Talaignair N. Venkatraman¹, Artek Tovmasyan², Ines Batinic-Haberle², Ivan Spasojevic², and Christopher D. Lascola^1
1Radiology, Duke University Medical Center, Durham, NC, United States, ²Radiation Oncology, Duke University Medical Center, Durham, NC, United States

This study investigates the potential impact of common biological moieties on the relaxation properties of our two lead candidate MnPs (MnTE-2-PyP5+ and MnTnHex-2-PyP5+). These include the most abundant intracellular redox mediator, ascorbate; (2) the most metabolically relevant counter-anion, citrate; (3) and the most abundant serum protein, albumin. With respect to likely biological redox modifiers, both MnP isoforms showed a systematic reduction in relaxivity in the presence of ascorbate, consistent with the hypothesis that metal center oxidation state will have a significant impact on relaxation properties of MnPs in vivo. Intriguingly, citrate anion does not negatively impact relaxation, and in the case of MnTE2PyP5+, may actually enhance contrast enhancement. These two isoforms of MnP demonstrate impressive relaxation properties that enable MR detection in vivo.

Yuegao Huang^1,2, Daniel Coman^1,2, Garry E. Kiefer³, and Fahmeed Hyder^1,4
1Diagnostic Radiology, Yale University, New Haven, CT, United States, ²Magnetic Resonance Research Center, Yale University, New Haven, CT, United States, ³Macrocyclics, Dallas, TX, United States, ⁴Biomedical Engineering, Yale University, New Haven, CT, United States

Temperature mapping has important biomedical applications. Unlike PARACEST agents that provide temperature contrast, the Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) method provides absolute temperature mapping, where directly imaging proton resonances of the lanthanide complexes with 3D CSI is key. Motivated by success of TmDOTMA^- with BIRDS for temperature mapping, we designed new agents with methyl groups on different positions of DOTA-based chelates. Comparison with TmDOTMA^- shows much higher temperature sensitivities with BIRDS are achieved with the new agents. Moreover, the new agents have strong PARACEST capabilities to allow quantitative molecular imaging by combining with BIRDS.

Yuegao Huang^1,2, Meser M. Ali³, Daniel Coman^1,2, Garry E. Kiefer⁴, and Fahmeed Hyder^1,5
1Diagnostic Radiology, Yale University, New Haven, CT, United States, ²Magnetic Resonance Research Center, Yale University, New Haven, CT, United States, ³Radiology, Henryford Health System, Detroit, MI, United States, ⁴Macrocyclics, Dallas, TX, United States, ⁵Biomedical Engineering, Yale University, New Haven, CT, United States

Temperature mapping using low molecular weight paramagnetic chelates has advantageous sensitivities compared to conventional MRI thermometry methods. 3D temperature maps can be generated with a method called Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), where directly imaging proton resonances of lanthanide complexes with 3D CSI is key. Considering success of BIRDS with low molecular weight individual chelates, in the present work we explore the possibilities to improve BIRDS sensitivity with larger biocompatible molecules, such as dendrimers. The BIRDS detection can be achieved with lower agent dosage when lanthanide chelates are conjugated to the surface of the dendrimers.

Kangan Li¹, Shihui Wen², Xiangyang Shi², Guixiang Zhang³, and Andrew C. Larson^1
1Department of Radiology, Northwestern University, Chicago, Illinois, United States, ²Chemical Engineering and Biotechnology, Donghua University, Songjiang, Shanghai, China, ³Department of Radiology, Shanghai Jiaotong University, Hongkou, Shanghai, China

A novel multifunctional dendrimer-based gold nanoparticles as a MRI/CT dual modality contrast agent for in vivo molecular imaging of breast cancer.

Wenlong Xu¹, Krishna Kattel¹, Md. Wasi Ahmad¹, Badrul Alam Bony¹, Tirusew Tegafaw¹, Woo Choul Heo¹, Cho Rong Kim¹, Yongmin Chang², and Gang Ho Lee^1
1Department of Chemistry, Kyungpook National University, Buk-gu, Daegu, Korea, ²Department of molecular medicine, Kyungpook National University, Buk-gu, Daegu, Korea

A dual imaging now emerges as a new and advanced imaging technique in clinical applications. The single-phase mixed DyEuO₃ and HoEuO₃ nanoparticles are potential candidates for dual imaging experiment. It is expected that it will play a key role to diagnose diseases by replacing conventional single-imaging techniques. For example for MRI-FI dual imaging, the fluorescence imaging can be used to locate a disease and then MRI can be used to obtain high resolution MR images around the disease. We developed a facile synthesis of ultra-small D-Glucuronic acid coated Eu³⁺ doped Dysprosium oxide nanoparticles and Holmium oxide nanoparticles. The capability of nanoparticles as T2 MRI contrast agent was proved in vivo through T2 MR images of a rat. The fluorescent images were observed in vitro by taking DU145 and NCTC1469 cells. The nanoparticles exhibited no appreciable cytotoxicity up to 100 M concentrations and in vivo MR experiment showed the negative contrast enhancement on mouse liver and kidneys after the injection of nanocolloid. Hence, it can be used as a fluorescence imaging agent as well as a T1 MRI contrast agent.

Md. Wasi Ahmad¹, Kattel Krishna¹, Badrul Alam Bony¹, Wenlong Xu¹, Tirusew Tegafaw¹, Woo Choul Heo¹, Yongmin Chang², and Gang Ho Lee^1
1Chemistry, Kyungpook National University, Daegu, Korea, ²Molecular Medicine School of Medicine, Kyungpook National University, Daegu, Korea

The surface modified Gd₂O₃ nanoparticles as an active ingredient has a higher relaxation rate compared to currently commercialized MRI contrast agent. The performance of nanoparticles for biomedical applications is highly dependent on the nature and quality of surface coating materials. In particular, the development of functionalized nanoparticles for magnetic resonance imaging (MRI) requires the grafting of hydrophilic and biocompatible polymers, this polymer enhances the steric repulsion and therefore the stability of the colloids

Badrul Alam Bony¹, Krishna Kattel¹, Wenlong Xu¹, Woo Choul Heo¹, Tirusew Tegafaw Mengesha¹, Md. Wasi Ahmad¹, Cho Rong KIM¹, Yongmin Chang², and Gang Ho LEE^1
1Department of Chemistry, Kyungpook National University, Daegu, Korea, ²School of Medicine, Kyungpook National University, Daegu, Korea

CuO doped Gd₂O₃ nanoparticles can be used as a MRI contrast agent clinically because of its enhanced relaxivity and less toxicity. The r₁ value of CuO doped Gd₂O₃ nanoparticles is 13.8 mM^-1s^-1 which is more than double of ordinary Gd₂O₃ nanoparticles. That is why, CuO doped Gd₂O₃ nanoparticles can be a novel candidate for T₁ MRI contast agent.

Shruti kanakia¹, Jimmy Toussaint¹, Sayan Mullick Chowdhury¹, Tanuf Tembulkar¹, Terry Button², Kenneth Shroyer³, William Moore², and Balaji Sitharaman^1
1Biomedical Engineering, Stony Brook Univeristy, Stony Brook, New York, United States, ²Radiology, Stony Brook Univeristy, Stony Brook, New York, United States, ³Pathology, Stony Brook Univeristy, Stony Brook, New York, United States

We report pre-clinical in vitro and in vivo small animal studies of a novel graphene-based MRI CA. The formulation called GNP-Dex consists of monodisperse graphene nanoplatelets (GNPs; small disc-shaped graphene nanoparticles with diameter ~40 nm and thickness ~3-4 nm), intercalated with manganese Mn2+ ions, and water-solubilized with dextran. The results show that the GNP-Dex formulation is safe (LD50 > 500 mg/kg). At potential therapeutic doses (≤100 mg/kg), they show no nephrotoxicity and are more efficacious than clinical MRI CAs Magnevist and Ablavar. The results indicate that GNP-Dex show potential for development as high performance clinical T1 MRI CA.

Jun-ichiro Jo^1,2, Ichio Aoki¹, Tsuneo Saga¹, and Yasuhiko Tabata^2
1Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba, Japan, ²Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Kyoto, Japan

The objective of this study is to design and prepare a new polymer-based contrast agent of magnetic resonance imaging (MRI) for the evaluation of therapeutic angiogenesis. Diethylenetriaminepentaacetic acid (DTPA), cyclic peptide containing an arginine-glycine-aspartic acid sequence (cRGD), and gadolinium ion (Gd3+) were introduced to dextran to obtain the dextran-based contrast agent (cRGD-dextran-DTPA-Gd). The cRGD-dextran-DTPA-Gd showed a higher longitudinal relaxivity compared with DTPA-Gd. The ischemic-angiogenic region could be clearly detected with MRI by the intravenous injection of cRGD-dextran-DTPA-Gd to mice with hindlimb ischemia. It is concluded that the cRGD-dextran-DTPA-Gd is a promising material to evaluate the therapeutic angiogenesis.

