Cell Tracing

                  1866.     Novel Perfluorooctylbromide Alginate Microcapsules for Enhanced Mesenchymal Stem Cells Survival and Noninvasive Imaging Using Clinical CT and ¹⁹F MRI

Yingli Fu¹, Dorota A. Kedziorek¹, Steven Shea², Yibin Xie¹, Ronald Ouwerkerk³, Gary Huang¹, Tina Ehtiati², Steffi Valdeig¹, Jeff WM Bulte^1,4, Frank Wacker¹, Dara Kraitchman¹

¹Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States; ²Imaging and Visualization, Siemens Corporate Research, Baltimore, MD, United States; ³National Institute of Diabetes and Digestiv and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States; ⁴Institute of Cell Engineering, Baltimore, MD, United States

To enable allogeneic mesenchymal stem cell therapy for peripheral arterial disease, we present here a novel perfluorootylbromide microcapsues that enhance cell survival and enable cell tracking using noninvasive clinical imaging modalities.

                  1867.     Assessment of Macrophage Depletion on Acute Cardiac Allograft Rejection by MRI

Danielle F. Eytan¹, T Kevin Hitchens¹, Qing Ye¹, Yijen L. Wu¹, Chien Ho¹

¹Pittsburgh NMR Center for Biomedical Research, Carnegie Mellon University, Pittsburgh, PA, United States

Abundant macrophage infiltration is observed in cardiac allograft rejection, yet their contribution to the rejection process and the tissue damage that results remains unclear. Here we investigated the role these cells play in our rat model of acute cardiac rejection by selectively depleting circulating macrophages using liposomal-clodronate. We used T2*-weighted imaging to detect immune-cell infiltration at sites of rejection by monitoring the accumulation of iron oxide-labeled cells, and cardiac cine-tagging to detect regional myocardial function loss. Our results indicate that macrophages contribute to tissue damage during acute rejection, and that their depletion may attenuate the damaging effects of rejection in rat cardiac allografts.

                  1868.     In-Vivo Tracking of Single Phagocytic Cells in a Mouse Brain After Traumatic Brain Injury Using Micron-Sized Iron-Oxide Particles

T. Kevin Hitchens^1,2, Parker H. Mills^1,2, Lesley M. Foley¹, John A. Melick³, Patrick M. Kochanek^3,4, Eric T. Ahrens^1,2, Chien Ho^1,2

¹Pittsburgh NMR Center for Biomedical Research, Carnegie Mellon University, Pittsburgh, PA, United States; ²Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States; ³Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States; ⁴Department of Critical Care Medicine and Anesthesiology, University of Pittsburgh, Pittsburgh, PA, United States

Cellular imaging is an important and growing field in magnetic resonance. The ability to non-invasively detect the trafficking and accumulation of cells in vivo has broad implications for both a better understanding of biological processes and the development of novel treatments for numerous conditions. Here explore using post processing techniques called Phase map cross-correlation Detection and Quantification or PDQ for detection and quantification of single MPIO-labeled cells in vivo. PDQ uses phase information to calculate a magnetic dipole moment for each detected cell.  This information can be used to correlate labeled cell between serial scans and imaging methods.

                  1869.     MR Imaging of Tumor Initiating Melanoma Cells

Sergey Magnitsky¹, Alexander Roesch², Stephen Pickup¹, Meenhard Herlyn², Jerry D. Glickson¹

¹Radiology, University of Pennsylvanian, Philadelphia, PA, United States; ²Wistar Institute, Philadelphia, PA, United States

Melanoma cells were labeled with iron oxide particles and allowed to proliferate. Small iron-retaining sub-cell population with “original” iron concentration has been detected after 21 days of proliferation. This sub-cell population exhibits high tumorigenicity, self-renewal capacity and drug resistance, and therefore fulfills a “definition” of tumor initiating cells. After implantation of labeled cells into NOD/SCID mice, iron-retaining cells have been detected by in vivo, ex vivo MRI and Prussian blue staining.

                  1870.     MR Cell Tracking in Reperfused Myocardial Infarction with Microvascular Obstruction and Haemorrhage: Fluorine-19 MR Could Be a Better Solution

Yuxiang Ye¹, Thomas C. Basse-Luesekrink¹, Paula Arias², Kai Hu², Thomas Kampf¹, Vladimir Kocoski³, Xavier Helluy¹, Peter M. Jakob^1,4, Karl-Heinz Hiller^1,4, Roland Jahns², Wolfgang R. Bauer²

¹Department for Experimental Physics 5, University of Wuerzburg, Wuerzburg, Bavaria, Germany; ²Deptment of Internal Medicine I, University Hospital Wuerzburg; ³Institute for Virology & Immunobiology, University of Wuerzburg, Germany; ⁴MRB Research Center, Magnetic-Resonance-Bavaria, Wuerzburg, Germany

MR Cell tracking with iron oxide labeling has high sensitivity but could be severely interfered by strong local magnetic susceptibility effects. We show that Fluorine-19 MRI could unambiguously detect blood monocytes/macrophages labeled with perfluorocarbon emulsion infiltrating the haemorrhagic myocardial infarct (MI) core both in vivo and ex vivo in a rat model at 7-T, despite the presence of strong local magnetic susceptibility effects caused by degraded hemoglobin products in microvascular obstruction or haemorrhage, which often occurs after reperfusion therapy . This finding suggests that Fluorine-19 MRI could be a better approach for MR cell tracking in where local T2* effects interfere the detection of magnetically labeled cells.

                  1871.     Migration of MPIO-Labeled Glioma Cells in the Rat Brain: Validation with Histology and Fluorescence Microscopy

Divya Raman¹, Anitha Priya Krishnan², Scott Kennedy³, John Olschowka⁴, Sammy N'dive², Delphine Davis⁵, Walter G. O'Dell²

¹Biomedical Engineering, University of Rochester, Rochester, NY, United States; ²Radiation Oncology, University of Rochester, Rochester, NY, United States; ³Biophysics, University of Rochester, Rochester, NY, United States; ⁴Neurobiology and Anatomy, University of Rochester, Rochester, NY, United States; ⁵Imaging Sciences, University of Rochester, Rochester, NY, United States

Our hypothesis is that paths of elevated diffusion provide a preferred route for migration of cancer cells away from primary tumor. This can be used to improve radiation treatment of gliomas. Toward this end, we have developed a computational model of cell migration based upon MR-DTI to predict microscopic spread of cancer in patients. Objective of this work is to track MPIO labeled rat glioma cells in rat brain and compare it to rat DTI model and thereby demonstrate that tumor cells migrate farther from the site of engraftment along major fiber tracts compared to gray matter.

                  1872.     SPIO-Labeled Natural Killer Cells: Cytotoxicity and in Vivo Imaging

Christiane L. Mallett^1,2, Catherine Ramsay¹, Paula J. Foster^1,2

¹Imaging Research Laboratories, Robarts Research Institute, London, Ontario, Canada; ²Medical Biophysics, The University of Western Ontario, London, Ontario, Canada

Purpose: We labeled natural killer cells and tested cytotoxicity against prostate cancer cells in vitro. In vivo MR tracking was performed. Methods: KHYG-1 cells were labeled with MoldayION by incubation. Toxicity against PC-3M prostate cancer cells was measured after 24 hours co-culture. Labeled KHYG-1 were injected into the flank of mice and tracked with MRI over 9 days. Results: Labeling efficiency (80%) and viability (>90%) were high.  Labeled KHYG-1 were toxic to PC-3M. Injected cells were tracked toward the popliteal lymph node in mice. Conclusions: KHYG-1 will be valuable in future in vivo investigations of immuno-therapy of prostate cancer.

                  1873.     Multimodality Imaging of Gene Delivery Via Fluoresecent Iron Oxide Nanoparticles

David Peter Cormode¹, Gitte Oskov Knudsen¹, Amanda Delshad¹, Nicole Parker², Peter Jarzyna¹, Torjus Skajaa³, Karen C. Briley-Saebo¹, Ronald E. Gordon⁴, Zahi Adel Fayad¹, Savio L C Woo², Willem J M Mulder¹

¹Radiology, Mount Sinai School of Medicine, New York, NY, United States; ²Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, United States; ³Clinical Institute and Dept. of Cardiology, Aarhus University, Skejby, Denmark; ⁴Pathology, Mount Sinai School of Medicine, New York, NY, United States

We have developed a fluorescent iron oxide nanoparticle platform with a gene transfection-enabling polymeric coating. This platform allows gene transfer to be studied via MRI, fluorescence and TEM imaging techniques. We have studied this platform in the setting of liver disease and the effect of varying the polymeric coating by increasing the PEG content from 0-25%. We found that the MRI and fluorescence contrast in the liver was unaffected by the particle coating, however, the cellular distribution was skewed from the Kupffer cells to the therapeutically relevant hepatocytes when the percentage of PEG was increased.

                  1874.     Improved Detection of Iron-Loaded Cells by Combining Balanced Steady-State Free Precession (BSSFP) Imaging with Susceptibility Weighted Imaging (SWI) Processing.

