Molecular Imaging
 

Wednesday 3 June 2015

William Dominguez-Viqueira¹, Benjamin Geraghty^1,2, Justin Y.C. Lau^1,2, Albert P Chen³, and Charles H Cunningham^1,4
1Imaging Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, ²Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, ³GE Healthcare, Toronto, Ontario, Canada, ⁴Medical Biophyscis, University of Toronto, Toronto, Ontario, Canada

Roemer-optimal coil combination using a Biot-Savart numerical model of the sensitivity maps coefficients has been successfully used previously in ¹³C images of the heart. The Biot-Savart numerical estimation method was extended to the 8-channel receiver array that will be used in human studies. Results were compared to a low-pass-filter method and to sum of squares. Estimated coefficients using Biot-Savart resulted in better image quality than using a low-pass-filter of the acquired images. SNR improvements of up to a 100 % in areas closer to the base of the heart were demonstrated by using the Roemer reconstruction, as compared with sum-of-squares.

Ute Bommerich^1,2, Thomas Trantzschel¹, Markus Plaumann¹, Denise Lego², Gerd Buntkowsky³, Grit Sauer³, Torsten Gutmann³, Joachim Bargon⁴, and Johannes Bernarding^1
1Institute for Biometrics and Medical Informatics, Otto von Guericke University Magdeburg, Magdeburg, Saxony-Anhalt, Germany, ²Special Lab Non-invasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg, Saxony-Anhalt, Germany, ³Eduard-Zintl-Institute for Inorganic Chemistry, Technical University Darmstadt, Hesse, Germany, ⁴Institute for Physical and Theoretical Chemistry, University Bonn, North Rhine-Westphalia, Germany

Fluorinated bis(styryl)benzene derivatives can improve the MR detection of amyloid plaques, that are supposed to play an important role in the progression of Alzheimer´s disease. These molecules enable ¹⁹F-MRI experiments with optimal contrast only restricted by the concentration of the applied markers. An increase of MR-sensitivity by orders of magnitude makes Parahydrogen Induced Polarization (PHIP) a promising tool. It is demonstrated that hyperpolarization of ¹⁹F nuclei in molecules that are structurally closely related to amyloid markers is feasible. This leads to an in-phase signal with improved intensity which could be further increased by a field cycling step.

Markus Plaumann¹, Thomas Trantzschel¹, Jan Wüstemann¹, Denise Lego², Grit Sauer³, Torsten Gutmann³, Joachim Bargon⁴, Gerd Buntkowsky³, Johannes Bernarding¹, and Ute Bommerich^1,2
1Department for Biometrics and Medical Informatics, Otto-von-Guericke University Magdeburg, Magdeburg, Saxony-Anhalt, Germany, ²Special Lab Non-Invasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg, Saxony-Anhalt, Germany, ³Eduard-Zintl-Institute for Inorganic Chemistry, Technical University Darmstadt, Darmstadt, Hesse, Germany, ⁴Institute of Physical and Theoretical Chemistry, University Bonn, Bonn, North Rhine-Westphalia, Germany

The chemical inertness of fluorinated alkanes makes them ideal for in vivo application, e.g. molecular imaging. Here, the hyperpolarization of four semifluorinated substrates is presented by using the parahydrogen induced polarization (PHIP). 1H,1H,2H-perfluorohexane, 1H,1H,2H-perfluorooctane, 1H,1H,2H-perfluorodecane and perfluoro-(4-methylpentane) are chosen to demonstrate the polarization transfer from protons over a chain of CF₂ respectively CF groups to the end-standing CF₃ groups, which leads in a nonuniform distribution of the polarization. Additionally studies in presence of cyclodextrin derivatives show a molecular interaction between cyclodextrin and the lipophilic semifluorinated substrate. This allows the transport into an aqueous solution, which is important for biomedical applications.