Giuseppe Digilio¹, Valeria Catanzaro², Valeria Menchise³, Sergio Padovan³, Martina Capozza⁴, Linda Chaabane⁵, and Silvio Aime^4
1Università del Piemonte Orientale "A. Avogadro", Alessandria, AL, Italy, ²Istituto di Ricerca Diagnostica e Nucleare SDN, Via Gianturco 113, Napoli, 80143, Na, Italy, ³CNR - IBB, Torino, TO, Italy, ⁴Department of Chemisty & Center for Molecular Imaging, University of Turin, Torino, TO, Italy, ⁵Institute for Experimental Neurology - INSpe, San Raffaele Scientific Institute, Milano, MI, Italy

A novel paramagnetic Gd-loaded liposome for the MRI assessment of the activity of Matrix Metalloproteinase-2 is described. It relies on a ratiometric R2p/R1p procedure that is independent of the total concentration of gadolinium.

Ananth Annapragada¹, Eric Tanifum¹, Ketan Ghaghada¹, and Divya Sabapathy^1
1Pediatric Radiology, Texas Childrens Hospital, Houston, TX, United States

Novel presentation of Gd atoms on nanoparticles were tested, to identify the mechanism of hyperrelaxivity of nanoparticle presented Gd. A new lipid construct with dramatically higher relaxivity is described.

Shawn Wagner^1,2, Denis Avdic¹, Alexander Grunfeld³, and Debiao Li^1,2
1Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States, ²Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States, ³Life Sciences, UCLA, Los Angeles, California, United States

½ spin nuclei like yttrium (89Y) and silicon (29Si) can have long T1 values. Recent literature has suggested that the T1 value in silicon particles is size dependent because the dominate relaxation is a result of spin diffusion from the surface to the core. In this work, we measured the T1 values of silicon nanoparticles of various sizes to verify whether the hypothesis is true. We found that small nanoparticles have longer than predicted relaxation times and would be suitable for development into molecular targeting agents which could be followed for several hours.

Naira P. Martinez Vera¹, Klaus Langer², Iavor Zlatev², Robert Wronski³, Manfred Windisch³, Ewald Auer³, Hagen von Briesen⁴, Sylvia Wagner⁴, Motti Deutsch⁵, Claus Pietrzik⁶, Franz Fazekas¹, Reinhold Schmidt¹, and Stefan Ropele^1
1Department of Neurology, Medical University of Graz, Graz, Styria, Austria, ²Institut für Pharmazeutische Technologie und Biopharmazie, Münster, North Rhine-Westphalia, Germany, ³JSW Life Sciences GmbH, Grambach, Styria, Austria, ⁴Department of Cell Biology & Applied Virology, Fraunhofer-Institute for Biomedical Engineering, St. Ingbert, Saarland, Germany, ⁵Physics Department, Schottenstein Center for the Research and Technology of the Cellome, Bar Ilan University, Ramat Gan, Israel, ⁶Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Rhineland-Palatinate, Germany

Nanoparticles (NP) have been suggested as a vehicle to selectively transport drugs over the blood brain barrier. In this work we investigated the feasibility of measuring the accumulation of HSA based NP in the rat brain after intravenous injection. The NP were labeled with magnetite in order to achieve a significant T1 relaxivity effect. The measurement of NP concentration was based on a histogram fitting technique which allowed to globally assess T1 changes in gray and white matter. This approach proved to be very sensitive and was validated with results from autofluorescence imaging.

Dirk Krueger¹, Gorka Salas², Macarena Calero², Silvia Lorrio González¹, Angeles Villanueva², María P. Morales³, and René M. Botnar^1
1Division of Imaging Sciences & Biomedical Engineering, King's College London, London, United Kingdom, ²Instituto IMDEA Nanociencia, Madrid, Spain,³Instituto de Ciencia de Materiales de Madrid, CSIC, Madrid, Spain

The aim of this project is to develop and validate multifunctionalised magnetic nanoparticles (MF-MNP) to selectively target and monitor delivery and treatment response of MNPs to cancer cells by MRI. We assessed eight MNPs on their MR imaging properties and investigated their effects on various cancer cell lines. The investigated 15 nm DMSA-coated MNP shows promising imaging (i.e. r1 and r2 relaxivities) and labelling properties without affecting viability of the cells and thus warrant in-vivo investigation in nude tumour bearing mice (BT474, MDA-MB-231, BxPc-3 PANC-1) to evaluate biodistribution, specificity and suitability for in vivo imaging and therapy.

Jing Huang¹, Liya Wang¹, and Hui Mao^1
1Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, United States

Superparamagnetic iron oxide nanoparticles (SPIOs) have been widely used as MRI contrast agents both in clinical applications (e.g. liver, lymph nodes imaging) and preclinical models (e.g. cell tracking, molecular imaging). Currently, most SPIOs are fabricated with size larger than 5 nm, therefore exhibit predominant shortening effect on T2, causing signal void in T2-weighted MRI. Here we report a new class of high r1 relaxivity, sub-5 nm, suprasmall iron oxide nanoparticles (sSIOs, ~3.5 nm) as intravascular T1-weighted MRI contrast agents, providing reverse T2 contrast and T1-T2 contrast switch, when taken up by cells and liver, or between labeled and lysed cells.

Sheikh Manjura Hoque¹, Yuegao Huang¹, Samuel Maritim¹, Daniel Coman¹, and Fahmeed Hyder^1
1Yale University, New Haven, CT, United States

Ferrite nanoparticles are used for contrast, but they also have potential for cancer therapy because nanoparticles can be heated by alternating RF. Since diamagnetic resonances are susceptibility-shifted with nanoparticles, temperature and/or pH mapping with typical MRI/MRS methods are difficult. To generate both tissue contrast and map temperature/pH in presence of nanoparticles, we used a new method called BIRDS, which requires that we detect protons emanating from a temperature/pH probe (e.g., TmDOTP5-) itself, instead of the agent’s effect on water proton relaxation times. Promising in vitro results from a family of Fe-Co mixed ferrite nanoparticles are discussed.

Deepak K. Kadayakkara¹, Hyam I. Levitsky¹, and Jeff W.M. Bulte^2,3
1Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States, ²Cellular Imaging Section, Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, United States, ³MRI research division, Johns Hopkins School of Medicine, Baltimore, Maryland, United States

We evaluated the effects of novel adjuvants in cancer vaccines using non-invasive imaging. ‘Magnetovaccination’ and MRI were used to evaluate dendritic cell-mediated antigen capture and delivery to regional lymph nodes. The ensuing effector immune response mediated by T cells was studied by antigen-specific transgenic T cells and bioluminescence imaging. We show that, unexpectedly, adjuvants reduced antigen delivery to lymph nodes; however they induced a more effective tumor therapeutic response suggesting an alternate and hitherto unreported pathway for T cell expansion and accumulation.

Cho Rong Kim¹, Eun Jung Lee¹, Woo Choul Heo², Yongmin Chang³, and Gang Ho Lee^1
1Chemistry, Kyungpook national university, Daegu, Korea, ²Chemistry, Kyungpook National University, Daegu, Korea, ³School of medicine, Kyungpook National University, Daegu, Korea

We synthesized D-glucuronic acid coated Gd(IO₃)₃.2H₂O nanomaterials and for the first time investigated their magnetic properties, water proton relaxivities, and X-ray phantom images. D-glucuronic acid coated Gd(IO₃)₃.2H₂O nanomaterials were paramagnetic, with very large longitudinal (r₁) and transverse (r₂) water proton relaxivities of 52.3 and 63.4 s^-1mM^-1, respectively, both of which were larger than those of commercial Gd-chelates. Hydrated water molecules seem to serve as a reservoir for strong MR signals. The stronger contrast enhancements in X-ray phantom images than those of commercial molecular iodine CT contrast agents were also observed. These results revealed that D-glucuronic acid coated Gd(IO₃)₃.2H₂O nanomaterials should be a potential candidate for a MRI-CT dual contrast agent.