Francisco Manuel Martinez-Santiesteban¹, Emeline J. Ribot¹, Paula J. Foster¹, Brian K. Rutt²

¹Robarts Research Institute, University of Western Ontario, London, Ontario, Canada; ²Department of Radiology, Stanford University, Palo Alto, CA, United States

We present a method that combines the high efficiency of a bSSFP pulse sequence with the image enhancement of susceptibility changes obtained with Susceptibility Weighted Imaging to improve the detection of iron-loaded cells. Benefits of both techniques are achieved with a bSSFP Echo Time larger than the conventional TR/2, increasing the information contained on the phase images. Using the proposed technique, we are able to detect more iron-loaded cells than with bSSFP alone, and the mean fractional signal loss of the detected cells is increased by approximately 20%, improving their visibility and quantification.

                  1875.     On Possible Pitfalls in Working on SPIO Labelled Cells with 2D UTE Sequences

Clemens Diwoky¹, Andreas Reinisch², Florian Knoll¹, Bernhard Neumayer¹, Dirk Strunk², Rudolf Stollberger¹

¹Institute of Medical Engineering, Graz University of Technology, Graz, Austria; ²Stem Cell Research Unit, Dept. of Hematology, Univ. Clinic of Internal Medicine, Medical University of Graz, Graz, Austria

Within this study we outline some crucial points concerning the use of 2D UTE sequences for the cell detection based on differential images. We show that especially in regions of high iron density many artefacts caused by the pulse sequence yields to misinterpretations or wrong quantitative results. On the basis of an ectopic labelled cell population we discuss the artefacts caused by a common 2D UTE acquisition strategy with half-pulse excitation.

                  1876.     The Changes of the Metabolite Profile as Human Mesenchymal Stem Cells Differentiate to Adipocytes Mesured by in Vitro 9.4T MR Spcetroscopy

Zhi-Feng Xu¹, Chong-Yang Shen², Lin-Ping Wu², Ye-Yu Xiao, Yao-Wen Chen, Ren-Hua Wu

¹medical imging, the 2nd Affiliated Hospital, the Medical College of Shantou University, shantou, guangdong, China; ²Multidisciplinary Research Center of Shantou University, shantou, guangdong, China

In this study, we attempt to study the alteration of metabolite of MSCs undergoing adipogenic differentiation to targeted fat cells in vitro, using 9.4T high-resolution 1H NMR spectroscopy.lastly, in our study,several major metabolites can be observed in the MR sepectroscopy that is before and after differentiation of MSCs£¬including choline, creatine, glutamate and myo-inositol, acetate and some fatty acids,etc.Quantification of metabolite concentrations was performed£¬the levels of intracellular metabolites, such as choline, creatine, glumate and acetate all decreased, with the increased level of methionine , succinate and fatty acids after the MSCs differentiation 2 weeks.It indiactes that we can mintor differentiation of MSCs,according the changes of metabolites.

                  1877.     Customizable PLGA-Encapsulated Perfluorocarbon Particles for in Vivo 19F MRI

Mangala Srinivas¹, Fernando Bonetto¹, Luis Javier Cruz¹, Arend Heerschap², Carl Figdor¹, I. J.M. de Vries¹

¹Tumor Immunology, NCMLS, Uni. Radboud, Nijmegen, Gelderland, Netherlands; ²Radiology, Nijmegen Centre for Molecular Life Sciences

We present a novel agent for in vivo ¹⁹F MRI that is customizable in several parameters including diameter, lifetime, fluorocarbon content, particle charge and coating. The particles can also be covalently bound to targeting agents, dyes, drugs or other moieties, and are stable for long-term storage. We test the particles for labeling primary human dendritic cells for use in cell-based vaccine therapy. The particles can be adapted for use in various experimental systems, as well as clinical use.

                  1878.     Lipid-Coated Iron Oxide: A Versatile, Biocompatible and Multimodal Material for Cellular Imaging

Geralda A.F. van Tilborg¹, Willem J.M. Mulder², Susanne M.A. van der Pol³, Louis van Bloois⁴, Annette van der Toorn¹, Gert Storm⁴, Helga E. de Vries³, Rick M. Dijkhuizen¹

¹Image Sciences Institute, University Medical Center Utrecht, Utrecht, Netherlands; ²Translational and Molecular Imaging Institute, , Mount Sinai School of Medicine, New York, United States; ³Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands; ⁴Department of Pharmaceutics, Institute for Pharmaceutical Sciences, Utrecht, Netherlands

In this study we propose a novel lipid-coated fluorescent iron oxide particle for simultaneous magnetic and fluorescent cell labeling. Murine macrophages (RAW) were incubated with the contrast agent and showed efficient labeling without inducing toxicity. Labeled cells were clearly detected with T2-weighted MRI, fluorescence microscopy and flow cytometry. The presented nanoparticulate agent represents a versatile and potent contrast material for cellular imaging, and can be particularly attractive for assessing the fate of in vivo administered labeled cells with multimodal imaging techniques.

                  1879.     Towards in Vivo Visualization of Pancreatic Beta-Cells in the Mouse: Molecular Imaging at 16.4 T

Sven Gottschalk¹, Dávid Zsolt Balla¹, Rolf Pohmann¹, Jörn Engelmann¹

¹High-Field Magnetic Resonance Center, Max Planck Institute for Biological Cybernetics, Tuebingen, Germany

Despite of decade-long research, no method exists that could either accurately or non-invasively determine the pancreatic beta-cell mass in vivo. We present in vivo MRI of the mouse pancreas at ultra high fields (16.4T) and the first attempt to visualize pancreatic islets with a newly developed beta-cell specific contrast agent. Structures <100µm and anatomical details of the pancreas were identified. However, the cellular architecture of the pancreas, i.e. the location or amount of islets of Langerhans remains difficult to assess. Using a novel targeted contrast agent in vivo, beta-cell containing islets of Langerhans were identified in an excised pancreas.

                  1880.     Magnetic Resonance Molecular Imaging of Neural Sprouts in Spine Explant Cultures

Ingrid E. Chesnick¹, Carol B. Fowler¹, Yeon Ho Kim², Helen E. D’Arceuil³, Jeffrey T. Mason¹, Kimberlee Potter¹

¹Department of Biophysics, Armed Forces Institute of Pathology Annex, Rockville, MD, United States; ²Defense and Veterans Brain Injury Center, Armed Forces Institute of Pathology Annex, Rockville, MD, United States; ³MRVision Co., Redwood City, CA, United States

Organotypic slice cultures of spinal cord allow for the study of axonal growth and regeneration, synapse formation, and myelination. Consequently, to better understand the dynamics of spinal cord repair in vivo, this model system was employed as a novel test platform to examine the specificity of actin-targeted Gd-liposomes to actin-rich neural sprouts.  Actin-targeted Gd-liposomes were tested on a monolayer of cells and all labeling experiments were confirmed by MRM and fluorescence microscopy. Similar labeling protocols applied to spine explants revealed MR signal enhancement around the neural tube and neural sprouts at the edge of the explants.

                  1881.     Magnetic Resonance Molecular Imaging of Bone Resorbing Osteoclasts

Ingrid E. Chesnick¹, Carol B. Fowler¹, Jeffrey T. Mason¹, Kimberlee Potter¹

¹Department of Biophysics, Armed Forces Institute of Pathology Annex, Rockville, MD, United States

The ability to detect osteoclasts on the surface of bone will allow for the development of more sensitive screening tools for monitoring changes in bone metabolism, specifically bone resorption, in response to therapeutic interventions. In this work, we demonstrate the sensitivity of ƒÑvƒÒ3-targeted Gd-liposomes to detect low numbers of  active osteoclasts in the presence of a mixed population of bone marrow derived cells. Additionally, we present a novel bisphosphonate MR constrast agent for selectively imaging the mineral not subjected to resoption by active osteoclasts. Our approach promises to transform in vivo bone resorption studies.

MR Sensors & Reposers

                  1882.     SPIO-Alginate Nanoparticles: New Platform for Calcium MR Imaging

Amnon Bar-Shir¹, Liat Avram¹, Smadar Cohen², Yoram Cohen¹

¹School of Chemistry, Tel Aviv University, Tel Aviv, Israel; ²Biotechnology Engineering, Ben-Gurion University of the Negev, Beer Sheva, Israel

Ca2+ plays an important role in many biological processes. Currently, the imaging technologies that are used for Ca2+ imaging are mostly based on optical methodologies. Based on the facts that alginates polysaccharides can be cross-linked, selectively, with Ca2+ ions and that SPIO aggregation may change the contrast of T2WI, we suggest the SPIO-alginate nanoparticles as "smart" MRI probes for Ca2+ detection. In this study we describe the synthetic procedure of the water-soluble SPIO-alginate nanoparticles and the MRI detectability of different Ca2+ concentrations in variable aqueous solutions (water, serum and culture cell media) at physiological conditions using this nanoparticles-based probe.