Stephen DeVience¹ and Dirk Mayer^1
1Diagnostic Radiology, University of Maryland School of Medicine, Baltimore, MD, United States

While hyperpolarized 13C metabolic imaging permits real-time investigation of metabolism in vivo, it requires fast acquisition schemes. We implemented an iterative reconstruction algorithm based on low-rank matrix completion that exploits spatiotemporal correlations in incoherently undersampled, time-resolved data. The algorithm was applied to both retro- and prospectively undersampled dynamic spiral chemical shift imaging (spCSI) data by pseudo-randomly omitting spatial interleaves and the results were compared to conventional reconstruction. The presented data demonstrate that LRMC reconstruction in combination with incoherent undersampling permits substantial reduction in minimum acquisition time of dynamic spCSI without significantly compromising image quality.

Lucia F Giles¹, Vicky Ball¹, and Damian J Tyler^1
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, Oxfordshire, United Kingdom

Pyruvate dehydrogenase (PDH) is a key regulatory enzyme in cardiac metabolism and is activated by dichloroacetate (DCA). The effects of DCA on PDH and glycolytic flux were investigated in vivo and the perfused heart using hyperpolarized [¹³C]pyruvate and [³H]glucose. PDH flux was enhanced in vivo following acute and chronic DCA treatment. This was accompanied by a decrease in glycolytic flux and lactate production despite the increase in PDH flux. This suggests that either glucose is oxidised more efficiently when coupling between glycolysis and glucose oxidation is enhanced or that increased glucose oxidation leads to inhibition of glycolysis via a negative feedback pathway.

Rajat K Ghosh¹, Mehrdad Pourfathi¹, Stephen J Kadlecek¹, and Rahim R Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Synopsis: Hyperpolarized (HP) bicarbonate has been used to image pH in vivo. However, its utilization has been limited by difficulties in generating high polarizations and concentrations. In this work, we describe a new technique for generating HP bicarbonate by de-carboxylating HP pyruvate. HP bicarbonate produced in this manner is then used to image pH in rat lungs at sub-mm resolutions. Production of HP bicarbonate through direct polarization is currently limited to concentrations of ~100mM. In contrast, our indirect decarboxylation approach generates 100-400mM bicarbonate, further increasing signal to allow for high-resolution pH imaging.

Karlos X Moreno¹, Santhosh Satapati¹, Ralph J DeBerardinis², Shawn C Burgess¹, Craig R Malloy¹, and Matthew E Merritt^1
1Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States, ²Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, United States

Direct observation of hyperpolarized glucose from a gluconeogenic substrate has not previously been observed. Isolated mouse livers perfused in a gluconeogenic or glycogenolytic state were injected with hyperpolarized [2-¹³C]dihydroxyacetone. In each condition, hyperpolarized glucose signals were observed. Purified effluent glucose confirmed the enrichment. Minimal differences in hyperpolarized glucose signals between the two conditions were observed. Triose intermediates of glycolysis showed large differences, the glycogenolytic condition having greater signals. This is the first study to demonstrate direct gluconeogenesis using hyperpolarization methods.

Rolf F Schulte¹, Martin A Janich¹, Ulrich Koellisch^1,2, Markus Durst^1,2, Florian Wiesinger¹, Eliane Ferral², Markus Schwaiger², Axel Haase², and Marion I Menzel^1
1GE Global Research, Munich, Germany, ²Technical University, Munich, Germany

Hyperpolarised metabolic imaging suffers from low resolution, which can hamper quantification due to partial volume effects. In this work, we implement and evaluate Partial-Volume Correction (PVC), which is a correction method applied in Positron Emission Tomography. It is possible to improve spatial resolution characteristics at the boundaries of the object with PVC.

Angus Z Lau^1,2, Jack J Miller^2,3, and Damian J Tyler^1,2
1Department of Cardiovascular Medicine, University of Oxford, Oxford, Oxfordshire, United Kingdom, ²Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, Oxfordshire, United Kingdom, ³Department of Physics, University of Oxford, Oxford, Oxfordshire, United Kingdom

Arif Wibowo¹, Jae Mo Park², Ralph Hurd³, Graham F Sommer⁴, Chaitan Khosla⁵, and Daniel M Spielman^6
1arifw@stanford.edu, Stanford, CA, United States, ²Stanford, CA, United States, ³GE healthcare, CA, United States, ⁴Diagnostic Radiology, Stanford University, CA, United States,⁵Chemistry and ChEM-H, Stanford University, CA, United States, ⁶Radiology, Stanford University, CA, United States

In this study, we evaluated the potential of cysteine (Cys), N-acetyl cysteine (NAC), and Mercaptopyruvate (MCP as hyperpolarized 13C substrate for assessing oxidative stress (OS) in vivo. Of these, MCP was identified as a viable substrate for in vitro OS assessment, and we are currently developing large-scale MCP synthesis for testing the potential of this substrate for in vivo OS measurements.

