carolyn Carr¹, Daniel Stuckey², Kieran Clarke¹, and Damian Tyler^1
1Physiology, Anatomy and Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom, ²Imperial College, London, United Kingdom

The aim of this work was to demonstrate the use of a combined dynamic nuclear polarization and chemical shift imaging protocol in the isolated perfused heart to image metabolism in the setting of both acute and chronic myocardial ischemia. The imaging protocol was successfully applied in both models, and in the acute ischemia model, metabolic disturbances could be clearly visualised. Future work will focus on the translation of these techniques into in vivo models of ischemia.

Yuhei Takado¹, Mor Mishkovsky^1,2, Tian Cheng^1,3, Rolf Gruetter^1,2, and Arnaud Comment^1,3
1LIFMET, EPFL, Lausanne, 1015, Switzerland, ²Department of Radiology, University of Lausanne, Lausanne, Switzerland, ³Institute of Physics of Biological Systems, EPFL, Lausanne, Switzerland

The real-time metabolic transformation of lactate in the mouse head was monitored following the injection of hyperpolarized 1-13C lactate at physiological doses. The results were compared with metabolic studies performed with hyperpolarized 1-13C pyruvate at similar blood concentration. From the observation that the lactate to alanine ratio was nearly identical following both the pyruvate and the lactate injections, we concluded that the substrate and its metabolites can be detected in real time at physiological concentrations after the injection of lactate.

Malgorzata Marjanska¹, Alexander Shestov¹, and Pierre-Gilles Henry^1
1Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States

The low sensitivity of ¹³C spectroscopy can be enhanced using hyperpolarization techniques such as dynamic nuclear polarization. Detection of [1-¹³C]pyruvate and its metabolic products including bicarbonate have been reported in the brain. In this work, we investigate the ability to detect bicarbonate under different anesthesia and modeling of that signal to determine value of rate constants of bicarbonate production.

David J Niles¹, Jeremy W Gordon¹, Matthew R Smith¹, Shannon Reese², Arjang Djamali², Elizabeth A Sadowski³, and Sean B Fain^1,3
1Medical Physics, University of Wisconsin, Madison, WI, United States, ²Medicine, University of Wisconsin, Madison, WI, United States, ³Radiology, University of Wisconsin, Madison, WI, United States

Obstructive nephropathy is the most common cause of end-stage renal disease in children. Currently we have a poor understanding of its pathogenesis, prognosis, and the best course of treatment. Non-invasive, non-radioactive diagnostic approaches are desirable. In this study we used MRI to monitor renal function during obstructive nephropathy in a 14-day unilateral ureteral obstruction (UUO) mouse model. Blood oxygen level-dependent (BOLD), dynamic contrast-enhanced (DCE), and hyperpolarized [1-¹³C] pyruvate (¹³C) MRI were used to assess renal oxygenation, perfusion, and pyruvate metabolism, respectively. The results show the potential of using functional MRI, particularly ¹³C MRI, to track the progression of obstructive nephropathy.

Stephen Kadlecek¹, Benjamin Pullinger¹, Kiarash Emami¹, Harrilla Profka¹, Masaru Ishii², and Rahim Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States, ²Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, United States

Difficulties with NMR studies of lung arising from low tissue density and air-tissue interfaces can be partially overcome using 13C-DNP NMR. This experiment studies the evolution of the [1-13C] lactate signal in isolated, perfused rat lungs after injection of pyruvate under normoxic and ischemic conditions in order to understand changes in lung oxidative state, central to ischemia-reperfusion injury, transplantation, and metabolic changes in cancer. A 25-minute period of ischemia is associated with both a ~5x elevated rate of pyruvatelactate conversion and a similar increase in the endogenous lactate pool as measured by proton NMR; both changes are reversible after reperfusion. 31P confirms previously published changes to the ATP and PCr pools during ischemia.

Guilhem Pages¹, Yee Ling Tan¹, and Philip William Kuchel^1
1Mechanistic Systems-biology NMR Group, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore, Singapore

Dynamic Nuclear Polarization (DNP) has opened up new avenues to characterize metabolism; we have extended it to study rapid membrane transport of a solute. We used hyperpolarized ¹³C-urea in the presence of urease in erythrocyte suspensions. We designed an extensive kinetic model, taking into account all chemical and transport reactions of the hyperpolarized urea and its products to extract estimates of rate constants of the reactions. The systems urea/urease and urea/erythrocytes were fully characterized with the detection of all chemical species. The success of this in vitro study albeit on a simple cell-type augurs well for similar in vivo experiments.