                  1883.     New Bullets for PISTOL: Linear and Cyclic Reporter Molecules for ¹H MR Oximetry

Praveen Kumar Gulaka¹, Vikram D. Kodibagkar^1,2

¹Biomedical Engineering, UT Arlington and UT Southwestern Medical Center at Dallas, Dallas, Tx, United States; ²Radiology, UT Southwestern Medical Center at Dallas, Dallas, Tx, United States

The ability to measure tissue oxygen tension non-invasively may have a significant impact in understanding mechanisms of tissue function and in clinical prognosis of disease. Previous research demonstrated hexamethyldisiloxane (HMDSO) as a 1H based pO2 reporter molecule by in vivo spectroscopy and imaging using  Proton Imaging of Siloxanes to map Tissue Oxygenation Levels (PISTOL) technique.  We now present in vitro data demonstrating the pO2 calibration curves of linear and cyclic siloxanes of different chain lengths as pO2 sensing reporter molecules for use in conjunction with PISTOL.

                  1884.     Hyperpolarized ¹³C MR Reporter Probe System with Acy-I Gene and [1-¹³C] N-Acetyl-L-Methionine

Albert P. Chen¹, Ralph E. Hurd², Yi-Ping Gu³, David M. Wilson⁴, Charles H. Cunningham³

¹GE Healthcare, Toronto, ON, Canada; ²GE Healthcare, Menlo Park, CA, United States; ³Imaging Research, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; ⁴Radiology, UCSF, San Francisco, CA, United States

With the recent development of techniques to achieve highly polarized nuclear spins states via dynamic nuclear polarization and retain the polarization in solution, it may be feasible to utilize a suitable hyperpolarized ¹³C substrate to target an enzyme reporter gene for non-invasive MR imaging of labeled cells/tissue.  In this study, a hyperpolarized ¹³C MR reporter system is demonstrated in cells transfected to overexpress a reporter gene, aminoacylase I (Acy-I), using pre-polarized [1-¹³C] N-acetyl-L-methionine as the reporter probe.

                  1885.     In Vivo Detection of CFos-GFP for Neural Activation Via Magnetization Transfer Contrast (MTC) Magnetic Resonance Imaging (MRI)

Carlos J. Perez-Torres^1,2, Robia G. Pautler^1,2

¹Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, United States; ²Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, United States

cFos is a widely utilized marker of neuronal activation that currently requires ex vivo immunohistochemistry for detection. We believe detecting cFos expression in vivo with MRI would provide an unparalleled means to assess neuronal activation in mouse models of human diseases.  Importantly, the levels of activation would be a direct measurement of neuronal function. . We have previously described a novel approach to detect Green Fluorescent Protein (GFP) expression in vivo using Magnetization Transfer MRI.  Here, we apply the MRI based detection of GFP to evaluate a cFos-GFP fusion model.

                  1886.     Dual  ¹H and ¹⁹F MR LacZ Gene Reporter Molecule

Rami Robert Hallac¹, Vikram D. Kodibagkar¹, Jian-Xin Yu¹, Ralph P. Mason¹

¹Radiology, UT Southwestern Medical Center at Dallas, Dallas, TX, United States

The detection of enzyme activity and gene expression in vivo is potentially important for the characterization of diseases and gene therapy. We demonstrate the use of a novel class of dual 1H/19F NMR lacZ gene reporter molecule to identify £]-gal expressing tumors in mice. The substrate shows a single 19F NMR signal and exposure to ƒÒ-galactosidase induces a large 19F NMR chemical shift response. The combination of Fe3+ and released aglycone product generates intense T2 contrast only in £]-gal expressing tumor. The dual modality approach allows both the detection of substrate and imaging of product.

                  1887.     Quantification of 3D T2*-Weighted MR Images Allows Evaluation of Different Viral Vectors for Stable MR Reporter Gene Expression in the Rodent Brain

Greetje Vande Velde¹, Janaki Raman Rangarajan², Tom Dresselaers¹, Jaan Toelen³, Zeger Debyser³, Veerle Baekelandt³, Uwe Himmelreich¹

¹Biomedical NMR unit/MoSAIC, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium; ²Medical Imaging Research Center/MoSAIC, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium; ³Molecular Medicine, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium

Utilizing lentiviral (LV) and adeno-associated (AAV) viral vector systems for delivering MRI reporter genes (e.g. ferritin) will allow stable labeling and in vivo visualization of marked cells, but their potential limitations for MRI are often insufficiently addressed. LV injection resulted in hypointense contrast at the injection site on T2*-weighted MRI, partially explained by an immune response. Contrasting with LV, AAV injection resulted in little background contrast and AAV-mediated MRI reporter overexpression resulted in significant contrast-to-background on T2*-weighted MRI. We developed an image analysis pipeline that permits to quantitatively compare the hypointense contrast parameters of timeline scans or different experimental groups.

                  1888.     Non-Invasive DNA Probe Delivery Enables MR Detection of Gene Up-Regulation Associated with Psychostimulant Sensitization

Christina H. Liu¹, Jia Q. Ren¹, Charng-ming Liu¹, Philip K. Liu¹

¹Radiology, Massachusetts General Hospital, Charlestown, MA, United States

Synopsis Intracerebroventricular infusion of therapeutics or MR contrast agents by lumbar or cortical puncture to the brains was the route of choice to bypass the blood brain barrier (BBB) and to achieve uniform distribution.  However, only limited number of delivery can be performed in the same subject, therefore, has limited longitudinal applicability.  Here we explore the feasibility of a non-invasive DNA-based MRI probe delivery route by intraperitoneal injection with BBB bypass to assess gene up-regulation associated with chronic drug exposure.

                  1889.     Remote MR Sensing of PH and Cell Viability Using LipoCEST-Filled Microcapsules

Kannie W. Y. Chan^1,2, G. Liu^1,3, D.R. Arifin^1,2, J. W.M. Bulte^1,2, M.T. McMahon^1,3

¹Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States; ²Cellular Imaging Section, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States; ³F.M. Kirby Center for Functional Brain Imaging, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Cell transplantation is widely used for treatment of various diseases, with cell viability being key for successful therapy. Semi-permeable microcapsules have been used to immunoprotect and visualize cell location, but not cell function. We demonstrate that LipoCEST-filled microcapsules can be used as a novel way to monitor cell viability. CEST contrast is dependent on pH, which in itself is closely related to cell activity and functionality. Our pH-responsive microcapsules showed a significant decrease in CEST signal when cell viability decreased at physiologically relevant pH’s, thus representing a useful non-invasive tool to monitor successful cell therapy.

                  1890.     Thiol Complexes of Gadolinium for Imaging Therapy-Induced Oxidative Stress in Pre-Clinical Tumors

Bhumasamudram Jagadish¹, Gerald P. Guntle², Vijay Gokhale³, Amanda F. Baker², Eugene A. Mash¹, Natarajan Raghunand⁴

¹Chemistry, The University of Arizona, Tucson, AZ, United States; ²Cancer Center, The University of Arizona, Tucson, AZ, United States; ³Pharmacology & Toxicology, The University of Arizona, Tucson, AZ, United States; ⁴Radiology, The University of Arizona, Tucson, AZ, United States

DO3A- and DOTA-based thiol complexes of gadolinium have been synthesized and characterized. The molecules are designed to covalently bind the conserved cysteine-34 site in circulating plasma albumin. Redox-sensitivity is conferred by differential relaxivities of the albumin-bound (in oxidizing microenvironments) and unbound (in reducing microenvironments) forms of the complexes. Oxidative stress was induced in tumor-bearing mice by 2-deoxyglucose challenge. The change in tumor T1 following administration of a candidate thiol complex of Gd was significantly lower in treated mice relative to control mice. This is consistent with a 2DG-induced ARE-driven reduction of the tumor microenvironment, and supporting evidence will be presented.

                  1891.     in Vitro and  in Vivo Evaluation of GdDO3NI as a Hypoxia Targeting MRI T₁ Contrast Agent

Vikram D. Kodibagkar^1,2, Praveen Kumar Gulaka¹, Federico Rojas-Quijano³, Zoltan Kovacs³, Ralph P. Mason, ¹², A Dean Sherry^2,3

¹Biomedical Engineering, UT Arlington and UT Southwestern Medical Center at Dallas, Dallas, Tx, United States; ²Radiology, UT Southwestern Medical Center at Dallas; ³Advanced Imaging Research Center, UT Southwestern Medical Center at Dallas, Dallas, Tx

Heterogeneously distributed hypoxic cores in tumors are known to affect radiation sensitivity and promote development of metastases, therefore the ability to image tumor hypoxia in vivo will provide useful prognostic information. Previous research demonstrated that 2-nitroimidazole accumulated in hypoxic tissues due to an enzyme mediated reduction of the nitro group in hypoxic conditions. Here we report the in vitro and in vivo evaluation of a GdDOTA monoamide conjugate of 2-nitroimidazole, GdDO3NI, as a novel hypoxia targeting MRI T1 contrast agent.

