Molecular & Cellular Probes
Tuesday 21 April 2009
Room 316BC 10:30-12:30


Michael T. McMahon and Willem M. Mulder

10:30  222. The Development of an MR Agent for Imaging of Malignant Micro-Calcification in Breast Cancer
    Kumar R. Bhushan1, Elena Vinogradov2, Ananth J. Madhuranthakam3, Atshushi Takahashi4, John V. Frangioni1,2, Robert E. Lenkinski2
Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA; 3Applied Science Laboratory, GE Healthcare, Boston, MA, USA; 4Applied Science Laboratory, GE Healthcare, Menlo Park, CA, USA
    We have developed lanthanide-chelated bisphosphonate derivatives that are suitable MRI agents for imaging hydroxyapatite. An ultra-short echo time (UTE) sequence was used to image these agents in the environment of micro-calcification. We found that these compounds possess very high relaxivity in the adsorbed state. The combination of UTE and the newly developed MR agents demonstrate the successful high specificity and high sensitivity detection of calcified substances in vitro and in vivo. This study provides a foundation for the design and development of methods for high sensitivity MR detection of micro-calcifications within breast tumors.
10:42 223.

Fluorine-19 MR Molecular Imaging of Angiogenesis on Vx-2 Tumors in Rabbits Using α ν β 3-Targeted Nanoparticles

    Jochen Keupp1, Shelton D. Caruthers2,3, Jürgen Rahmer1, Todd A. Williams3, Samuel A. Wickline3, Gregory M. Lanza3
Philips Research Europe, Hamburg, Germany; 2Philips Healthcare, Andover, MA, USA; 3Washington University, St. Louis, MO, USA
    Anti-angiogenic therapy in combination with established chemotherapy or radiation therapy has entered clinical practice for lung, colon and breast cancer. However, effectiveness of anti-angiogenic pre-treatment is substantially varying among patients. Given the high cost and severe side effects, there is a strong clinical need for enhanced patient stratification, which could be based on MRI of angiogenesis using targeted imaging agents. ανβ3-integrin targeted nanoparticle (NP) emulsions, labeled with R1-enhancing Gd-chelates, were previously shown to allow three-dimensional MR mapping of tumor angiogenesis in small animals. These studies were based on δR1 mapping from two image sets taken before and after NP injection. The present study shows, that the perfluorocarbon (PFC) core of the same targeted NP can be used as a 19F MR label to map angiogenesis around Vx-2 tumors (adenocarcinoma) in rabbits. With simultaneous 19F and 1H MR, diagnostic imaging is only required at a single time point post-injection injection and may offer the ability of direct absolute quantification.
10:54 224. In Vivo Molecular MRI of Atherosclerotic Plaque Progression in Mice Using a Novel Elastin-Binding Contrast Agent
    Marcus R. Makowski1, Ulrike Blume1, Andrea J. Wiethoff1, Christian Jansen1, Joel Lazewatsky2, Simon Robinson2, Rene M. Botnar3
King’s College London BHF Centre of Research Excellence, Imaging Sciences Division, London, UK; 2Lantheus Medical Imaging, USA; 3King’s College London BHF Centre of Research Excellence, Imaging Sciences Division, UK
    The extracellular matrix (ECM) plays a pivotal role in the pathogenesis of atherosclerosis and ECM remodeling. Elastin is an essential component of the ECM of the arterial vessel wall. Male ApoE -/- mice have been shown to reproducibly develop progressive atherosclerotic plaques in the innominate artery over a short period on a high fat diet (HFD). With the advent of a novel elastin binding contrast agent (BMS -753951) imaging of ECM formation in atherosclerosis has become feasible. In this study, we demonstrate the successful non-invasive assessment of alterations in atherosclerotic plaque size in an ApoE mouse model using serial MRI together with a novel elastin specific contrast agent. Molecular alterations, with regard to elastin formation in atherosclerosis can be differentiated using BMS-753951.
11:06 225. MR Imaging of an Arachidonic Acid-Induced Mouse Model of Thrombosis Using an Activated Platelets-Targeted Paramagnetic Contrast Agent
    Ahmed Klink1,2, Eric Lancelot3, Sébastien Ballet3, Walter Gonzalez3, Christelle Medina3, Claire Corot3, Jean-Etienne Fabre4, Willem J.M Mulder1, Ziad Mallat2, Zahi A. Fayad1
Translational and Molecular Imaging Institute, Mount Sinai School Of Medicine, New York, NY, USA; 2INSERM U689, Paris, France; 3Research Division, Guerbet, France; 4Atherothrombosis Laboratory, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France
    P975 is a paramagnetic MRI based contrast agent with specificity for activated platelets via a peptide that binds to the glycoprotein GPIIb/IIIa. This agent was used in an arachidonic acid-induced mouse model of thrombosis to visualize thrombi formation and monitor thrombogenic activity.


11:18 226. in Vivo CEST Imaging Using Eu(III)-Water Molecule Exchange System
    Tomoyasu Mani1,2, Osamu Togao1, Todd C. Soesbe1, Masaya Takahashi1, Allan Dean Sherry1,2
Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; 2Department of Chemistry, University of Texas at Dallas, Richardson, TX, USA
    Chemical exchange saturation transfer (CEST) imaging has attracted considerable attention. Ln(III)-based exogenous CEST agents (PARACEST) can be used to enhance the sensitivity of CEST imaging. As part of a program to develop more effective agents, a newly designed Eu(III)-DOTA-tetraamide complex was applied in vivo. The CEST effect from this agent were somewhat smaller when the agent was dissolved in blood plasma at body temperatures (35-39 C) compared to when it was dissolved in pure water. No differences in CEST were observed at lower temperatures (20-27 C). CEST contrast in liver and kidney of mouse (20%) were successfully observed using low presaturation pulse (7µT) to avoid competitive inherent MT effects.