Charlie J Daniels¹, Mary A McLean², Nicholas McGlashan¹, Martin J Graves¹, Fraser J Robb³, David J Lomas¹, Rolf F Schulte⁴, Kevin M Brindle², and Ferdia A Gallagher^1,2
1Department of Radiology, University of Cambridge, Cambridge, United Kingdom, ²Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom,³USA Instruments Inc., Aurora, Ohio, United States, ⁴GE Global Research, Munich, Germany

Hyperpolarized imaging with ¹³C-labelled endogenous molecules is on the verge of clinical translation. A simple, robust and objective method of quantitative analysis is required to process hyperpolarized data clinically, however there is currently debate over the best methods to apply. We assessed four quantitative methods by imaging conversion of [1-¹³C]pyruvate to [1-¹³C]lactate using a clinical polarizer system at 3 T and a pyruvate concentration predicted for future patient studies. We conclude that extracting data from a single voxel is sufficiently robust and suggest the area under the curve ratio be taken forward as a standardised clinical parameter.

Roha Afzal^1,2, Gary V. Martinez¹, and Robert J. Gillies^1
1Cancer Imaging and Metabolism, H.Lee Moffitt Cancer Centre, Tampa, Florida, United States, ²Chemical and Biomedical Engineering, University of South Florida, Tampa, Florida, United States

This study demonstrates the first application of 31P Dynamic Nuclear Polarization to the Phosphonates. The experimental conditions (glassing agents, radicals microwave irradiation frequencies, maximum polarization build-up time, etc.) were optimized for the hyperpolarization of Dimethyl Methyl Phosphonate. An in-vivo experiment was then carried out at these optimum conditions and the hyperpolarized 31P image and signal were observed in the animal.

Jian-Xiong Wang^1,2, Leila Fidelino³, Karlos Moreno³, A. Dean Sherry^3,4, Craig Malloy^3,5, and Matthew E Merritt^1,6
1AIRC, UT Southwestern Medical Center, Dallas, TX, United States, ²Radiology, UT Southwestern Medical Center, Dallas, TX, United States, ³AIRC, UT Southwestern Medical Center, TX, United States, ⁴Chemistry, University of Texas at Dallas, TX, United States, ⁵Internal Medicine, UT Southwestern Medical Center, TX, United States, ⁶Radiology, UT Southwestern Medical Center, Dallas, United States

Hyperpolarized [1-¹³C]pyruvate can be metabolized in the liver via flux through pyruvate dehydrogenase (PDH) or pyruvate carboxylase (PC). In normal rats, PDH dominates the generation of [¹³C]bicarbonate in vivo. The Zucker rat is a model of diabetes that displays high levels of hepatic gluconeogenesis. In fasting, [¹³C]bicarbonate production is maintained, contrary to the normal animal. Sources of the [¹³C]bicarbonate production (PDH versus PC) will be identified.

Lotte Bonde Bertelsen¹, Simon Lauritsen¹, Christoffer Laustsen¹, Preben Daugaard¹, Xiaolu Zhang¹, and Hans Stødkilde-Jørgensen^1
1The MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus University Hospital, Aarhus, Denmark

Development of a MR-compatible bioreactor system for measuring metabolic fluxes in cells grown in scaffold makes it possible to examine various cell types with different hyperpolarized ¹³C bio-probes. The 3D printed scaffold system facilitates a dynamic cell culture environment with controlled nutrient flow, oxygen supply and a large surface area for growth of adherent cells with minimal disturbance of the cells. Ongoing studies are focusing on evaluation of low cell numbers in scaffold and in suspension in this bioreactor design.