                  1892.     In Vivo Detection of the Metabolism of Novel Hypoxia Probes in Models of Glioma by ¹H NMR

Jesus Pacheco-Torres^1,2, Rocio Pérez-Carro¹, Paloma Ballesteros², Pilar Lopez-Larrubia¹, Sebastian Cerdan¹

¹Instituto de Investigaciones Biomédicas "Alberto Sols" - CSIC, Madrid, Spain; ²Laboratory of Organic Synthesis and Molecular Imaging, UNED, Madrid, Spain

We propose a novel protocol to evaluate tumor hypoxia in vivo by monitoring the reduction of intratumoral nitromidazolil probes using PRESS spectroscopy. We injected C6 tumors implanted in the flank of nude mice with a solution containing a mixture of the oxygen sensitive probe misonidazole and TSP, an oxygen insensitive probe. It is shown that the rate of disappearance of injected misonidazole depended on the intratumoral local oxygen tension in vivo, as modified by air or oxygen breathing. In contrast, the rate of disappearance of the TSP reference remained independent of the same changes in local oxygen tension.

                  1893.     Noninvasive Assessment of Lymph Node Metastasis of Melanoma Using Molecular MR Reporter Gene of Ferritin

Seung Hong Choi¹, Hye Rim Cho², Hyeonjin Kim³, Hoe Suk Kim², Woo Kyung Moon²

¹Radiology, Seoul National University, Seoul, ., Korea, Republic of; ²Seoul National University Hospital, Korea, Republic of; ³Gacheon Univeristy of Medicine and science, Korea, Republic of

This study shows the possibility of noninvasive assessement of lymph node metastasis of cancer cells using MR reporter gene of ferritin. In addition, MR imaging seems to be superior to optical imaging in the evaluation of deep organ metastasis of cancer cells.

                  1894.     Enzyme Mediated MRI Probes: Design, Synthesis and Relaxivity Behaviour of a Beta-Galactosidase Reporter

Eliana Gianolio¹, Jebasingh Bhagavath Singh¹, Markus Aswendt², Francesca Arena¹, Alessandro Barge³, Mathias Hoehn², Silvio Aime¹

¹Chemistry IFM and Molecular Imaging Center, University of Torino, Torino, TO, Italy; ²In-vivo-NMR Laboratory, Max Planck Institute for Neurological Research, Cologne, Germany; ³Department of Drug Science and Technology, University of Torino, Torino, Italy

We report about the synthesis and the characterization of a Gd-DOTAgal derivative that has been proven to be a good â-galactosidase expression reporter. It consists in a system that can undergo polymerization in the presence of Tyrosinase upon  beta-gal activated cleavage of the tyr-gal bond.

Novel Imaging Agents

                  1895.     Solution, Cell and Animal Studies in Molecular MRI of Estrogen Receptor α

Adi Pais¹, Chidambaram Gunanathan¹, Inbal Biton¹, Raanan Margalit¹, David Milstein¹, Hadassa Degani¹

¹Weizmann Institute of Science, Rehovot, Israel

We have develop a non-invasive molecular MRI method for detecting, and investigating the level, activity and degradation of estrogen receptor alpha (ER) in breast cancer cells, tumors and metastases. Two novel contrast agents, composed of a gadolinuim-pyridiniumtetraacetic acid conjugated to 17â-estradiol or to tamoxifen  were synthesized and characterized for their solution chemistry as well as their biological activity and MRI parameters in cells and tumors. These agents demonstrated selective binding with high affinity to ER and significant enhancement of the water T1 and T2 relaxivity in ER+ as compared to ER- systems, and served to identify ER localization in vivo.

                  1896.     In Vivo Imaging of Liposomal TmDOTMA: A Potential Method for Waterless MR Angiography and Molecular Imaging

Todd C. Soesbe¹, Navin Bansal², Ananth V. Annapragada³, Ketan B. Ghaghada³, Zoltan Kovacs¹, A. Dean Sherry^1,4

¹Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States; ²Department of Radiology, Indiana University School of Medicine, Indianapolis, IN, United States; ³School of Health Information Sciences, The University of Texas at Houston, Houston, TX, United States; ⁴Department of Chemistry, The University of Texas at Dallas, Dallas, TX, United States

Liposomal delivery of MR contrast agents offers improved steady-state imaging and signal-to-noise due to their long blood circulation life-time. Also, the relative small size of the liposomes (¡Ö 100 nm in diameter) allows them to have direct uptake in certain tumor lines that exhibit "leaky" vasculature (e.g. MBA-MD-231 breast cancer cells). The 1H methyl group of TmDOTMA has a chemical shift that is about -100 ppm away from bulk water. This TmDOTMA peak can be imaged using chemical shift selective (CHESS) techniques in which the water signal is completely absent. By using this method we can obtain "waterless" MR images where the only signal is due to the TmDOTMA filled liposomes. This is analogous to images obtained in nuclear medicine where the only signal is from the radioactive isotope. Liposomal TmDOTMA imaging has the potential to produce high resolution MR angiograms and molecular targeted images that are not contaminated by the bulk water signal. We explored this hypothesis by injecting a 5.8 mM solution of TmDOTMA liposomes, both intravenously and intratumorally, into a tumor-bearing mouse.

                  1897.     Gadoxane – a Novel Degradable Silsesquioxane Based Macromolecular MRI Contrast Agent

Joern Engelmann¹, Joerg Henig², Sven Gottschalk¹, Hermann A. Mayer²

¹High Field MR Center, Max Planck Institute for Biological Cybernetics, Tuebingen, Germany; ²Institute for Inorganic Chemistry, University of Tuebingen, Tuebingen, Germany

Silsesquioxane-based macromolecular MRI-contrast agents have recently been reported to have a compact globular structure resulting in significantly higher relaxivities when compared to smaller MRI-probes. The stability of the core under physiological conditions is unknown so far. We therefore studied the stability of Gadoxane, a new silsesquioxane-based contrast agent connected to eight DOTAGA-gadolinium chelates. The silsesquioxane core was almost completely hydrolyzed under physiological conditions while the integrity of the gadolinium chelate was maintained. In conclusion, these probes cannot be considered as stable anymore. However, their degradability might improve their in vivo-applicability due to a faster renal excretion of the smaller fragments.

                  1898.     Targeting Sentinel Lymph Nodes with Macrophages Labeled with FIONs on 1.5 T MR Imaging

Seung Hong Choi¹, Hye Rim Cho², Nohyun Lee³, Taeghwan Hyeon⁴, Woo Kyung Moon², Chul-Ho Sohn¹

¹Radiology, Seoul National University, Seoul, ., Korea, Republic of; ²Seoul National University Hospital, Korea, Republic of; ³School of Chemical and Biological Engineering, Seoul National University, Seoul, Korea, Republic of; ⁴School of Chemical and Biological Engineering, Seoul National University, Korea, Republic of

The purpose of the present study was to confirm if metastatic lymph nodes can be targeted by macrophages labeled FIONs by using a mouse melanoma model.

                  1899.     Multimeric Iron Oxide Micro Particles: Novel High Sensitivity and Biodegradable MRI Contrast Agents.

Francisco Perez-Balderas¹, Benjamin G. Davis², Sander van Kasteren², Alexandr Khrapichev¹, Daniel Anthony³, Nicola R. Sibson¹

¹CR-UK/MRC Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, United Kingdom; ²Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom; ³Department of Pharmacology, Univerity of Oxford, Oxford, United Kingdom

Biodegradable multimeric iron oxide microparticles were obtained by conjugation of iron oxide nanoparticles through peptides. These multimeric particles constitute an ideal platform for new highly sensitive and specific MRI contrast agents.

                  1900.     Effect of PEG Corona Lengths on MR Relaxivity and Off-Resonance Saturation Sensitivity of Superparamagnetic Polymeric Micelles

Chalermchai Khemtong¹, Osamu Togao², Jimin Ren², Chase W. Kessinger¹, Masaya Takahashi², A Dean Sherry², Jinming Gao¹

¹Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, United States; ²Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States

Herein, we report the effect of PEG corona lengths on MR relaxivity and ORS sensitivity of SPPM. Results showed that the length of the pegylated shell is a critical physical parameter that controls MR relaxivity and ORS sensitivity of SPPM.  SPPM with shorter PEG corona has a higher T2 relaxivity and hence ORS sensitivity.  Results from this study provide the fundamental insights on the design of SPPM as ultrasensitive MRI nanoprobes for in vivo molecular imaging applications.

                  1901.     Enhancing the Relaxivity of Gd-Based Liposomes and Micelles by Restricting the Local Motions

Mauro Botta¹, Filip Kielar¹, Lorenzo Tei¹, Enzo Terreno²

¹Environmental and Life Sciences, Universita' del Piemonte Orientale, Alessandria, Italy; ²Center for Molecular Imaging, Department of Chemistry IFM, University of Turin, Turin, Italy

A novel GdDOTA derivative was prepared featuring two adjacent glutamic acid moieties. Reaction with dodecyl amine yields an amphiphilic complex that maintains the favorable properties of the parent complex in terms of stability, relaxivity and water exchange rate. The self-assembling process in aqueous solution results in micelles and liposomes of enhanced relaxivity (+ 140 % at 0.47 T; + 100 % at 1.5 T) over that of corresponding single-chain systems that is explained in terms of a strong limitation of the local rotation about the hydrophobic chains.