Hugo Groult^1,2, Andrea Bianchi³, Moreno Zamai⁴, Jesus Ruiz-Cabello¹, Yannick Crémillieux³, and Fernando Herranz-Rabanal^1
1Advanced imaging unit, CNIC (centro nacional de investigaciones cardiovasculares), Madrid, Madrid, Spain, ²CIBERES (Centro de Investigacíon biomedica en red Enfermedades Respitorias), Bunyola, Mallorca, Spain, ³Cardio-thoracic Center of Bordeaux, University of Bordeaux Segalen, Bordeaux, Aquitaine, France, ⁴Microscopy and Dynamic imaging Unit, CNIC (centro nacional de investigaciones cardiovasculares), Madrid, Madrid, Spain

One of the most attractive approaches in molecular imaging is the combination of fluorescence with MRI, providing high sensitivity and resolution together with structural and functional data. We present here the physicochemical characterization and the in vitro and in vivo multimodal study (MR and fluorescence imaging) of a new class of nanoparticles based on UpConverting NanoPhosphors albumin-coated. These nanoparticles present the unique feature of converting low energy near-infrared (NIR) light into higher visible light and/or NIR emission, which allow to overcome all the typical problems of fluorescent probes. At the same time they can be combined to MR imaging modality.

Tirusew Tegafaw Mengesha¹, Krishna kattel¹, Wenlong Xu¹, Badrul Alam Bony¹, Woo Choul Heo¹, Kim Cho Rong¹, Md. Wasi Ahmad¹, Yong Min Chang², and Gang Ho Lee^1
1Departement of Chemistry, Kyungpook National University, Daegu, Korea, ²Departement of molecular medicine, Kyungpook National University, Daegu, Korea

MRI is a very useful technique in diagnosing diseases because of its high spatial resolution and good sensitivity. Detection of diseases can be further improved by using MRI contrast agents through contrast enhancement. Fluorescein coated gadolinium oxide nanoparticles are promising candidates as either T1 MRI-CL or MRI-FI dual agents because gadolinium oxide nanoparticles show a longitudinal relaxivity (r1) which is much larger than those of Gd (III) -chelates while dyes generally provide a very strong fluorescent intensity. The enhanced r1 of gadolinium oxide nanoparticles with respect to those of Gd (III) - chelates is due to a high density of probing Gd (III) ions in nanoparticles. Gadolinium oxide nanoparticles must be biocompatible and completely excreted from the body through the renal system to avoid any danger such as nephrogenic systemic fibrosis. Therefore, nanoparticles should be well-coated with water-soluble and biocompatible ligands. In this work, fluorescein is conjugated to hydrophilic and biocompatible polyethyleneimine (PEI) (Mn = y1200 amu) to improve both water-solubility and biocompatibility of fluorescein through the EDC/NHS coupling method. Finally, fluorescein-PEI was conjugated to gadolinium oxide nanoparticles. We demonstrated MRI-CL dual functionality of fluorescein-PEI coated gadolinium oxide nanoparticles both in vivo and in vitro.

Shizhen Chen¹, Yuqi Yang¹, Qi Wang¹, Haidong Li¹, and Xin Zhou^1
1Wuhan Center for Magnetic Resonance,Wuhan Institute of Physics and Mathematics,CAS, Wuhan, Hubei, China

We developed a novel nanosized and pH-trigged biosensor, which encapsulates high-sensitive 19F MRI contrast agent in gold nanoparticles (AuNPs)-capped mesoporous silica nanoparticles (MSNs) platform,and this biosensor is capable to specifically target to lung cancer cell (A549) for intracellular MRI.

Maria Yanez Lopez¹, Marie-Christine Pardon², Dorothee P. Auer¹, and Henryk Faas^1
1Radiological and Imaging Sciences, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom, ²School of Biomedical Sciences, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom

This study assesses the short term inflammatory response in the brain to a standard immune challenge, lipopolysaccharide injection, with serial MR Spectroscopy and imaging using Chemical Exchange Saturation Transfer. Results show in vivo MRS changes three hours after lipopolysaccharide administration: increase in the microglial marker myo-inositol and decrease in total choline (both effects absent in controls with PBS administration). They also indicate that CEST can assess, at high spatial resolution, metabolic changes following low dose lipopolysaccharide administration, since CEST images at offset frequencies of 0.5-1, 1.8-2.2 ppm in the z-spectrum, showed a correlation with myo-inositol and total creatine MRS ratios.

Lindsey Alexandra Crowe¹, Frank Tobalem², Marije Koenders³, Eline Vermeij³, Fons A. van de Loo³, Azza Gramoun¹, Jatuporn Salaklang⁴, Anthony Redgem⁴, Alke Petri-Fink⁵, Heinrich Hofmann⁶, Wim van der Berg³, and Jean-Paul Vallée^1
1Radiology / Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland, ²Radiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, ³Department of Rheumatology, Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ⁴Adolphe Merkle Institute, Université de Fribourg, Fribourg, Switzerland, ⁵Adolphe Merkle Institute and Chemistry Departement, Université de Fribourg, Fribourg, Switzerland, ⁶Institute of Materials, Powder Technology Laboratory, EPFL, Lausanne, Switzerland

Many pre-clinical studies are carried out on clinical MRI systems due to translational possibilities and availability of technology. For small sample sizes, an adapted coil to give high signal intensity is needed. Diagnostic potential of signal loss and positive contrast difference Ultrashort Echo (dUTE) sequences for iron oxide nanoparticle detection (amino-PVA-SPIONs) was compared in a mouse model of antigen induced arthritis. SPION administration routes and doses in arthritic and control knees are compared for synovial uptake with high sample throughput.

Lesley M. Foley¹, Steven L. Shein^2,3, Vincent A. Vagni², T Kevin Hitchens^1,4, Chien Ho^1,4, and Patrick M. Kochanek^2,5
1Pittsburgh NMR Center for Biomedical Research, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States, ²Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States, ³Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States, ⁴Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States,⁵Departments of Critical Care Medicine, Pediatrics and Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States

Secondary insults are known to worsen outcome following traumatic brain injury (TBI). Though there is conflicting clinical evidence with regards to hyperthermia, it is generally considered as detrimental and for patients that exhibit pyrexia it is important temperature control. In animal models there is no question about the role of hyperthermia and it’s detrimental effect on outcome. In our study there was a significant increase in macrophage influx to the brain following TBI and moderate hyperthermia.

Ilwoo Park¹, Peder E.Z. Larson¹, Jim Tropp², Lucas Carvajal¹, Mark VanCriekinge¹, Robert A. Bok³, John Bringas⁴, Adrian Kells⁴, Philip Pivirotto⁴, Krystof Bankiewicz⁴, Daniel B. Vigneron⁴, and Sarah J. Nelson^1,5
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, ²GE Healthcare, Menlo Park, CA, United States, ³Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States,⁴Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, United States, ⁵Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States

We have designed a hyperpolarized ¹³C metabolic imaging experimental setup for the human brain and demonstrated its feasibility by acquiring in vivo data from a healthy non-human primate brain. ¹³C coils and pulse sequences were designed and tested using phantom and rats. Dynamic ¹³C data acquired from a healthy non-human primate brain showed excellent detection of pyruvate and lactate in brain. The metabolite conversion kinetics showed distinctive characteristics between the brain and its surrounding tissues. These results suggest that this technique may provide a unique way to investigate in vivo metabolism in patients with brain tumors.

Angus Z. Lau^1,2, Albert P. Chen³, Michelle Ladouceur-Wodzak¹, Krishna S. Nayak⁴, and Charles H. Cunningham^1,2
1Imaging Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, ²Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, ³GE Healthcare, Toronto, Ontario, Canada, ⁴Department of Electrical Engineering, University of Southern California, Los Angeles, California, United States

The recent identification of functional brown adipose tissue (BAT) in humans has implications for the treatment of obesity. In this study, dynamic, spatially resolved hyperpolarized 13C imaging was used to non-invasively identify functional BAT in vivo in a rodent model. BAT was activated using intraperitoneal injection of norepinephrine and detected following infusion of pre-polarized 13C pyruvate. Increases in 13C bicarbonate (3.7-fold) and 13C lactate (3.5-fold) signal in the interscapular region correspond to a known rodent BAT deposit. The radiation-free nature of this imaging exam may potentially facilitate trials of therapeutics targeting BAT activation in humans.

Tiago B. Rodrigues¹, Eva M. Serrao¹, Brett W.C. Kennedy¹, De-En Hu¹, Kevin M. Brindle¹, and Mikko I. Kettunen^1
1Biochemistry/CRUK, University of Cambridge, Cambridge, United Kingdom

Tumor cells frequently display high rates of aerobic glycolysis, resulting in increased lactate production and correlating with a poor prognosis and increased tumor aggressiveness and metatasis. We show here that hyperpolarized [U-²H, U-¹³C]glucose allows real-time monitoring of tumor glycolysis in vivo, through the production of hyperpolarized [U-¹³C]lactate, and that this flux is substantially reduced in murine EL4 lymphoma tumors by 24 h after etoposide treatment. Although the sensitivity of MR detection of hyperpolarized [U-²H, U-¹³C]glucose is much lower than PET detection of FDG, it has some significant potential advantages for detecting tumor treatment response.