Ulrich Koellisch¹, Christoffer Laustsen², Thomas S. Nørlinger², Concetta V. Gringeri³, Marion I. Menzel⁴, Rolf F. Schulte⁴, Axel Haase¹, and Hans Stødkilde-Jørgensen^2
1Institute of Medical Engineering, Technische Universität München, Munich, Germany, ²MR Research Centre, Aarhus University, Aarhus, Denmark, ³Nuklearmedizinische Klinik und Poliklinik, Technische Universität München, Germany, ⁴GE Global Research, Munich, Germany

In the metabolism of acetate several enzymes are involved, which play an important role for free fatty acid oxidation. Therefore it might serve as a marker for pathological changes of cells' fuel selection in particular in the myocardium. The goal of this study was to investigate whether the ratio of acetylcarnitine to acetate could serve as a marker for myocardial, hepatic and renal metabolic changes under Streptozotocin induced diabetes in vivo.

Alfonso Mastropietro¹, Chiara Cordiglieri², Ilaria Tirotta^3,4, Francesca Baldelli Bombelli^3,4, Fulvio Baggi², Giuseppe Resnati^3,4, Pierangelo Metrangolo^3,4, Maria Grazia Bruzzone⁵, and Ileana Zucca^1
1Scientific Direction Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Milan, Italy, ²Neurology IV Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy,³Laboratory of Nanostructured Fluorinated Materials (NFMLab), Department of Chemistry, Materials, and, Politecnico di Milano, Milan, Italy, ⁴Fondazione Centro Europeo Nanomedicina, Milan, Italy, ⁵Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Milan, Italy

This work aims at the magnetic characterization of a novel superfluorinated 19F MRI contrast agent. Preliminary data on labeled Fibroblasts and T cells using a 7T MRI scanner are presented.

Hunter Mehrens¹, Tao Jin¹, and Seong-Gi Kim^1,2
1Radiology, University of Pittsburgh, Pittsburgh, PA, United States, ²Center for Neuroscience Imaging Research, Institue for Basic Science, SKKU, Suwon, Korea

Recent studies showed an increase of chemical exchange-sensitive spin-lock (CESL) MRI signal during administration of 2-deoxy-glucose (2DG) with high sensitivity. However, the toxicity of 2DG is a concern for its clinical and preclinical application. 3-O-methyl-D-glucose (3OMG) is a non-metabolizable glucose analogue with minimal toxicity, therefore, it may have better potential as a contrast agent for the study of glucose transport. In this work, we demonstrated that 3OMG has similar chemical exchange properties as 2DG and glucose, and unique advantages relative to 2DG and glucose for in vivo studies.

Mojmir Suchy¹, Alex X. Li², Robert Bartha², and Robert H. E. Hudson^1
1Department of Chemistry, University of Western Ontario, London, Ontario, Canada, ²Centre for Functional and Metabolic Mapping, University of Western Ontario, London, Ontario, Canada

A synthetic methodology has been developed for the preparation of Tm(III) complexes derived from DOTMA as new type of PARACEST MRI contrast agent. Agents were identified that possessed CEST peaks at chemical shifts beyond the frequency range of the endogenous macromolecule magnetization transfer. The CEST effects of these agents investigated were found to be sensitive to both temperature and pH.

Sonia Waiczies¹, Stefano Lepore¹, Min-Chi Ku¹, Helmar Waiczies^1,2, Conrad Martin¹, Susanne Drechsler¹, Karl Sydow³, Margitta Dathe³, Andreas Pohlmann¹, and Thoralf Niendorf^1
1Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Germany, Germany, ²MRI.Tools GmbH, Berlin, Germany, ³Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany

Magnetic resonance (MR) methods to detect and quantify fluorine nuclei provide the opportunity to study the fate of cellular transplants in vivo. Challenges pertaining to MR signal sensitivity and cell detection exist. This study addresses these issues by examining the uptake mediating potential of nanoparticles enriched with phosphatidylethanolamines to improve dendritic cell detection.