                  1902.     New Window on Human Cognition: 13C Assays of Glutamate Neurotransmission in Frontal Brain

Napapon Sailasuta¹, Thao T. Tran^1,2, Brian D. Ross^1,2

¹Huntington Medical Research Institutes, Pasadena, CA, United States; ²Rudi Schulte Research Institute, Santa Barbara , CA, United States

Cognitive function in humans is currently imaged in real time only with radioactive PET or with task-driven fMRI.  True molecular imaging on the underlying neurochemical events, here ascribed predominantly to glutamate neurotransmission, has been developed using non-radioactive, stable carbon isotopes infused intravenously and selectively taken up and metabolized by EITHER neurons or glia, in frontal brain (a totally novel application relevant to imaging of cognition) and in posterior brain.  The tests have been evaluated in more than 20 normal human subjects and several prototypical disorders of cognition with promising results which complement or replace PET.

                  1903.     Biodegradable MPIO and SPIO Using FDA Approved Polymers

Michael K. Nkansah¹, Durga Thakral¹, Erik M. Shapiro, ¹²

¹Department of Biomedical Engineering, Yale University, New Haven, CT, United States; ²Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, United States

Magnetic cell labeling has primarily been accomplished using dextran-coated iron-oxide nanoparticles. A drawback to their use is the low iron content per particle, coupled with cessation of commercial production. As an alternative, micron-sized iron-oxide particles (MPIOs) have been used, the benefits of which are that they contain ~ 30% iron. The downside is that MPIOs are composed of inert, non-degradable and not FDA-approved polymers, potentially limiting clinical utility. Here we demonstrate the fabrication of fluorescent, biodegradable MPIOs, composed of PLGA and cellulose, two FDA-approved polymers. These particles have high relaxivity and are capable of labeling cells for MRI-based cell tracking.

                  1904.     Nitroxide Compound CPTO-EG as an MRI Contrast Agent

Andrew Nencka¹, Xiping Liu¹, Joy Jeseph¹, Shi-Jiang Li¹, Balaraman Kalyanaraman¹

¹Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States

The conventional T1 contrast agent, gadolinium-DTPA complex, does not cross the blood brain barrier (BBB) in the absence of injury or tumor. Nitroxides possess a single unpaired electron but generally do not cross the BBB.  The compound we developed can cross the BBB and provide MRI contrast in brain imaging by shortening the longitudinal relaxation time (T1) of water protons (1).  Present study reports the progress of the development of a contrast agent, 2,2,5,5- tetramethylpyrroline 1-oxide 3-ethyleneglycolcarboxylate (CTPO-EG), which can cross the BBB and has significantly greater relaxivity.

                  1905.     Magnetite Liposomes as Potential Theranostic Agents for MRI and Magnetic Hyperthermia of Vascular Inflammation

Hisanori Kosuge¹, Toshiro Kitagawa¹, Takeshi Kobayashi², Michael V. McConnell¹

¹Cardiovascular Medicine, Stanford University, Stanford, CA, United States; ²Biological Chemistry, Chubu University, Kasugai, Aichi, Japan

Inflammation plays a critical role in the progression of atherosclerosis. Magnetite liposomes (MLs) have been used for magnetic hyperthermia of cancer cells and for cellular MR imaging. Thus, they may have the potential to both image and treat vascular inflammatory cells. We demonstrate that MLs show macrophage uptake and effective magnetic hyperthermia and cell death in vitro. ML also imaged mouse carotid vascular inflammation by 7T MRI.

                  1906.     Macrocyclic Ferrocenyl DTPA-Bis (Amide) for Gd-Chelate as a New Class of MRI Blood Pool Contrast Agents

Hee-Kyung Kim¹, Nasiruzzaman Sk Md², Ji-Ae Park³, Seung-Tae Woo⁴, Tae-Jung Kim⁵, Yongmin Chang^1,6

¹Department of Medical & Biological Engineering, Kyungpook National University, Daegu, Korea, Republic of; ²Advanced Research Institute for Recovery of Human Sensitibiliy, Daegu, Korea, Republic of; ³Korea Institute of Radiological & Medical Science, Seoul, Korea, Republic of; ⁴Bayer Schering Pharma Korea, Seoul, Korea, Republic of; ⁵Department of Applied Chemistry, Kyungpook National University, Daegu, Korea, Republic of; ⁶Department of Diagnostic Radiology and Molecular Medicine, Kyungpook National university, Daegu, Korea, Republic of

We report the synthesis of 1,1’-ferrocendiylamines (L) and their Gd(III) complexes of the type [Gd(L)(H2O)], referred to as Ferromides, as a new family of BPCAs. Also reported is the investigation of their thermodynamic and magnetic resonance properties along with in vitro and in vivo MR studies. They all exhibit greater thermodynamic stability (ie., logKsel) than their acyclic and cyclic analogues such as DTPA-BMA, DTPA, and DOTA and compare favorably to MS-325, a well-known BPCA. The R1 relaxivities of Ferromides are quite high as compared with other MRI CAs currently in use. In the case of Ferromide-1, for instance, the R1 relaxivity is 7.5 mM–1sec–1, which is twice as high as that of structurally related Dotarem® (R1=3.6 mM–1sec–1). The R1 relaxivity is further increased in an aqueous saline solution of HSA (4.5% w/v) to be compared quite favorably to that of MS-325, and most strikingly, the increase is observed even in the absence of the electrostatic phosphate-HSA interaction. The in vivo MR images of mice obtained with Ferromide-1 show the contrast enhancement not only in heart and bladder but also in abdominal aorta, clearly demonstrating the blood-pool effect.

                  1907.     Mn-Loaded Apoferritin: A High Sensitivity, Biologically Compatible MRI Agent.

Simonetta Geninatti-Crich¹, Ferenc Kalman¹, Ibolya Szabo¹, Stefania Lanzardo¹, Juan Carlos Cutrin¹, Laura Conti¹, Silvio Aime¹

¹University of Torino, Torino, Italy

An innovative approach to the design of MRI Contrast Agents has been pursued through the entrapment of Mn(II) aqua ions inside the inner cavity of Apoferritin. This imaging probe can be proposed in the diagnosis of a variety of liver diseases involving an alteration in the hepatic iron storing capabilities (e.g. hepatocellular carcinoma, fibrosis, cirrhosis).

                  1908.     [Gd(Try-TTDA)] ^2-: Magnetic Resonance Based Sensor for the Specific Detection of Cu²⁺ in Living Cells

Gin-Chung Liu^1,2, Dayananda Kasala³, Tsung-Sheng Lin³, Chiao-Yun Chen^1,4, Twei-Shiun Jaw^1,2, Yu-Ting Kuo^1,2, Yun-Ming Wang³

¹Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; ²Department of Radiology,Faculty of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; ³Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan; ⁴Department of Radiology,Faculty of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung , Taiwan

In this study, we have developed a new contrast agent [Gd(Try-TTDA)] ^2- that can recognize Cu²⁺ ion in the living cells.  In addition, the Gd³⁺ complex attributes excellent selectivity for Cu²⁺ over a choice of other metal ions. A gradual increases in the relaxivity and signal intensity of ex vitro and in vitro MR imaging upon Cu²⁺ detection. These results implicate that a new MR based contrast agent [Gd(Try-TTDA)])] ^2- can serve as a Cu²⁺ sensor using relaxometry and MR imaging

                  1909.     In Vivo quantification of SPIO Nanoparticles with Phase Gradient Mapping

Jason A. Langley¹, E Kay Jordan², Wei Liu³, Joseph A. Frank², Qun Zhao¹

¹Department of Physics and Astronomy, The University of Georgia, Athens, GA, United States; ²Experimental Neuroimaging Section, Laboratory of Diagnostic Radiology Research, National Institutes of Health, Bethesda, MD, United States; ³Phillips Research, North America, Briarcliff Manor, NY, United States

A method for quantifying concentrations of SPIO nanoparticles is presented in this abstract and the proposed method is tested on SPIO-labeled tumors that were implanted in the flank of nude mice. Each voxel within the tumor was modeled as a homogeneous sphere with magnetization m. The magnetic field gradient from each voxel was then superimposed to form the theoretical magnetic field gradient of the tumor, which was then fitted to the gradient of the experimental field map, measured by the acquired phase maps. The results from the x-component of the phase gradient accord well with the known SPIO concentrations.