Kundan Thind^1,2, Elaine Hegarty¹, Albert P. Chen³, Heeseung Lim^1,2, Francisco Martinez¹, Michael Jensen², Eugene Wong^1,4, Timothy J. Scholl¹, and Giles E. Santyr^1,5
1Robarts Research Institute, Western University, London, ON, Canada, ²Dept. of Medical Biophysics, Western University, London, ON, Canada, ³GE Healthcare, Toronto, ON, Canada, ⁴Dept. of Physics and Astronomy, Western University, London, ON, Canada, ⁵Dept. of Medical Imaging, Western University, London, ON, Canada

Sprague Dawley rats were irradiated using conformal radiotherapy to lower-medial right lung (18.5 Gy) to induce RILI (Radiation Induced Lung Injury). Hyperpolarized ¹³C-pyruvate was injected and regional lactate-to-pyruvate signal ratio was quantified day 10 and 15 (early RILI) post radiotherapy. Statistically significant increase in lactate-to-pyruvate signal ratio was observed in both left lung and right lung of irradiated animals compared to age matched healthy animals at day 10 and day 15. Onset of inflammation during early RILI was confirmed using histology. Lack of systemic spread of injury was confirmed by measuring blood lactate concentration.

Sonal Josan^1,2, Jae Mo Park², Yi-Fen Yen², Ralph Hurd³, Adolf Pfefferbaum^1,2, Daniel Spielman², and Dirk Mayer^1,2
1SRI International, ²Stanford University, ³GE Healthcare

Hyperpolarized [1-13C]-pyruvate MRS has been used to measure changes in cardiac PDH flux via measurement of 13C-bicarbonate, but may not reflect tricarboxylic acid (TCA) cycle activity. This work investigates the metabolic fate of the corresponding acetyl-CoA produced using [2-13C]-pyruvate to track the 13C label into glutamate and acetyl-carnitine, comparing the response to increased cardiac workload with dobutamine at two different pyruvate doses.

Lanette J. Friesen-Waldner^1,2, Trevor P. Wade^1,2, Curtis N. Wiens³, Kundan Thind^1,2, Jacqueline K. Harris¹, Kevin J. Sinclair¹, Colin M. McCurdy¹, Albert P. Chen⁴, Nica M. Borradaile⁵, and Charles A. McKenzie^1,2
1Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada, ²Imaging Research Labs, Robarts Research Institute, London, Ontario, Canada, ³Department of Physics and Astronomy, University of Western Ontario, London, Ontario, Canada, ⁴GE Healthcare, Toronto, Ontario, Canada, ⁵Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada

Brown fat is more metabolically active than white fat. The purpose of this study was to detect metabolism in brown fat using hyperpolarised ¹³C MRS and CSI. 2D CSI of hyperpolarised [1-¹³C]pyruvate in the subscapular fat pad of mice showed more metabolism to lactate in brown fat than white fat. The ratio of lactate to total carbon was 53% in brown fat, and 22% in white fat. These results suggest that hyperpolarised [1-¹³C]pyruvate MRS and CSI can be used to differentiate the metabolic activity of brown fat from white fat.

Samira Kazan¹, Steven Reynolds², Tooba Alizadeh¹, Adriana Bucur², Aneurin Kennerley³, Vincent Cunningham⁴, Martyn Paley², and Gillian M. Tozer^1
1CR-UK/YCR Sheffield Cancer Research Centre, University of Sheffield, Sheffield, South Yorkshire, United Kingdom, ²Academic Unit of Radiology, University of Sheffield, Sheffield, South Yorkshire, United Kingdom, ³Signal Processing in Neuroimaging and Systems Neuroscience, University of Sheffield, Sheffield, South Yorkshire, United Kingdom, ⁴Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, Scotland, United Kingdom

Mathematical models are required to estimate kinetic parameters of [1-¹³C] pyruvate-lactate interconversion from magnetic resonance spectroscopy data. It has been shown previously that the use of a measured arterial input function provides a robust and more comprehensive analysis of the kinetics compared to using a hypothetical box-car input function. A measured AIF reduces the number of free parameters for fitting and provides physiologically meaningful values not only for the rate constant of conversion of pyruvate to lactate, but also for clearance of pyruvate from the blood to the tissue. This parameter would be of particular relevance if blood flow effects were of interest in a study. Urea has been used previously as a perfusion marker to track the perfusion of pyruvate to the site of interest. In this study, by simultaneous injection of hyperpolarized ¹³C pyruvate and urea we measured both AIFs in order to compare the clearance/perfusion rates obtained using both methods at a tumor site.

Georgios Batsios¹, Divya Vats¹, Catherine Germanier¹, Michael Batel², Marcin Krajewski¹, and Markus Rudin^1,3
1Institute for Biomedical Engineering, ETH and University of Zurich, Zurich, Switzerland, ²Laboratory of Physical Chemistry, ETH Zurich, 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, particularly in the field of cancer. In this study we compare the lactate dehydrogenase (LDH) activity by measuring the conversion of pyruvate to lactate using same type of tumor cells growing at different implantation sites and different genetic background mice and using different tumor cell lines. We show that the pyruvate to lactate conversion depends mostly on the tumor type and not on the tumor environment. This indicates that the pyruvate processing through the LDH reaction reflects an intrinsic property of the tumor cell line.

Vickie Zhang^1,2, Robert A. Bok³, Jessie Lee², Subramaniam Sukumar¹, Adam Cunha⁴, I-Chow Hsu⁴, Jean Pouliot⁴, Daniel B. Vigneron^1,2, and John Kurhanewicz^1,2
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, United States, ²Graduate Program in Bioengineering, University of California, San Francisco & University of California, Berkeley, Berkeley, California, United States, ³Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States, ⁴Department of Radiation Oncology, University of California, San Francisco, San Francisco, California, United States

Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) has shown great clinical potential for assessing prostate cancer presence and aggressiveness prior to and after radiation therapy. Co-polarization of 13C pyruvate and urea also allows the simultaneous assessment of tumor perfusion and metabolism in a single MR acquisition (3,4). However, whether hyperpolarized 13C urea provides the same information as DCE MRI remains to be answered. This study investigated tumor perfusion prior to therapy and following radiation therapy in a transgenic murine model of prostate cancer using both HP 13C urea and DCE-MRI.

Eva M. Serrao¹, Tiago B. Rodrigues¹, Mikko I. Kettunen¹, Ferdia A. Gallagher¹, Brett Kennedy², De-En Hu³, Keith Burling⁴, Joan Boren¹, Helen Sladen¹, and Kevin M. Brindle^3
1Cambridge Research Institute CRUK, Cambridge, Cambridge, United Kingdom, ²Biochemistry, Cambridge University, Cambridge, Cambridge, United Kingdom, ³University of Cambridge, Cambridge, Cambridge, United Kingdom, ⁴Clinical Biochemistry, Addenbrook’s Hospital, Cambridge, Cambridge, United Kingdom

Hyperpolarized [1-13C]pyruvate has shown great promise for clinical oncology, particularly in the assessment of early response to treatment, and has also been the only hyperpolarized substrate to be used in humans. Determination of its reproducibility as a probe and the factors that affect reproducibility are important in order to understand if changes in its metabolism reflect real effects of therapy or changes in mouse physiology. We show that hyperpolarized[1-13C]pyruvate is a reproducible probe, showing relatively little variability when injected into fasted mice, suggesting that the fasted state may be more optimal for performing this technique in humans.

Ralph Hurd¹, Sonal Josan^2,3, Jae Mo Park^2,4, Yi Fen Yen², Dirk Mayer^2,3, and Daniel Spielman^2,4
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, CA, United States

With the increased use of hyperpolarized [2-13C]pyruvate in metabolic spectroscopy and imaging, there is an emerging need for optimized sampling of the metabolically labeled [2-13C]lactate. Toward that goal, the T1 of [1-13C]lactate was measured in vivo and used to calculate optimum flip angles for time-resolved spectroscopic data collection. An equimolar mixture of 40 mM [1-13C]pyruvate and 40 mM [2-13C]pyruvate was used to compare the apparent in vivo T1’s and to optimize the time-resolved sampling of [2-13C]lactate with [1-13C]lactate.