David E J Waddington^1,2, Mathieu Sarracanie^1,3, Huiliang Zhang^3,4, David Reilly², Ronald L Walsworth^3,4, and Matthew S Rosen^1,3
1MGH/A.A. Martinos Center for Biomedical Imaging, Charlestown, MA, United States, ²ARC Centre of Excellence for Engineered Quantum Systems, School of Physics, University of Sydney, Sydney, NSW, Australia, ³Department of Physics, Harvard University, Cambridge, MA, United States, ⁴Harvard-Smithsonian Center for Astrophysics, Cambridge, MA, United States

This work aims to develop a new bio-probe based on the detection and tracking of nontoxic nanoparticles in biological environments. We report the first DNP enhancement of 1H in a nanodiamond/water solution at very low magnetic field. Overhauser-enhanced MRI (OMRI) utilizes the nuclear hyperpolarization of hydrogen to detect paramagnetic species. A –1.36 times enhancement of the 1H signal has been demonstrated in a 10%/wt solution of 100 nm natural nanodiamonds (Microdiamant) and DI water at 6.5 mT. This result will drive further research into the use of OMRI methodologies as a means of tracking nanoparticles in vivo.

Shatadru Chakravarty^1,2, Lixin Ma¹, Lalit N. Goswami¹, Satish S. Jalisatgi¹, and M. Frederick Hawthorne^1
1Radiology, International Institute of Nano and Molecular Medicine-University of Missouri-Columbia, Columbia, MO, United States, ²Radiology, Michigan State University, East Lansing, MI, United States

The signal intensity and the overall detail and clarity of an image obtained in an MRI exam is enhanced spectacularly by the administration of chemical species known as Contrast Agent (CAs). Despite several years of research, the current batch of clinically approved CAs are mostly small molecular weight species that suffer from low relaxivity, poor tissue selectivity and extremely short intravascular half-lives. We herein report a novel class of CAs based on a closo-borane framework with multifold improvements in relaxivity. These multifunctional molecules are based on the novel and unique twelve-fold functionalization of closo-B12(OH)122- with a modified Gd- AAZTA chelate.

Miriam Filippi¹, Deyssy Patrucco¹, Jonathan Martinelli², Lorenzo Tei², Mauro Botta², and Enzo Terreno^1,3
1Department of Molecular Biotechnology and Health Sciences, Molecular Imaging Center, University of Turin, Turin, To, Italy, ²Department of Sciences and Technological Innovation, University of Eastern Piedmont 'A. Avogadro', Alessandria, Al, Italy, ³Center for Preclinical Imaging, University of Turin, Colleretto Giacosa, To, Italy

Vesicles composed of newly synthesized amphiphilic dendrimers were investigated to understand their effective applicative potential as theranostic tools, based on their biocompatibility, stability in biological environments and capability to encapsulate Magnetic Resonance Imaging (MRI) agents and drugs. Dendrimeric vesicles revealed to be extremely safe and appropriate for vascular administration, besides displaying a very high membrane water permeability, preserving the Longitudinal Relaxivity of encapsulated paramagnetic MRI probes from undesired quenching effects. Specifically, 3,5-C12-EG-(OH)4–based vesicles were provided with highest stability, becoming interesting candidates for further development as theranostic tools.

Francesca Garello¹, Sandip Vibhute², Serhat Gunduz², Nikos K Logothetis², Goran Angelovski², and Enzo Terreno^1
1University of Torino, Torino, Italy, ²Max Planck Institute for Biological Cybernetics, TŸbingen, Germany

This contribution reports a methodology that enables the preparation of paramagnetic liposomes loaded with an amphiphilic ligand capable to coordinate selectively and sequentially Gd(III) and Ca(II) ions, respectively. The presence of Gd(III) imparts the ability to generate MRI contrast, which is remarkably boosted (ca. 400%) by the coordination of Ca(II), thus improving the calcium responsiveness of the nanoprobes with respect similar agents previously investigated.