                  1910.     Study of Gd-Based MR Contrast Agents Encapsulated in the Phosphatidylglyceroglycerol-Based Thermosensitive Liposomes for Improved MR-Guided Chemothermotherapy

Tungte Wang^1,2, Martin Hossann^1,2, Michael Peller³, Maximilian Reiser³, Rolf Dieter Issels^1,2, Lars Hans Lindner^1,2

¹Department of Internal Medicine III, University Hospital, Grosshadern, Munich, Bavaria, Germany; ²CCG Hyperthermia, Institute of Molecular Immunology, Helmholtz Center Munich – German Research Center for Environmental Health, Munich, Bavaria, Germany; ³Department of Clinical Radiology, University Hospital, Grosshadern, Munich, Bavaria, Germany

Phosphatidylglyceroglycerol (DPPGOG)-based thermosensitive liposomes (TSL) with encapsulated proton MR Gd-based T1 contrast agent (CA) have been proposed for noninvasive MR thermometry during tumor treatment using chemothermotherapy. In this work, the DPPGOG-TSL with four separately encapsulated Gd-based CAs which have diverse chemical structures were studied in vitro by measuring the temperature dependence of their T1 while heated from 30 to 50 °C. The measurements revealed that the release of macrocyclic nonionic Gd-based CA from the DPPGOG-TSL resulted in the most percent T1 decrease and thus the DPPGOG-TSL with such encapsulated CA has the potential for the optimal T1 enhancement effect.

                  1911.     Porous Mn²⁺ - Fe₃O₄ Nanoparticles with High T₁ and T₂ Relaxivity

Veronica Clavijo Jordan¹, Michael R. Caplan¹, Kevin M. Bennett¹

¹Bioengineering, Arizona State University, Tempe, AZ, United States

We report a protein based nanoparticle with a Fe₃O₄ crystal core and Mn²⁺ bound to surface channels. The metal core size ranged from 3 to 6nm in diameter, and ICP results indicate 7 Mn²⁺ per protein. HRTEM shows that the core metal is magnetite with a lattice spacing of 0.25nm. Following the proposed synthesis, we suspect that the high per-ion T₁ (338mM^-1s^-1) and T₂ (133 mM^-1s^-1) relaxivity are due to a cooperative effect contributed by the Mn²⁺ and the Fe₃O₄ crystal.  MRI scans of rat brain inoculations show it can be detected in vivo.

                  1912.     Apparent Diffusion Coefficient of Gd-Based Contast Agents Assessed in Vivo in the Rat Brain Using Dynamic T1 Mapping

Benjamin Marty¹, Julien Flament¹, Céline Giraudeau¹, Caroline Robic², Marc Port², Franck Lethimonnier¹, Fawzi Boumezbeur¹, Julien Valette¹, Denis Le Bihan¹, Sébastien Mériaux¹

¹CEA/DSV/I2BM/Neurospin, Gif-Sur-Yvette, France; ²Research Division, Guerbet, Roissy-Charles de Gaulle, France

Gadolinium-based contrast agents (Gd-based CA) have been used for many years for various MRI applications including MR-based molecular imaging with targeted compounds. One of the most important factors to consider for brain applications is the diffusivity of these probes through the cerebral tissue to their target. This study proposes a methodology allowing quantification of Gd-based CA concentration by acquiring dynamic T1 maps. This approach has been applied to estimate in vivo in the rat brain the apparent diffusion coefficient of five compounds with different hydrodynamic diameters opening the way to a better understanding of diffusion mechanisms of supra-molecular imaging probes.

                  1913.     Novel Nanoparticle Formulations with Enhanced ¹⁹F Relaxation

Anke De Vries¹, Muhammed Yildirim², Sander Langereis², Rolf Lamerichs², Klaas Nicolay¹, Holger Gruell, ¹²

¹Biomedical NMR, Faculty of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands; ²Philips Research, Eindhoven, Netherlands

Nanoparticle formulations incorporating Gd(III) complexes in the surfactant layer increases the longitudinal relaxation rate more than two-fold, resulting in a substantial sensitivity gain.

                  1914.     Fluorinated Lanthanide (III) Probes for 19F Magnetic Resonance Imaging.

Ian Wilson^1,2, Gilberto S. Almeida^1,2, Andrew M. Blamire², Kirsten H. Chalmers³, David Parker³, Ross J. Maxwell^1,2

¹Northern Institute of Cancer Research, Newcastle University, Newcastle Upon Tyne, Tyne and Wear, United Kingdom; ²Newcastle Magnetic Resonance Centre, Newcastle University, Newcastle Upon Tyne, Tyne and Wear, United Kingdom; ³Department of Chemistry, Durham University, Durham, United Kingdom

New cancer treatments are being developed against specific molecular targets, but imaging methods are required to demonstrate drug-target interaction. Fluorinated 19F MR probes are of great interest due to their sensitivity, large chemical shift and minimal endogenous signal. This study evaluates novel fluorinated lanthanide probes in vitro and in vivo. Relaxation results show 100-fold reduction in T1 corresponding to an improvement in signal:noise per unit time of about 10-fold. In vivo results showed limited tumour uptake of the diamide complex, L4Gd, compared to gadoteridol. This strategy is useful for pharmacokinetic evaluation of fluorinated lanthanide complexes.

                  1915.     A Peptide Based Dual-Labeled Agent Targeted to Interleukin 11 Receptor Alpha-Chain for Molecular Imaging

Ying-Hsiu Lin¹, Gin-Chung Liu^2,3, Twei-Shiun Jaw^2,3, Yu-Ting Kuo^2,3, Chiao-Yun Chen^2,3, Yun-Ming Wang¹

¹Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan; ²Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; ³Department of Radiology,Faculty of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

This study describes the synthesis and biologic evaluation of a IL11 peptide targeted dual-labeled imaging agent as a potential probe for detecting human breast cancer. The IL11 peptide substrate was synthesized and conjugated with the TTDA chelating moiety and cy5.5 via solid-phase peptide synthesis. The results of in vitro optical and MR imaging indicated that the targeted contrast agent specifically targeted to human breast cancer cell and lead to significant enhancement. The preliminary results also demonstrated that the bimodal IL-11 peptide analog could be used to detect IL-11Rα positive breast cancer with MRI and fluorescence microscope at the cellular level.

                  1916.     A Dual Modality Nanoparticle MRI/CT Contrast Agent with Enhanced T₁ and T₂ Relaxivity

Simon A. Lubek¹, Veronica Clavijo Jordan¹, Kevin M. Bennett¹

¹Bioengineering, Arizona State University, Tempe, AZ, United States

We report a dual MRI/CT protein based W-Fe nanoparticle contrast agent with high T₁  (4,497 mM^-1s^-1) and T₂ (458,143 mM^-1s^-1) per particle relaxivities. The T₁ relaxivities observed demonstrated a 58 fold increase over iron oxide particles. TEM results showed nanoparticles ranging from 9 to 13nm in diameter.  Rat striatum MRI scans demonstrated the agent is detectable in vivo.  Furthermore, a CT comparison demonstrated a 1.5 fold contrast increase as compared to iron oxide particles.

                  1917.     Optimization of 19F MR Quantification of Administrated PFC Nanoparticle in Vivo: Mathematical Simulation and Experimental Validation

Lingzhi Hu¹, Lei Zhang¹, Junjie Chen¹, Gregory M. Lanza¹, Samuel A. Wickline¹

¹Washington University School of Medicine, St. Louis, MO, United States

Acquisition parameters for in vivo 19F MR quantification of administrated PFC nanoparticle (NP) have been optimized, in the sense of minimizing the oxygenation effect and maximizing the SNR. Bloch equation based simulation has been performed to simulate the acquired intensity of perfluoro-15-crown-5-ether NP under normoxia and hyperoxia condition. Subsequently, in vivo 19F MR imaging, T1 measurement and 19F quantification have been carried out on C57BL/6 mouse under normoxia and hyperoxia respectively. Both simulation and experiment have validated (1) the optimal TR for achieving high is 1.5*T1; (2) the quantification is insensitive to oxygen level given TR≥ 3* T1.

                  1918.     Multimeric Gd-Based Contrast Agents for High Field MR-Imaging

Lorenzo Tei¹, Giuseppe Gugliotta¹, Mauro Botta¹

¹Dipartimento di Scienze dell'Ambiente e della Vita, Università del Piemonte Orientale "A. Avogadro", Alessandria, Italy

New T₁ agents that would take advantage of current 1.5 – 3 T scanners showing excellent relaxation properties over a broad range of imaging field strengths are object of intense research. Multimeric Gd^III agents with medium molecular weight (~3-4 KDa) exhibit improved relaxivity values also at high fields. Gd^III di-, tri-, tetra-, hexa- and octameric complexes based on stable and efficient Gd-AAZTA derivatives were synthesised. ¹H relaxivity data as a function of magnetic field strength and temperature as well as T₁-weighted phantom MR-images at different fields were acquired. These multimeric Gd^III contrast agents exhibit improved efficiency for application in both clinical MRI and Molecular Imaging protocols.

                  1919.     3D δR2 Microscopy MRA with a New Blood Pool Contrast Agent: A Comparison with Resovist®

Chien-Yuan Lin¹, Si-Han Wu², Ming-Huang Lin¹, Yann Hung², Chung-Yuan Mou², Chen Chang¹

¹Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; ²Department of Chemistry, National Taiwan University, Taipei, Taiwan

We have recently developed a new blood pool contrast agent (Fe3O4@SiO2/PEG) which possesses higher transverse relaxivity and long intravascular half-life. This study was aimed to assess the ability of Fe3O4@SiO2/PEG to improve high-resolution magnetic resonance angiography in visualizing cerebral microvasculature.