David J. Niles¹, Jeremy W. Gordon², Gengwen Huang³, Kevin M. Johnson¹, Arjang Djamali⁴, and Sean B. Fain^1,5
1Medical Physics, University of Wisconsin, Madison, WI, United States, ²Medical Physics, University of Wisconsin-Madison, Madison, WI, United States,³Surgery, University of Wisconsin, Madison, WI, United States, ⁴Medicine, University of Wisconsin, Madison, WI, United States, ⁵Radiology, University of Wisconsin, Madison, WI, United States

Congenital obstructive nephropathy is the most common cause of end-stage renal disease in children, and there is a need to improve tools for early diagnosis. In this study we used hyperpolarized ¹³C MRI to longitudinally and non-invasively assess the hemodynamic and metabolic changes in the kidney following partial unilateral ureteral obstruction. We observed reduced blood flow to the obstructed kidney and a preferential shift toward glycolysis in both kidneys. Our results may contribute to the understanding of the pathogenesis of obstructive nephropathy and to the development of improved approaches for clinical assessment.

Deborah K. Hill¹, Jessica K.R. Boult¹, Rafal Panek¹, Harold G. Parkes¹, Matthew R. Orton¹, Anne-Christine L.F. Wong Te Fong¹, Maysam Jafar¹, Simon P. Robinson¹, Martin O. Leach¹, Thomas R. Eykyn^1,2, and Yuen-Li Chung^1
1CR-UK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom, ²Division of Imaging Sciences and Biomedical Engineering, Kings College London, St Thomas Hospital, London, United Kingdom

Clinical MR platforms offer superior hardware advances, larger available field of view and clinically relevant field strengths. The lower field strengths are particularly advantageous for Dynamic Nuclear Polarisation studies, where hyperpolarised signals decay more slowly, increasing the time available for data acquisition. In this study we have developed and acquired apparent hyperpolarised [1-¹³C]pyruvate-[1-¹³C]lactate exchange rates from subcutaneous xenografts in mice on a 3T clinical platform. Full kinetic modelling provided a sensitive assay to detect significant treatment response induced by the PDK inhibitor, dichloroacetate, which exemplifies this technique as a superior analysis method when handling data from small animal cohorts.

Duan Xu¹, Zinaida Vexler², Subramaniam Sukumar¹, Robert A. Bok¹, John Kurhanewicz¹, and Xiaoliang Zhang^1
1Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States, ²Department of Neurology, University of California San Francisco, San Francisco, CA, United States

Hypoxic-ischemic injury occurs in approximately 25,000 live births in the US every year. Injuries evolve over days to weeks, with some neurons rapidly undergoing necrotic cell death while others suffer delayed impairment in energy metabolism and die more slowly. Animal studies involving rats have shown that average diffusivity is reduced on diffusion weighted imaging, lactate is increased on proton MRS, and ratio of phosphocreatine (PCr) to inorganic phosphate (Pi) is increased during hypoxic-ischemic insult. This preliminary study is designed to test the ability of using hyperpolarized 13C metabolic imaging to assess tissue metabolism after ischemic insult.

Franz Schilling^1,2, Stephan Düwel^1,2, Ulrich Köllisch^1,3, Markus Durst^1,3, Steffen J. Glaser², Axel Haase¹, Marion I. Menzel³, and Angela M. Otto^1
1Institute of Medical Engineering, Technische Universität München, Garching, Germany, ²Department of Chemistry, Technische Universität München, Garching, Germany, ³GE Global Research, Garching, Germany

Using a modified pulsed gradient spin echo sequence, we analyzed MCF-7 tumor cell spheroids under detrimental conditions by measuring ADCs of hyperpolarized ¹³C-metabolites. Such conditions were given by treating cells with Triton X-100 to gradually permeabilize the cell membrane to mimic a necrotic process. The ADC_lac/ADC_pyr ratio increased with time. Fluorescent staining showed that an increase of the ADC_lac/ADC_pyr ratio correlates to an increase in the fraction of dead cells. As a new technique, ¹³C-metabolite ADCs are indicators of necrosis in tumor cells potentially making them useful tools for monitoring the pathological state of tumors in-vivo.

Seungwook Yang¹, Joonsung Lee¹, Yoonho Nam¹, Eunhae Joe¹, Jae-Eun Suk², Ho-Taek Song², and Dong-Hyun Kim^1
1Electrical and Electronic Engineering, Yonsei University, Seoul, Korea, ²Department of Radiology, College of Medicine, Yonsei University, Seoul, Korea

A method for accurate quantification of hyperpolarized pyruvate and the product lactate in in vitro experiment is described. By using a narrow-band RF excitation pulse with alternating acquisition at every TR, metabolic product can be selectively excited with a higher flip angle for increased SNR while the hyperpolarized magnetization of the substrate can be minimally perturbed with a low flip angle. Also, baseline signals from neighboring resonances can be suppressed to accurately quantify the metabolism kinetics. Furthermore, with the modified version of the two-site exchange model that is also presented, calculation of the rate constants associated with the conversion is also possible.

Ulrich Köllisch¹, Rolf F. Schulte², Markus Durst¹, Jan Henrik Ardenkjaer-Larsen³, Francesca Frijia⁴, Luca Menichetti⁵, Massimo Lombardi⁴, Axel Haase¹, and Florian Wiesinger^2
1Institute of Medical Engineering, Technische Universität München, Garching, Germany, ²GE Global Research, Garching, Germany, ³GE Healthcare, Brøndby, Denmark, ⁴Fondazione CNR-Regione Toscana G.Monasterio, Pisa, Italy, ⁵Institute of Clinical Physiology of CNR, Pisa, Italy

Metabolic imaging with hyperpolarized [1-13C]pyruvate has high potential for examination of myocardial viability. In this work a 3D cardiac sequence for imaging the metabolism of hyperpolarized [1-13C]pyruvate over the whole porcine heart is presented. Therefore a multiband pulse was implemented using the polarization very efficiently. The results demonstrate, that the presented acquisition scheme is feasible for [1-13C]pyruvate metabolic imaging by accurately depicting pyruvate lactate and bicarbonate distributions over the entire left ventricle.

Oleksandr Khegai^1,2, Rolf F. Schulte², Martin A. Janich², Marion I. Menzel², Eliane Farrell³, Angela M. Otto⁴, Jan Henrik Ardenkjaer-Larsen^5,6, Steffen J. Glaser¹, Axel Haase⁴, Markus Schwaiger³, and Florian Wiesinger^2
1Department of Chemistry, Technische Universität München, Munich, Germany, ²GE Global Research, Munich, Germany, ³Institute of Nuclear Medicine, Technische Universität München, Munich, Germany, ⁴Institute of Medical Engineering, Technische Universität München, Munich, Germany, ⁵MST-ASL MR, GE Healthcare, Copenhagen, Denmark, ⁶Department of Electrical Engineering, Technical University of Denmark, Copenhagen, Denmark

Hyperpolarization of [1-13C]pyruvate in solution enables dynamic imaging of pyruvate metabolism using MRS methods. In this work, we present methods for the quantification of dynamic hyperpolarized 13C signals, with an emphasis on spatially resolved apparent rate constant mapping. This novel type of quantitative contrast comprehensively visualizes metabolic activity of underlying tissues and organs. In comparison to individual metabolite images, apparent rate constant maps emphasize metabolically active tissues and suppress regions of high perfusion but low conversion (e.g. blood vessels). Based on high metabolic activity of the tumor, its location can be clearly identified from the apparent rate constant maps.

Steven Reynolds¹, Tooba Alizadeh², Becky Bibby², Matthew Fisher², Adriana Bucur¹, Samira Kazan², Martyn Paley¹, and Gillian M. Tozer^2
1Academic Radiology, University of Sheffield, Sheffield, South Yorkshire, United Kingdom, ²Department of Oncology, University of Sheffield, Sheffield, South Yorkshire, United Kingdom

There has been recent interest in using hyperpolarised ¹³C₁-pyruvate for studying cancer metabolism. The methodology has been used to study the effect of dichloroacetate (DCA) on tumour metabolism which disrupts pyruvate dehydrogenase kinase (PDK). However, these studies have been acute treatments up to 24h. In this study we examine the effect of chronic oral DCA dosing on P22 bearing BDIX rats over 17 days. The data showed a strong negative linear correlation between conversion of pyruvate to lactate and tumour volume and that there was a significant difference in the slope of the correlation between control and DCA treated rats.