Lixia Huang¹, Chenggong Yan¹, Danting Cui¹, Xiang Liu¹, Xiaodan Lu¹, Yichen Yan², Xiangliang Tan¹, Jun Xu³, Yingjie Mei⁴, Xinwei Lu², Yikai Xu¹, and Ruiyuan Liu^2
1Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, ²School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China, ³Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, ⁴Philips Healthcare, Guangzhou, Guangdong, China

Polyacetylenes containing 2,2,6,6-tetramethyl-piperidinooxy and poly(ethylene glycol) conjugated with carboxyl fluorescein and folic acid (FA) are synthesized by metathesis polymerization of corresponding substituted acetylenes for targeted bimodal MRI /optical imaging of tumors. In vitro studies confirm excellent binding specificity and subsequent enhanced cellular internalization of the targeted ORCAs (PA-TEMPO-FI-FA). In vivo T1-weighted MRI and optical imaging demonstrate the active tumor targeting ability of PA-TEMPO-FI-FA to generate specific contrast enhancement in mice bearing HeLa tumors. These results indicate that the multifunctional ORCAs may provide a tumor-targeted delivery platform for further molecular imaging guided cancer therapy.

Alex John Taylor¹, James Lee Krupa², Huw Williams³, Dorothee P Auer¹, Simon R Johnson⁴, Neil R Thomas², and Henryk Michael Faas^1
1Sir Peter Mansfield Imaging Centre, School of Medicine, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom, ²School of Chemistry, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom, ³Centre for Biomolecular Sciences, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom, ⁴School of Medicine, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom

A novel chemical sensor is presented which is able to detect matrix metalloproteinases (MMPs) using ¹⁹F MR. The contrast mechanism uses an “on/off” principle with paramagnetic gadolinium linked to a fluorine source via an enzyme substrate. Two examples of synthesised sensors are shown; one for MMPs 2 and 9, the other for all types of MMP. Upon addition of MMP 9, both sensors show an increased T₁ relaxation time due to enzymatic cleavage which causes an increase in the fluorine-gadolinium distance. Fluorine signal intensity is also increased by a factor of 3.5 after MMP addition.

Ina Vernikouskaya^1,2, Alexander Pochert³, Mika Linden³, and Volker Rasche^1,2
1Internal Medicine II, University Hospital of Ulm, Ulm, Baden-Wuerttemberg, Germany, ²Small Animal MRI, University of Ulm, Ulm, Baden-Wuerttemberg, Germany, ³Inorganic Chemistry II, University of Ulm, Ulm, Baden-Wuerttemberg, Germany

19F offers great potential for in vivo quantification without any background signal. Perfluorocarbons (PFC) are typically applied due to their high 19F density. Mesoporous amorphous silica nanoparticles have attracted a lot of interest as drug carriers. However more attractive particle architecture would be hollow spheres with a porous shell that would allow higher PFC loadings per particles. 250nm-sized hollow mesoporous silica spheres (HMSS) are loaded with perfluoro-15-crown-5-ether (PFCE) and evaluated as a new contrast agent. PFCE-HMSS was characterized using MRI. 19F MRS was performed for quantification of the fluorine load. A good fluorine signal localized in the liver and in the brown fat was detected in vivo.

Xiang Liu¹, Xiaodan Lu¹, Chenggong Yan¹, Danting Cui¹, Yichen Yan², Xinwei Lu², Queenie Chan³, Jun Xu⁴, Yikai Xu¹, and Ruiyuan Liu^2
1Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, ²School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China, ³Philips Healthcare, HongKong, China, ⁴Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

Multifunctional and folate (FA) modified gadolinium oxide (Gd2O3) nanocarriers were developed for targeted molecular MRI of FA receptor positive HeLa tumors. Gd2O3-based nanoparticles were conjugated with 5(6)-carboxyfluorescein (FI) for fluorescence and functionalized with poly(ethylene glycol) (PEG) segments bearing FA group. Enhanced cellular uptake of the targeted Gd2O3 nanocarriers in Hela tumor cells was observed.in vitro. Moreover, the targeted Gd2O3 naoparticles showed more remarkable contrast enhancement than the control probes according in vivo MRI. Thus, these Gd2O3 nanoparticles may be a promising nano-platform for combined targeted antitumor drug delivery and molecular MRI cancer diagnosis in future clinical applications.