                  1920.     Improving T1-Weighted "Hot Spot" Imaging with Colloidal Iron Oxide Nanoparticles

Shelton D. Caruthers¹, Angana Senpan¹, Dipanjan Pan¹, Grace Hu¹, Samuel A. Wickline¹, Gregory M. Lanza¹

¹C-TRAIN, Washington University, St. Louis, MO, United States

Iron oxide nanoparticles have been extensively used for nontargeted and targeted imaging applications based upon highly sensitive T2* imaging properties, which typically result in negative contrast effects.  Colloidal Iron Oxide Nanoparticles offer both traditional T2* detection and T1 weighted "hot spot" detection.  This work explores the mechanisms for improving this T1 detectability.

                  1921.     Lanthanide Trifluoride Nanoparticles for Dynamic Contrast Enhanced MRI

Wendy Oakden¹, Evelyn Ning Man Cheung², R Scott Prosser, ^2,3, Greg Jan Stanisz^1,4

¹Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; ²Department of Biochemistry, University of Toronto, Toronto, ON, Canada; ³Department of Chemistry, University of Toronto, Toronto, ON, Canada; ⁴Imaging Research, Sunnybrook Health Science Centre, Toronto, ON, Canada

We present a new class gadolinium-based contrast agents for MR imaging. The contrast agent consists of nanoparticles with a lanthanide fluoride core (Gadolinium and Cerium trifluoride) surrounded by a coating of polyacrilic acid.  Chemical similarity between different lanthanide-series elements allows core elements to be varied, altering size and relaxivity as well as rendering the nanoparticles visible under fluorescence microscopy via the addition of Europium or Terbium. The polyacrilic acid coating can be functionalized to allow for cellular uptake. This flexible contrast agent has been successfully used in vivo for dynamic contrast enhanced MR imaging.

                  1922.     Enhanced Targeted MRI Contrast Using Silica Coated Magnetite Nanoparticles

Jyoti Lodhia¹, Dodie Pouniotis², Giovanni Mandarano¹, Peter Eu, ^1,3, Simon Cowell¹

¹Medical Radiations Research Group, School of Medical Sciences, RMIT University, Melbourne, Victoria, Australia; ²Cancer and Tissue Repair Research Group, School of Medical Sciences, RMIT University, Melbourne, Victoria, Australia; ³Centre for Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

MRI is a high spatial resolution non-invasive technique but it has low specificity for targeting explicit pathologies. To achieve a more targeted delivery an MRI contrast agent must be biocompatible, have high chemical stability, be easily functionalised and retain a high net magnetisation value.This study using a highly efficient biocompatible iron oxide nanoparticle with well defined magnetic properties (80emu/g and a T2 of 235.5 mmol-1l s-1) was able to specifically target and image a cancer. The results demonstrated the potential for targeted iron oxide silica nanoparticles in the MRI of specific pathologies.

                  1923.     Silver Nanoparticles Functionalized with High Gadolinium Chelate Payload as Effective in Vivo T1-Brightening Contrast Agents

Lindsay Kathleen Hill¹, Talha S. Siddiqui², Dung Minh Hoang¹, Susan Pun¹, Marc Anton Walters², Youssef Zaim Wadghiri¹

¹Radiology, NYU School of Medicine, New York, United States; ²Chemistry, New York University, New York, United States

In the research described here we designed a new silver multimodal nanoparticle containing GdDTPA and tested the effect of coligated  polyethyleneglycol (PEG) chains on particle distribution, clearance and contrast enhancement. The resulting  GdDTPA content, relaxivity and solubility were characterized in vitro and their biodistribution was assessed by abdominal MRI.

Molecular Imaging TN Disease Models

                  1924.     Early Detection of Brain Metastasis Using Novel MRI Contrast Agent Targeting VCAM-1

Sebastien Serres¹, Lukxmi Balathasan, Thomas Weissensteiner, Shawn W. Carbonell, Martina A. McAteer², Robin P. Choudhury², Daniel C. Anthony³, Ruth Muschel, Nicola R. Sibson

¹Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, Oxon, United Kingdom; ²Department of Cardiovascular Medicine, University of Oxford; ³Department of Pharmacology, University of Oxford

Early detection of brain metastasis using novel MRI contrast agent targeting VCAM-1

                  1925.     Anti-IL17 Treatment Reduces Clinical Score and VCAM-1 Expression in EAE-ABH Mice Detected by in Vivo Magnetic Resonance Imaging

Sebastien Serres¹, Silvy Mardiguian², Martina A. McAteer³, Robin P. Choudhury⁴, Sandra J. Campbell⁵, Paul Smith⁶, Fay Saunders⁷, Nicola R. Sibson⁸, Daniel C. Anthony²

¹Gray Institute for Radiation Oncology and Biology, Oxford, Oxon, United Kingdom; ²Department of Pharmacology, University of Oxford; ³Department of Cardiovascular Medicine; ⁴Department of Cardiovascular Medicine, University of Oxford; ⁵Department of Pharmacology, university of Oxford; ⁶Department of Pharmacology, UCB, Slough; ⁷Department of Antibody Biology, UCB, Slough,; ⁸Gray Institute for Radiation Oncology and Biology, University of Oxford

Anti-IL17 treatment reduces clinical score and VCAM-1 expression in EAE-ABH mice detected by in vivo magnetic resonance imaging

                  1926.     T1 Mapping of the Heart with Cardio-Respiratory-Gated Look-Locker MRI Quantifies T1 Shortening Due to Gd-Labeled Macrophage Infiltration After Acute Myocardial Infarction

Nivedita Naresh¹, Moriel Vandsburger¹, Alexander Klibanov, ¹², Patrick Antkowiak¹, Yaqin Xu¹, Brent A. French^1,3, Frederick H. Epstein^1,3

¹Biomedical Engineering, University of Virginia, Charlottesville, VA, United States; ²Division of Cardiovascular Medicine, University of Virginia; ³Department of Radiology, University of Virginia

Macrophages play the critical role of clearing necrotic debris in the wound healing response that follows myocardial infarction (MI). Two days after MI, we labeled macrophages in vivo using intravenous liposomes containing gadolinium.  On day 5 after MI, cardiorespiratory-gated (CRG) Look-Locker MRI of the heart quantified T1 shortening of the infarct zone secondary to infiltration of the labeled macrophages.  The T1 shortening effect was dependent upon the dose of liposomes.  Macrophage labeling with Gd-liposomes and T1-mapping with CRG Look-Locker imaging may prove useful for quantitative MRI of post-MI macrophage infiltration in preclinical murine studies.

                  1927.     Development and Validation of a Peptide-Vectorized Superparamagnetic Imaging Probe Designed for the Detection of Inflammation in Atherosclerotic Plaque

Carmen Burtea¹, Sophie Laurent¹, Eric Lancelot², Olivier Rousseaux², Sébastien Ballet², Coralie Thirifays¹, Marc Port², Gérard Toubeau³, Luce Vander Elst¹, Claire Corot², Robert Nicolas Muller¹

¹General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium; ²Research Center, Guerbet, Aulnay-sous-Bois, France; ³Laboratory of Histology, University of Mons, Mons, Belgium

A VCAM-1-targeted cyclic heptapeptide  peptide was conjugated to USPIO (USPIO-R832), and VCAM-1 binding was first confirmed on HUVEC stimulated with TNF-alpha. Subsequently, USPIO-R832 was evaluated by MRI at 4.7T on ApoE-KO mice, by using T2 and T2*-weighted imaging sequences. The ability to bind to atherosclerotic plaque of this molecular imaging probe was furthermore corroborated by histochemistry. The control imaging probe was represented by USPIO vectorized by a non-specific peptide (USPIO-NSP).

                  1928.     Non Invasive Assessment of Plaque Progression in ApoE-/- Mice Using T2* Weighted and Positive Contrast SGM-MRI

Marcus R. Makowski¹, Gopal Varma, Christian Jansen, Andrea J. Wiethoff, Tobias Schaeffter, Mathias Taupitz², Rene M. Botnar

¹King’s College London, Division of Imaging Sciences, , London, United Kingdom; ²Radiology, Charite –, Berlin, Germany

Macrophages have been identified as a contributor to plaque instability in atherosclerosis. The aim of this study was to noninvasively assess iron oxide uptake at different stages of plaque development in the innominate artery of apoE-/- mice and to evaluate the effect of anti-inflammatory treatment using T2* weighted and positive contrast susceptibility gradient mapping (SGM) MRI. Molecular alterations in plaque composition with regard to macrophage content could be detected using iron oxide particles in combination with T2* weighted and SGM MRI. Anti-inflammatory treatment with statins resulted in a smaller SGM signal and smaller signal voids on T2* weighted images.

                  1929.     Target-Binding of Perfluoro-Carbon Nanoparticles Alters Optimal Imaging Parameters Using F-19 Molecular MRI: A Study Using Fast in Vitro Screening and in Vivo Tumor Models.