Heeseung Lim¹, Kundan Thind¹, Timothy Pok Chi Yeung^1,2, Francisco M. Martinez-Santiesteban¹, and Timothy J. Scholl^1,3
1Medical Biophysics, Western University, London, Ontario, Canada, ²London Regional Cancer Program, LHSC, London, Ontario, Canada, ³Imaging Research Laboratories, Robarts Research Institute, Western University, London, Ontario, Canada

This study monitors the effects of radio- and chemotherapy on glioblastoma multiforme in a rat model through chemical-shift imaging of hyperpolarized [1-¹³C]pyruvate. Preliminary results suggest that both radiotherapy and chemotherapy alter tumor metabolism (determined by the observed lactate-to-pyruvate ratio) as early as 2 days after treatment. Seven days after treatment, the lactate-to-pyruvate ratio in tumors was similar to healthy tissue. Response to therapy was more immediate for tumours receiving radiotherapy. Further animal studies will better quantify the time course of therapeutic response and to investigate the effects of combined therapies.

Markus Plaumann¹, Ute Bommerich², Thomas Trantzschel¹, Denise Lego², Sonja Dillenberger³, Joachim Bargon⁴, Gerd Buntkowsky³, and Johannes Bernarding^5
1Department of Biometry and Medical Informatics, Otto-von-Guericke-University Magdeburg, Magdeburg, Saxony-Anhalt, Germany, ²Special Lab Non-Invasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg, Saxony-Anhalt, Germany, ³Eduard-Zintl-Institute for Inorganic Chemistry, Technical University Darmstadt, Darmstadt, Hesse, Germany, ⁴Inst. of Physical and Theoretical Chemistry, University Bonn, Bonn, North Rhine-Westphalia, Germany, ⁵Department of Biometry and Medical Informatics, Otto von Guericke University, Magdeburg, Saxony-Anhalt, Germany

GABA is one of the most important inhibitory neurotransmitter in the central nervous system. Knowledge of changes in the GABA metabolism can help to understand different disease pattern. Therefore, the ParaHydrogen Induced Polarisation can be used to enhance signals for MR studies. In this contribution we described a new method to hydrogenate unsaturated organic amines in aqueous solution and present first spectra of hyperpolarized vigabatrin, allylglycine and GABA. All spectra were detected at 7 T. This new approach opens the way to hyperpolarize further biologically important molecules which were inaccessible to PHIP until now, like amino acids and peptides.

Albert P. Chen¹ and Charles H. Cunningham^2,3
1GE Healthcare, Toronto, ON, Canada, ²Imaging Research, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, ³Dept. of Medical Biophysics, University of Toronto, Toronto, ON, Canada

Preparation of hyperpolarized [1-13C]lactate in solution was demonstrated in this study using neat [1-13C]lactic acid as the DNP sample. Hyperpolarized [1-13C]lactate was also compared to [1-13C]pyruvate for in vivo investigation of cardiac PDH flux at the same dose in the same subjects. Hyperpolarized [1-13C]lactate may provide non-invasively assessment of cardiac PDH flux with minimal perturbation of the enzymes involved in this metabolic pathway.

Niki Zacharias¹, Maja Cassidy², Mark Lingwood³, Napapon Sailasuta⁴, Nicholas Whiting¹, Jingzhe Hu^5,6, Song-I Han³, Brian Ross⁴, Charles Marcus^2,7, and Pratip Bhattacharya^8
1Experimental Diagnostic Imaging, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, United States, ²Harvard University, Cambridge, MA, United States, ³Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA, United States, ⁴Enhanced MR Laboratory, Huntington Medical Research Institutes, Pasadena, CA, United States, ⁵Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States, ⁶Bioengineering Department, Rice University, Houston, TX, United States, ⁷University of Copenhagen, Copenhagen, Denmark, ⁸Experimental Diagnostic Imaging, University of Texas, Houston, TX, United States

Hyperpolarized magnetic resonance is a non-toxic, non-radioactive method for assessing tissue metabolism and other physiologic properties. Hyperpolarization allows for over 10,000-fold signal enhancement relative to conventional magnetic resonance imaging (MRI) or spectroscopy (MRS). My laboratory has worked on three different modalities of hyperpolarization, both on technique development as well as advancing novel in vivo applications. The research described here is focused on the different in vivo applications of Parahydrogen Induced Polarization (PHIP) (and subsequent transfer to 13C), continuous flow Dynamic Nuclear Polarization (DNP) of water (1H), and long lived DNP hyperpolarized signal of Silicon nanoparticles (29Si) as molecular imaging agents.

Erika Mariotti¹, Kilian Weiss², Sebastian Kozerke^1,2, and Thomas R. Eykyn^1,3
1Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom, ²Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland, ³CRUK and EPSRC Cancer Imaging Centre, Royal Marsden NHS Trust, The Institute of Cancer Research, Sutton, Surrey, United Kingdom

Using dynamic spatial-spectral imaging techniques,heterogeneity of myocardial metabolism can be studied and ischemic regions identified. Kinetic information on the underlying metabolic activities can be obtained by fitting the metabolite time series with kinetic models. In this work, we considered the detection limit of hyperpolarized 13C metabolic imaging in identifying local myocardial ischemia depending on ischemic transmurality, SNR and image resolution. A numerical signal model was implemented to simulate in vivo hyperpolarized 13C dynamic images with a range of SNRs and spatial resolutions and a kinetic model of the conversion of pyruvate to bicarbonate was used to extract enzymatic reaction rates

Sonal Josan^1,2, Ralph Hurd³, Yi-Fen Yen², Adolf Pfefferbaum^1,4, Daniel Spielman², and Dirk Mayer^1,2
1SRI International, Menlo Park, CA, United States, ²Radiology, Stanford University, Stanford, CA, United States, ³GE Healthcare, ⁴Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States

Spectroscopic imaging with hyperpolarized ¹³C substrates has been widely used to measure metabolic processes in real time in vivo. There has been growing interest recently in using hyperpolarized [2-¹³C]pyruvate, to follow the ¹³C label into metabolic products including glutamate (in exchange with α-ketoglutarate in the TCA cycle), citrate, acetyl-carnitine and acetoacetate as well as lactate and alanine. CSI with [2-¹³C]Pyr is challenging given the wide spectral dispersion of the resonances. This work uses a spectrally selective excitation to perform 3D CSI of spectral sub-bands containing metabolites of interest. Dynamic data is acquired from multiple sub-bands alternately in vivo in rat heart.

Shawn Wagner^1,2, Jose Agraz³, and Debiao Li^1,2
1Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States, ²Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States, ³Bioengineering, UCLA, Los Angeles, California, United States

Hyperpolarization by field cycling and RF transfer utilizing parahydrogen requires a fast addition of hydrogen to preserve the spin alignment of the parahydrogen. To effectively utilize PHIP to produce the highest hyperpolarization, characterization of the reaction kinetics is required. The purpose of this research is to demonstrate how to systematically characterize the reaction kinetics to calibrate and evaluate instrument performance using a common PHIP standard, 2-hydroxyethyl acrylate (HEA). We demonstrate for HEA, catalyst concentration has the greatest contribution to reaction rate.

Kelvin Billingsley¹, Sonal Josan^1,2, Jae Mo Park^1,3, Yi-Fen Yen¹, Ralph Hurd⁴, Dirk Mayer^1,2, Dwight G. Nishimura³, James Brooks⁵, and Daniel Spielman^1,3
1Department of Radiology, Stanford University, Stanford, CA, United States, ²Neuroscience Program, SRI International, Menlo Park, CA, United States,³Department of Electrical Engineering, Stanford University, Stanford, CA, United States, ⁴Applied Science Laboratory, GE Healthcare, Menlo Park, CA, United States, ⁵Department of Urology, Stanford University, Stanford, CA, United States

This work investigates a new biomarker, branched-chain amino transaminase (BCAT) activity, in prostate cancer. In addition, the feasibility of imaging the metabolism of hyperpolarized [1-13C]-KIC in human prostate cancer cell line-derived xenografts is explored.

Leo L. Tsai¹, Xiaoen Wang¹, Gopal Varma¹, David C. Alsop¹, and Aaron K. Grant^1
1Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, United States

Hyperpolarized ¹³C-tert-butanol is a freely diffusible agent which allows for high SNR cerebral perfusion imaging. At 9.4 Tesla, we demonstrate relatively long in-vivo cerebral relaxation times (T2 = 0.71 ± 0.03 s and T1 = 78 ± 26 s), demonstrating feasibility for high-field imaging and spectroscopy with this agent.

Kelvin Billingsley¹, Sonal Josan^1,2, Jae Mo Park^1,3, Sui Seng Tee¹, Yi-Fen Yen¹, Ralph Hurd⁴, Dirk Mayer^1,2, and Daniel Spielman^1,3
1Department of Radiology, Stanford University, Stanford, CA, United States, ²Neuroscience Program, SRI International, Menlo Park, CA, United States,³Department of Electrical Engineering, Stanford University, Stanford, CA, United States, ⁴Applied Science Laboratory, GE Healthcare, Menlo Park, CA, United States

This work explores the synthesis, development and application of [1,4-13C]-diethylsuccinate ([13C]-DES) via DNP polarization. These studies provide a reassignment of the metabolites observed in previous reports and a reexamination of the role of the TCA cycle in processing [13C]-labeled diethylsuccinate probes.