Jing Huang^1,2, Liya Wang^1,2, Hui Wu^1,2, Lily Yang³, and Hui Mao^1,2
1Laboratory of Functional-Molecular Imaging and Nanomedicine, Emory University School of Medicine, Atlanta, GA, United States, ²Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, United States, ³Surgery, Emory University, Atlanta, GA, United States

Engineered nanoparticles are delivered to the tumor mainly through the enhanced permeability and retention (EPR) effect, which is dependent on and limited by nanoparticle size. Here we report ultrafine iron oxide nanoparticles (uIONPs) with a core diameter of 3.5 nm and dual T1-T2 contrast to facilitate the EPR effect for improved MRI and drug delivery. uIONPs are highly dispersed in circulation but can undergo reversible self-clustering at pH below 7, when entering tumor interstitial space, leading to switching from bright T1 contrast to dark T2 contrast while promoting tumor accumulation by 1.6 fold compared to nanoparticles with larger sizes.

Veronika Mamaeva^1,2, Tina Pavlin^3,4, Didem Sen Karaman⁵, Diti Desai⁵, Melanie Ostermann¹, Jessica Rosenholm⁵, and Emmet McCormack^1,2
1Department of Clinical Science, Hematology Section, University of Bergen, Bergen, Norway, ²Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway, ³Department of Biomedicine, Molecular Imaging Center, University of Bergen, Bergen, Norway, ⁴Department of Radiology, Haukeland University Hospital, Bergen, Norway, ⁵Laboratory of Physical Chemistry, Åbo Akademi University, Turku, Finland

A novel mesoporous silica nanoparticle MRI probe with theranostic prospects for targeted drug delivery was developed and applied to imaging of subcutaneous tumors in mice. Animals were injected either with Gd-doped MSNPs, pristine MSNPs, or Dotarem, and T1-weighted RARE images were collected pre- and at various time points post contrast injection. We observed a slight, but significant, increase of SI on T1-weighted images of GadoNPs-treated tumors at 24 hours. Conclusion: Gd–doped MSNPs are retained for at least 96 hours in tumor tissue and can be visualized by MRI, suggesting feasibility of using this NP platform for future theranostic applications.

Hirotada G Fujii¹, Miho C Emoto¹, Mayumi Yamato², and Ken-ichi Yamada^2
1Center for Medical Education, Sapporo Medical University, Sapporo, Hokkiado, Japan, ²Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

Seizure-induced neuronal death is thought to be caused by oxidative stress resulting from generation of reactive oxygen species (ROS). The purpose of this study was to examine the effect of oxidative stress in a pentylenetetrazol (PTZ)-induced seizure mouse model using a redox-sensitive nitroxide, 3-methoxycarbonyl-PROXYL, and to visualize brain redox status by noninvasive EPR imaging. In particular, a remarkable change in redox status in hippocampus of kindled mice was detected by EPR. An in vitro assay showed decreased concentrations of glutathione in the hippocampus after repeated seizures. Both results supported the involvement of ROS generation in epileptic-seizure mouse brain.

Run Lin^1,2, Jing Huang¹, Liya Wang¹, Yuancheng Li¹, Prieto Ventura Veronica E¹, Kevin Kim¹, and Hui Mao^1
1Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, United States, ²Department of Radiology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China

Vascular endothelial growth factor (VEGF) plays a pivotal role in the cascade of development and progression of cancers by promoting angiogenesis. Targeting this biomarker would be a logical strategy for imaging based cancer detection and anti-angiogenesis treatment. Bevacizumab is a recombinant humanized monoclonal antibody directly against VEGF and is currently used in clinic for treating various cancers with VEGF overexpression. In this study, a VEGF targeted molecular imaging probe was developed by conjugating near infrared dye (NIR830) labeled bevacizumab to magnetic iron oxide nanoparticles (IONP) for optical and magnetic resonance (MR) imaging of cancers overexpressing VEGF.