Jochen Keupp¹, Anne H. Schmieder², Samuel A. Wickline², Gregory M. Lanza², Shelton D. Caruthers²

¹Philips Research Europe, Hamburg, Germany; ²C-TRAIN, Washington University, St. Louis, MO, United States

Patient stratification using molecular MRI of angiogenesis could change standard of care in anti-angiogenic therapy. Previously, α _ν β ₃-integrin targeted nanoparticles (NP) have been shown to detect and quantify angiogenesis in small-animal tumor models based on ¹⁹F-MRI. These promising results using Perfluoro-Crown-Ether labels are currently translated to more clinically-relevant Perfluoro-Octyl-Bromide (PFOB) NP. The complex spectral properties of PFOB and the sensitivity to the target-binding process, as observed in this work, require a thorough optimization of imaging parameters on target. In vitro optimization on fibrin clots and in vivo detection of angiogenesis-targeted NP in the vasculature of Vx2-tumor bearing rabbits by ¹⁹F-MRI is demonstrated.

                  1930.     In Vivo CEST-Based Molecular Imaging Using RGD-LipoCEST in U87 Mice Brain Tumor

Julien Flament¹, Benjamin Marty¹, Céline Giraudeau¹, Sébastien Mériaux¹, Julien Valette¹, Christelle Médina², Caroline Robic², Marc Port², Franck Lethimonnier¹, Gilles Bloch¹, Denis Le Bihan¹, Fawzi Boumezbeur¹

¹NeuroSpin, I²BM, Commissariat à l'Energie Atomique, Gif-sur-Yvette, France; ²Guerbet, Research Division, Roissy-Charles de Gaulle, France

LipoCEST are a new class of contrast agents for CEST-MRI which provide a tremendous amplification factor and can be easily functionalized by grafting specific peptide on their outer membrane in order to target pathology specific biomarker. We present our promising preliminary result to image αvβ3, integrin expressed during tumor growth, with CEST-based MRI using RGD-LipoCEST contrast agents. It constitutes to our knowledge the first attempt towards brain tumor detection using LipoCEST contrast agents in vivo.

                  1931.     Molecular Susceptibility Contrast MRI of Tumor Angiogenesis with Targeted Iron Oxide Nanoparticles

Martijn Wolters^1,2, Marlies Oostendorp^1,3, Bram F. Coolen², Mark J. Post^3,4, Gustav J. Strijkers², Klaas Nicolay², Walter H. Backes^1,3

¹Department of Radiology, Maastricht University Medical Center, Maastricht, Netherlands; ²Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands; ³Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands; ⁴Department of Physiology, Maastricht University, Maastricht, Netherlands

The purpose of this study was to evaluate Susceptibility Gradient Mapping (SGM) for molecular MRI to selectively detect tumor angiogenesis in mice with cNGR-labeled SPIOs. SGM is a positive contrast technique to detect susceptibility effects of SPIOs. In this experimental study we found CNR values for SGM comparable to gradient echo (GE) images. Furthermore, a trend towards stronger contrast enhancement for targeted SPIOs compared with untargeted SPIO was perceived.

                  1932.     MR Imaging of Angiogenesis in Tumor Xenografts by α _vβ ₃ - Targeted Magnetofluorescent Micellar Nanoprobes

Chase W. Kessinger¹, Chalermchai Khemtong¹, Osamu Togao¹, Masaya Takahashi¹, Jinming Gao¹

¹UT Southwestern Medical Center, Dallas, TX, United States

Here we report the use of αvβ3- targeted magnetofluorescent micellar nanoprobes that allowed detection of angiogenic tumor vessels by both fluorescent and magnetic resonance imaging methods. The αvβ3-targeting specificity and temporal tumor accumulation profiles were demonstrated in a human lung tumor xenograft model in nude mice using 3D gradient echo sequences and T2* - weighted dynamic contrast enhancement MRI over one hour.

                  1933.     Lectinized Liposomes for Multimodal in Vivo Molecular Imaging of the Tumor Endothelium

Arvind P. Pathak¹, Yoshinori Kato¹, Nicole Benoit¹

¹JHU ICMIC Program, Russel H. Morgan Dept. of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

Here we describe the development of dual contrast lectinized liposomes that improve our ability to image the structural and functional changes in tumor blood vessels using MRI and optical imaging. Limitations of conventional contrast-enhanced in vivo MRI include low spatial resolution because of relatively short circulation half-life of such agents, and loss of contrast due to extravasation from permeable tumor vessels. We developed a blood vessel-specific nanoparticle targeted to Bandeiraea Simplicifolia lectin, a carbohydrate-binding protein that binds to α-D-galactosyl residues on endothelial cells. MRI and optical imaging demonstrate that multi-modal, targeted liposomes greatly enhance our ability to characterize tumor angiogenesis.

                  1934.     Quantitative Molecular Imaging of Atherosclerotic Endothelial Dysfunction with Perfluorocarbon (19F) Nanoparticle Magnetic Resonance Imaging and Spectroscopy

Lei Zhang¹, Huiying Zhang¹, Kristin Bibee¹, Stacy Allen¹, Junjie Chen¹, Gregory M. Lanza¹, Samuel A. Wickline¹

¹Washington University School of Medicine, St. Louis, MO, United States

Disturbed endothelial barrier function in atherosclerosis has been detected by MRI by imaging gadolinium leakage into the vascular interstitium but not yet quantified. Alternatively, we propose that the unique, no background 19F signal from crown ether perfluorocarbon-core nanoparticles (NP: ~250 nm) might both visualize and quantify endothelial disruption in advanced atherosclerosis.For both advanced experimental atherosclerosis and native human atherosclerosis tissues, nontargeted NP rapidly penetrate the leaky endothelial barrier, which can be visualized and quantified ex vivo with the use of ¡°no background¡± 19F MRI and MRS. This experimental strategy offers a potential new approach for quantification of endothelial dysfunction employing both in vivo and ex vivo incubation with nanoparticle tracers.  

                  1935.     MRI-Guided Fluorescence Imaging of Glial Reactivity in Chronic Neuropathic Pain

Scott C. Davis¹, Lisa H. Treat, ¹², Edgar Alfonso Romero-Sandoval^2,3, Kimberley S. Samkoe¹, Brian W. Pogue¹, Joyce A. DeLeo^2,3

¹Thayer School of Engineering, Dartmouth College, Hanover, NH, United States; ²Department of Anesthesiology, Dartmouth College, Hanover, NH, United States; ³Department of  Pharmacology and Toxicology, Dartmouth College, Hanover, NH, United States

Glial reactivity plays an important role in the biochemical processes associated with acute and chronic pain and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. This study demonstrates the potential to image Glial Fibrillary Acidic Protein (GFAP) expression in the brains of rats after peripheral nerve injury using MR-guided fluorescence molecular tomography (MRg-FMT).  MRg-FMT images showed elevated GFAP expression in the brains of injured animals, indicating enhanced astrocytic reactivity as compared to control animals.  Quantitative imaging of glial reactivity in vivo would be an important innovation for investigating and deploying new treatment strategies that target glial mechanisms.

                  1936.     MR Molecular Imaging of HER-2 in a Murine Tumor Xenograft by SPIO Labeling of Anti-HER-2 Affibody.

Manabu Kinoshita¹, Yoshichika Yoshioka², Yoshiko Okita¹, Naoya Hashimoto¹, Toshiki Yoshimine¹

¹Department of Neurosurgery, Osaka University Medical School, Suita, Osaka, Japan; ²High Performance Bioimaging Research Facility, Osaka University, Graduate School of Frontier Biosciences, Suita, Osaka, Japan

In vivo molecular imaging is a rapidly growing research area both for basic and clinical science. Non-invasive imaging of in vivo conditions in a molecular level will help understand the biological characteristics of normal and diseased tissues without performing surgical invasive procedures. Among various imaging modalities, magnetic resonance imaging (MRI) has gained interest as a molecular imaging modality for its high special resolution. In this research, we have demonstrated that the combined use of HER-2 targeting Affibody, a small 7kDa molecule that behaves similarly to antibodies, and superparamagnetic iron oxide (SPIO) can non-invasively image HER-2 expressing cells or tissues both in vitro and in vivo by MRI. This preliminary study demonstrates that Affibody-SPIO is a feasible target specific contrast agent for in vivo MR-molecular imaging.

                  1937.     Creation of an Multimeric Anti-P53 ScTCR-SPIO Conjugate for the Detection of Cancer in MR

Richard Wong^1,2, Tian Liu^1,2, Xiao-Yun Zhu³, Hing C. Wong³, Yi Wang^1,4

¹Cornell University, Ithaca, NY, United States; ²Department of Radiology, Cornell University - Weill Medical College, New York, NY, United States; ³Altor Bioscience Corp, Miramar, FL, United States; ⁴Department of Radiology, Weill Medical College, New York, NY, United States

We have created an anti-p53 scTCR-SPIO for use as a generalized cancer detection contrast agent for use in MR.  In vitro models demonstrate the effectiveness of this molecule in labeling p53-expressing cells and suggests future application in in vivo cancer models.