Jeremy W. Gordon¹, David J. Niles¹, Kevin M. Johnson¹, Matthew Smith¹, Krishna N. Kurpad¹, Eric Peterson¹, and Sean B. Fain^1,2
1Medical Physics, University of Wisconsin-Madison, Madison, WI, United States, ²Radiology, University of Wisconsin-Madison, Madison, WI, United States

Proton data can be used to aid in the reconstruction of hyperpolarized ¹³C metabolites, but motion between scans diminishes reconstruction fidelity. This works seeks to improve ¹³C reconstruction by utilizing simultaneously acquired ¹H data, which are inherently registered both spatially and temporally. A simultaneous acquisition scheme was implemented in spiral and Cartesian sequences to demonstrate the feasibility and utility of concurrently acquired ¹H data. Metabolite images show excellent registration with the underlying anatomy, while phase related artifacts were mitigated when ¹³C data was reconstructed with simultaneously acquired field maps, as compared to a field map acquired prior to simultaneous imaging.

Irene Marco-Rius^1,2, Michael C. D. Tayler³, Mikko I. Kettunen^1,2, Eva M. Serrao^1,2, Timothy J. Larkin^1,2, Tiago B. Rodrigues², Kerstin N. Timm^1,2, Giuseppe Pileio³, Malcolm H. Levitt³, and Kevin M. Brindle^1,2
1Biochemistry, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom, ²Cancer Research UK, Cambridge, Cambridgeshire, United Kingdom,³Chemistry, University of Southampton, Southampton, Hampshire, United Kingdom

Hyperpolarized NMR is a promising technique for non-invasive imaging of tissue metabolism in vivo. However, the range of reactions that can be investigated is limited by the fast T1-dependent decay of the nuclear spin order. In metabolites with coupled nuclear spin-1/2 pairs, polarization may be maintained for a longer time by exploiting the non-magnetic singlet (spin-0) state of the pair. We show here that the 13C singlet lifetime of [1,2-13C2]pyruvate is longer than T1 in human blood and in a mouse in vivo at low field, albeit shorter than its T1 in high magnetic field.

Jae Mo Park^1,2, Sonal Josan^1,3, Taichang Jang⁴, Milton Merchant⁴, Ronald D. Watkins¹, Yi-Fen Yen¹, Ralph Hurd⁵, Lawrence Recht⁴, Daniel Spielman^1,2, and Dirk Mayer^1,3
1Radiology, Stanford University, Stanford, California, United States, ²Electrical Engineering, Stanford University, Stanford, California, United States,³Neuroscience Program, SRI International, Menlo Park, California, United States, ⁴Neurology and Neurological Science, Stanford University, Stanford, California, United States, ⁵Applied Science Laboratory, GE Healthcare, Menlo Park, California, United States

We developed a fast volumetric chemical shift imaging sequence for imaging of hyperpolarized [2-13C]Pyruvate and its products, without suffering chemical shift displacement artifact due to the large spectral dispersion of [2-13C]Pyruvate and its products, and applied it to measuring brain metabolism in healthy and C6 glioma-bearing rats.

Erika Mariotti¹, Fiona Shaughnessy¹, Rodolfo A. Medina¹, Joel T. Dunn¹, Richard Southworth¹, and Thomas R. Eykyn^1,2
1Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom, ²CRUK and EPSRC Cancer Imaging Centre, Royal Marsden NHS Trust, The Institute of Cancer Research, Sutton, Surrey, United Kingdom

To obtain information on the underlying metabolic activities, hyperpolarized data are usually fit using kinetic models to derive rates. In this work, we show the feasibility of analysing hyperpolarized data without prior assumptions of a model and, at the same time, overcoming the “multiple local minimum” problem by applying a hybrid Maximum-Entropy/NonLinear-Least-Squares (MEM/NLS) method4 to hyperpolarized 13C data both in vitro in whole blood and ex vivo in the isolated rat heart.

Haifeng Zeng¹, Jiadi Xu², Joseph Gillen^1,2, Michael T. McMahon^1,2, Dmitri Artemov¹, Jean-Max Tyburn³, Joost Lohman⁴, Ryan Mewis⁵, Kevin Atkinson⁵, Simon Duckett⁵, and Peter C.M. van Zijl^1,2
1Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²F.M.Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, ³Bruker BioSpin GmbH, Silberstreifen, Rheinstetten, Germany, ⁴Bruker UK Limited, Banner Lane, Coventry, United Kingdom, ⁵Department of Chemistry, University of York, Heslington, York, United Kingdom

Here we investigated the possibility to use SABRE to polarize several drugs used daily in the clinic. These are isoniazid and pyrazinamide used for treating tuberculosis (TB) and temozolomide for treating brain tumors.

Marcin Krajewski¹, Michael Batel², Kilian Weiss¹, Andreas Bjoern Joakim Sigfridsson¹, Georgios Batsios¹, Matthias Ernst², and Sebastian Kozerke^1
1Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland, ²Laboratory of Physical Chemistry, ETH Zurich, Zurich, Switzerland

A new DNP polarizer device suitable for laboratory or small animal imaging applications is be presented. In order to facilitate construction and operation of such a system, a greatly simplified design is introduced here permitting polarization of up to four samples for rapid sequential dissolution with less than 10 min latency in-between. Basic design criteria and performance measurements are presented.

Gopal Varma¹, Xiaoen Wang¹, David C. Alsop¹, Rupal Bhatt², and Aaron K. Grant^1
1Radiology, Division of MR Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States, ²Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States

Balanced steady-state free precession (bSSFP) is a fast, signal efficient sequence for imaging of hyperpolarized 13C. By exploiting the dependence of the bSSFP signal on the chemical shift, or, equivalently, the phase advance between successive RF excitation pulses, it is possible to extract chemical shift selective images of multiple metabolites. The method is illustrated in phantoms and for imaging of pyruvate and its metabolites in a mouse model of renal cell carcinoma.

Marie A. Schroeder¹, Mohammad Ali¹, Alzbeta Hulikova¹, Claudiu T. Supuran², Kieran Clarke¹, Richard D. Vaughan-Jones¹, Damian J. Tyler¹, and Pawel Swietach^1
1Physiology, Anatomy and Genetics, University of Oxford, Oxford, Oxon, United Kingdom, ²University of Florence, Florence, Italy

CO2 is produced in vast quantities by cardiac mitochondria and efficient means of its venting are required to support metabolism. A range of metabolic and physiological adaptations for improving energy provision has been identified1, yet little is known about mechanisms for improving CO2 venting. Carbonic anhydrases (CAs), expressed at various sites in ventricular cardiomyocytes, may affect mitochondrial CO2 clearance by catalyzing CO2 hydration (to H+ and HCO3−) and changing trans-membrane [CO2]-gradients for diffusion. In this study, we demonstrated that mitochondrial CO2 venting is facilitated by concentrating CA activity near (but not within) mitochondria, and that this distribution improves myocardial energetics.

Jae Mo Park^1,2, Yi-Fen Yen¹, Priti Balchandani^1,3, Sonal Josan^1,4, Ralph Hurd⁵, Dirk Mayer^1,4, and Daniel Spielman^1,2
1Radiology, Stanford University, Stanford, California, United States, ²Electrical Engineering, Stanford University, Stanford, California, United States, ³Radiology, Mount Sinai School of Medicine, New York, New York, United States, ⁴Neuroscience Program, SRI International, Menlo Park, California, United States, ⁵Applied Science Laboratory, GE Healthcare, Menlo Park, California, United States

We exploit the long T2 of [1-13C]-labeled pyruvate and metabolic products by developing a spectrally interleaved multi-echo sequence using spectral-spatial RF pulses to increase SNR of the labeled metabolites.

