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 Bulte1,4, 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.
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 Hitchens1,2, Parker H. Mills1,2, Lesley M. Foley1, John A. Melick3, Patrick M. Kochanek3,4, Eric T. Ahrens1,2, Chien Ho1,2
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. Jakob1,4, Karl-Heinz Hiller1,4, 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.
Christiane L. Mallett1,2, Catherine Ramsay1, Paula J. Foster1,2
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.
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.
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.
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.
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. Kodibagkar1,2
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.
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-Torres1,2, Robia G. Pautler1,2
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.
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. Chan1,2, G. Liu1,3, D.R. Arifin1,2, J. W.M. Bulte1,2, M.T. McMahon1,3
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. Kodibagkar1,2, Praveen Kumar Gulaka1, Federico Rojas-Quijano3, Zoltan Kovacs3, Ralph P. Mason, 12, A Dean Sherry2,3
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-Torres1,2, 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.
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 Sherry1,4
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. Tran1,2, Brian D. Ross1,2
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 Chang1,6
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 Liu1,2, Dayananda Kasala3, Tsung-Sheng Lin3, Chiao-Yun Chen1,4, Twei-Shiun Jaw1,2, Yu-Ting Kuo1,2, 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 Wang1,2, Martin Hossann1,2, Michael Peller3, Maximilian Reiser3, Rolf Dieter Issels1,2, Lars Hans Lindner1,2
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 Wilson1,2, Gilberto S. Almeida1,2, Andrew M. Blamire2, Kirsten H. Chalmers3, David Parker3, Ross J. Maxwell1,2
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 Liu2,3, Twei-Shiun Jaw2,3, Yu-Ting Kuo2,3, Chiao-Yun Chen2,3, 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 GdIII agents with medium molecular weight (~3-4 KDa) exhibit improved relaxivity values also at high fields. GdIII 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 GdIII 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.
Wendy Oakden1, Evelyn Ning Man Cheung2, R Scott Prosser, 2,3, Greg Jan Stanisz1,4
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.
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. French1,3, Frederick H. Epstein1,3
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.
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 Wolters1,2, Marlies Oostendorp1,3, Bram F. Coolen2, Mark J. Post3,4, Gustav J. Strijkers2, Klaas Nicolay2, Walter H. Backes1,3
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-Sandoval2,3, Kimberley S. Samkoe1, Brian W. Pogue1, Joyce A. DeLeo2,3
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 Wong1,2, Tian Liu1,2, Xiao-Yun Zhu3, Hing C. Wong3, Yi Wang1,4
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.