11:30 227. Magnetization Transfer Detection of GFP: A New MRI Gene Reporter
    Carlos J. Perez-Torres1, Cynthia A. Massaad2, Faridis Serrano2, Robia G. Pautler1,2
Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX, USA; 2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA
    To visualize gene expression via any imaging modality, a reporter system needs to be instituted that causes sufficient contrast between the tissues where the gene is expressed compared to other tissues where the gene is not expressed. Green Fluorescent Protein (GFP) is a widely used molecular and gene expression marker. We report a technique to detect GFP by using Magnetic Resonance Imaging (MRI) through Magnetization Transfer Contrast (MTC). GFP was detected with MTC MRI both in vitro and in vivo. This system provides a flexible, non-invasive in vivo molecular imaging system that has the advantage of combining readily available materials.
11:42 228. Chimeric Ferritin as a Reporter for MRI

Bistra Iordanova1, Clinton S. Robison1, Eric T. Ahrens1,2
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA; 2Pittsburgh NMR Center for Biomedical Research, Carnegie Mellon Univeristy, Pittsburgh, PA, USA

    Several recent molecular MRI techniques utilize the iron storage protein ferritin as a probeless reporter. One of the practical limitations of ferritin as a reporter for MRI is that it is a relatively weak contrast agent, especially at lower magnetic field strengths. To enhance MRI sensitivity, we fixed its heavy and light subunit stoichiometry by engineering a fusion single-chain ferritin. In this study we show that the new ferritin chimera loads significantly more iron and exhibits higher transverse relaxation rates than wild type ferritin both in human cells and in mouse brain.
11:54 229. In Vivo MR and PET Imaging of a Highly Sensitive Polymeric PARACEST Contrast Agent
    Todd C. Soesbe1, Yunkou Wu2, Guiyang Hao3, Xiankai Sun1, A. Dean Sherry1,2
Advanced Imaging Research Center, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; 2Department of Chemistry, The University of Texas at Dallas, Dallas, TX, USA; 3Department of Radiology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
    Chemical exchange saturation transfer (CEST) agents create contrast in MR images by exchanging their saturated lanthanide bound protons with those of bulk water. These agents have great potential to further extend the functional and molecular imaging capabilities of MR. Polymeric paramagnetic CEST (PARACEST) agents have recently been prepared by our group. The polymeric agents increase the CEST effect by creating a higher concentration of lanthanide ions at the target site. These agents offer an order on magnitude improvement in sensitivity which greatly reduces in vivo dose levels. The improved sensitivity of the polymeric agents also helps overcome the magnetization transfer (MT) effect due to endogenous macromolecules in tissue, which can mask the CEST effect. We present the first in vivo images of a polymeric Eu3+ PARACEST agent using a simple fast spin echo pulse sequence. We also show that this agent could be used for simultaneous PET/MR imaging by labeling the polymer with Cu-64.


12:06 230. Rational Design of a High Relaxivity MR Probe
    Luca Frullano1, Peter Caravan1
Radiology, Massachusetts General Hospital, Charlestown, MA, USA
    The synthesis and characterization of a new Gd-based contrast agent is described. A dual strategy of increasing inner-sphere and second-sphere hydration was used to design an agent with more than 150% higher relaxivity than other low molecular weight contrast agents. Relaxivity is unaffected by the presence of coordinating anions such as phosphate or citrate and the high relaxivity is maintained over a broad field range (0.5 – 9.4T). This complex also contains a pendant carboxylate for linkage of this contrast agent to a putative targeting moiety such as a peptide.
12:18 231.

Well-Defined, Multifunctional Nanostructures of a Paramagnetic Lipid and a Lipopeptide for Macrophage Imaging

    Honorius M.H.F. Sanders1,2, Esad Vucic3, Nico A.J.M. Sommerdijk2, Enzo Terreno4, Francesca Arena4, Silvio Aime4, Klaas Nicolay1, Margaritta Dathe5, Zahi A. Fayad3, Willem J.M. Mulder3
Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Brabant, Netherlands; 2Soft Matter Cryo-TEM Research Unit, Eindhoven University of Technology, Eindhoven, Brabant, Netherlands; 3Translational and Molecular Imaging Institute and Imaging Science Laboratories, Mount Sinai School of Medicine, New York, USA; 4Department of Chemistry IFM and Molecular Imaging Center, University of Torino, Torino, Italy; 5Leibniz Institute of Molecular Pharmacology, Berlin, Germany

In the field of targeted molecular imaging and therapy the pharmacokinetic profile as well as the tissue penetration potential of nanoparticulate formulations is of paramount importance. Hence, there is a great demand for nanostructures of which the final morphology and size can be judiciously controlled.

By controlling the ratio of two amphiphilic molecules, the paramagnetic lipid Gd-DTPA-DSA and P2fA2, a fluorscein labeled apolipoprotein E derived lipopeptide, we created a variety of well-defined multifunctional and nano-sized structures. NMRD-profiling disclosed excellent and tunable MRI properties, while in vitro experiments with macrophage cells demonstrated efficient uptake.