Christoffer Laustsen^1,2, Sean Bowen³, Mads Sloth Vinding⁴, Niels Christian Nielsen⁴, and Jan Henrik Ardenkjaer-larsen^3,5
1The MR Research Centre, Aarhus University, Aarhus, Denmark, ²Danish Research Centre for Magnetic Resonance, Hvidovre Hospital, Hvidovre, Denmark,³Department of Electrical Engineering, Technical University of Denmark, Lyngby, Denmark, ⁴Center for Insoluble Protein Structures (inSPIN), Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhs, Denmark, ⁵GE healthcare, Broendby, Denmark

Hyperpolarized compounds has so far been limited by the T1 decay of the magnetization. Recently the novel method magnetization-to-singlet order (M2S) and singlet order-to-magnetization (S2M), has been shown applicable on pre-clinical MRI systems, extending the hyperpolarized life time several orders of magnitude. However, several limitations are imposed by clinical MRI systems with typical hardware constraints such as low maximum B1 amplitude and lower static magnetic field B0. The large B1 and B0 inhomogenties combined with T2 relaxation impose severe limitations on the efficiency of the method. Here we show a possible solution via optimal control theory, finding pulses with maximum efficiency even under clinical conditions.

Lloyd L. Lumata¹, Matthew E. Merritt¹, Craig R. Malloy¹, A. Dean Sherry^1,2, Johan van Tol³, Likai Song³, and Zoltan Kovacs^1
1Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States, ²Department of Chemistry, University of Texas at Dallas, Richardson, TX, United States, ³National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL, United States

We demonstrate the efficiency of stable free radicals BDPA, DPPH, and galvinoxyl as polarizing agents for dissolution dynamic nuclear polarization (DNP) NMR spectroscopy. Large NMR signal enhancements were achieved for biologically important labeled substrates such as [1-13C]pyruvic acid and [15N]choline. In addition, these hydrophobic free radicals can be easily filtered out in aqueous hyperpolarized liquids using a simple mechanical filtration process.

Titus Lanz¹, Markus Durst^2,3, Matthias Müller¹, Francesca Frijia⁴, Giulio Govanetti⁵, Luca Menichetti⁵, Massimo Lombardi⁴, Jan Henrik Ardenkjaer-Larsen^6,7, and Rolf F. Schulte^2
1Rapid Biomedical, Rimpar, Germany, ²GE Global Research, Munich, Germany, ³Technical University Munich, Munich, Germany, ⁴Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy, ⁵Institute of Clinical Physiology of CNR, Pisa, Italy, ⁶GE Healthcare, Copenhagen, Denmark, ⁷Danish Technical University, Copenhagen, Denmark

We show a setup for doing 13C imaging on hyperpolarised media in pigs on a clinical 3 T MR system. A 16 channel 13C Rx array is combined with a Tx birdcage, allowing the MR system's body coil for 1H imaging. Due to the low frequency the array is not sample noise dominated, but allows accelerated 13C imaging which is essential for efficient usage of the hyperpolarised magnetisation. First results of metabolic imaging on the pig heart are shown.

Marc S. Ramirez¹, Jaehyuk Lee¹, Vlad Sandulache², Christopher M. Walker¹, Yunyun Chen³, Stephen Y. Lai³, and James A. Bankson^1
1Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States, ²Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX, United States, ³Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States

The use of multislice projection acquisitions for hyperpolarized 13C MRI is evaluated, where dynamic time courses and spatial images from multiple metabolites may be simultaneously derived from one acquisition. This strategy reduces the high preparation costs and injected tracer volume associated with separate spatial and dynamic hyperpolarized acquisitions. Projection acquisition strategies based on echo-planar spectroscopic imaging (EPSI) and multiband frequency encoding (MBFE) MRI are compared and used to extract vascular input functions and conversion kinetics of hyperpolarized pyruvate and lactate in mice bearing anaplastic thyroid tumors.

Steven Reynolds¹, Adriana Bucur¹, Michael Port², Tooba Alizadeh³, Samira Kazan³, Gillian M. Tozer³, and Martyn Paley^1
1Academic Radiology, University of Sheffield, Sheffield, South Yorkshire, United Kingdom, ²Biological Services Unit, University of Sheffield, Sheffield, South Yorkshire, United Kingdom, ³Department of Oncology, University of Sheffield, Sheffield, South Yorkshire, United Kingdom

Modelling of hyperpolarized pyruvate to lactate conversion can be improved upon with consistent and reliable injections using an automated system. We have improved upon our previously designed injector by using a completely MR compatible direct drive peristaltic pump with a stepper motor and microcontroller. The new injector allows faster injections, no syringe filling, and arbitrary injection volumes. We show excellent correlation between demand and delivered volumes in the range 0.100-10.00ml and faster delivery of hyperpolarized pyruvate into a test phantom.

Shawn Wagner^1,2, Jose Agraz³, Alexander Grunfeld⁴, and Debiao Li^1,2
1Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States, ²Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States, ³Bioengineering, UCLA, Los Angeles, California, United States, ⁴Life Sciences, UCLA, Los Angeles, California, United States

Hyperpolarization by RF irradiation spin transfer utilizing parahydrogen requires low magnetic fields. These fields have been created with solenoids using current to determine the field strength. This abstract is intended to show how noise in the current results in magnet field noise, leading to sporadic loss of polarization in echo sequences. The loss in temporal refocusing is a crucial issue in the reliability of RF irradiation spin transfer PHIP hyperpolarization, since the last part of such sequences contains an echo period in the transverse plane.

Adriana Bucur¹, Steven Reynolds¹, Samira Kazan², Tooba Alizadeh², Michael Port³, Gillian M. Tozer², and Martyn Paley^1
1Academic Radiology, University of Sheffield, Sheffield, United Kingdom, ²Department of Oncology, University of Sheffield, Sheffield, United Kingdom, ³Biological Services Unit, University of Sheffield, Sheffield, United Kingdom

In vivo tumour models are the most relevant for comparison with human disease models. However, they are costly, time consuming and have ethical limitations. Additionally, hyperpolarisation experiments require long waits between injections. Using bioreactors provides useful information of cellular metabolism and response to treatment. We developed a multiple chamber MR compatible bioreactor to simultaneously acquire up to 4 datasets with identical hyperpolarised metabolite concentration and polarisation. The throughput increases by four times and consequently reduces the experimental time, by the efficient use of hyperpolarised PA in MR/DNP studies on cells, a possible important step in drugs effects investigation in animals.

Mehrdad Pourfathi¹, Nicholas N. Kuzma¹, Rajat Kumar Ghosh¹, Stephen J. Kadlececk¹, and Rahim Rizi^1
1Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States

Dynamic Nuclear Polarization (DNP) of ¹²⁹Xe lags far behind that of [1-¹³C]pyruvate under similar experimental conditions. Understanding the interplay between DNP, spin diffusion and nuclear relaxation at the microscopic scale requires theoretical modeling as well as experimental probes of the local DNP parameters. We use the recently reported measurements in micro-clustered ¹²⁹Xe/1-propanol/trityl solid mixtures to validate our first-principles theory of the observed spin-diffusion bottleneck at the cluster boundaries. In our self-contained model, the factor of ~ 30 apparent drop in the local ¹²⁹Xe polarization at the cluster boundary is obtained analytically across a thin “insulating” layer of the matrix immediately surrounding the cluster, in good agreement with the measurements. We estimate cluster size, intrinsic temperature, and T₁ relaxation rates by fitting the model to the data. These findings have enabled us to increase the achievable ¹²⁹Xe polarization from 5% to 21%.

Maxim Terekhov¹, Kathrin Gerz¹, Jan Krummenacker², Vasyl Denysenkov², Thomas Prisner², and Laura Maria Schreiber^1
1Department of Radiology, Section of Medical Physics, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany, ²Institute of Physical and Theoretical Chemistry, Center for Bimolecular Magnetic Resonance, Goethe-University Frankfurt-am-Main, Frankfurt-am-Main, Germany

Dynamic Nuclear Polarization is a technique to achieve the polarization of MRI agents over that at thermal equilibrium by microwave irradiation of electron spins. The liquid-state “Overhauser DNP” (ODNP) allows placing the polarizer core inside MRI magnet close to the imaging objects and delivery of hyperpolarized agent in continuous flow mode . The net efficiency of ODNP-polarizer is a complicated trade-off for which, to our knowledge, no theoretical model exists. We performed the study to establish a method of ODNP-magnetization build-up quantification in order to optimize the SNR of the MR-images obtained with hyperpolarization of 1H and 13C nuclei.

Peter J. Shin¹, Peder E.Z. Larson¹, Martin Uecker², Michael Lustig², and Daniel B. Vigneron^1
1Radiology and Biomedical Imaging, UCSF, San Francisco, California, United States, ²Electrical Engineering and Computer Science, UC Berkeley, Berkeley, California, United States

In hyperpolarized 13C experiments, data acquisition window is limited by the rapid metabolism and T1 relaxation of the hyperpolarized signal. This necessitates fast imaging schemes such as echo planar imaging (EPI). In this project, we developed a fast 3D EPI sequence for rapid 13C data acquisition and an accompanying multi-channel chemical separation method based on joint estimation of coil sensitivities and images of different molecules.