Manasmita Das¹, Heather K Decot¹, Yu-Chieh Kao¹, Oyarzabal Esteban¹, and Yen-Yu Ian Shih^1
1Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

The advent of novel genetic tools has triggered a renaissance in neuroscience research, providing tremendous opportunities to study the neuronal correlates of complex brain function with high spatiotemporal control. This study offers the first, direct evidence of fMRI responses to pharmacogenetic activation of excitatory neurons in rat primary motor cortex (M1) using Gq-coupled Designer Receptors Exclusively Activated for Designer Drugs (DREADDs). This novel technology contributes a potent toolbox for noninvasive mapping of GPCR-mediated cell signaling in vivo, a critical insight of which is necessary to understand various physiological and molecular phenomena and thus broaden the range of new therapeutic interventions.

Jens T Rosenberg^1,2, Kristen MJ Ahlschwede^3,4, Edward K Agyare⁵, Geoffery L Curran⁴, Samuel C Grant^1,2, and Karunya K Kandimalla^3,4
1National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL, United States, ²Chemical & Biomedical Engineering, Florida State University, Tallahassee, FL, United States, ³Pharmaceutics and Brain Barriers Research Center, University of Minnesota, Minneapolis, MN, United States, ⁴Neurology, Neuroscience and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, United States, ⁵College of Pharmacy and Pharmaceutical Science, Florida A&M University, Tallahassee, FL, United States

This work demonstrates a novel MRI-detectable multifunctional nanoparticle targeting cerebrovascular amyloids by conjugating Gd-DTPA with the amyloid antibody Ig 4.1 while at the same time providing drug delivery capabilities. This theranostic nanovehicle shows hypointense contrast for targeted cerebrovascular amyloids on MR microimages acquired at the ultrahigh field of 21.1 T. The approach potentially can provide a heretofore sought after diagnostic and therapeutic tool for cerebral amyloid angiopathy.

Zheng Han¹, Zhuxian Zhou¹, Maneesh Gujrati¹, and Zheng-Rong Lu^1
1Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States

This work uses ZD2-(HP-DO3A), a peptide-based targeting agent, for MRI molecular imaging of cancer metastasis. Accuracy and sensitivity of cancer metastasis imaging can be improved due to the sensitive targeting of this imaging agent to EDB fibronectin.

Yuancheng Li^1,2, Hongyu Zhou³, Run Lin^1,2, Liya Wang^1,2, Jing Huang^1,2, Hui Wu^1,2, Lily Yang³, and Hui Mao^1,2
1Laboratory of Functional-Molecular Imaging and Nanomedicine, Emory University School of Medicine, Atlanta, Georgia, United States, ²Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, United States, ³Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, United States

Biomarker-targeted pancreatic tumor imaging has been investigated by MRI using the anti-biofouling iron oxide nanoparticle (IONP) previously developed in our group. This nanomaterial demonstrated an excellent anti-biofouling effect to prevent the formation of protein corona and the non-specific cellular uptake. As a consequence of the excellent anti-biofouling property, PEG-b-AGE coated IONP conjugated with targeting ligands showed significantly improved targeting specificity and efficiency by reducing off-target and non-specific interactions with biological media. After systemic administration of IGFR targeted IGF-IONP and non-targeted BSA-IONP, in vivo MRI showed 44% and 21% signal intensity drop in pancreatic tumor.

Amerigo Pagoto¹, Rachele Stefania², Francesca Garello², Francesca Arena², Giuseppe Digilio³, Silvio Aime², and Enzo Terreno^2
1University of Torino, Torino, Italy, ²University of Torino, Italy, ³University of Eastern Piedmont, Italy

Imaging inflammation is still a hot topic for its relevance in both diagnosis and therapeutic fields. To overcome the poor sensitivity in the detection of MRI contrast agents, we target the intravascular inflammation-associated receptors VCAM-1 (Vascular Cell Adhesion Molecule-1) that are involved in the recruitment of immune cells from blood to the inflammation site. To further increase sensitivity, micellar nanoparticles containing a high number of Gd(III) complexes were prepared. Such micelles, which exposed the MRI agents, a specific peptide targeting VCAM-1, and a fluorescent dye for histological validation, were successfully tested on mouse models of peripheral, and brain inflammation.

Chieh-Yin Chang¹, Chi-Ru Lai¹, Bor-Show Tzang², Vincent Chin-Hung Chen³, Yeu-Sheng Tyan^1,4, and Jun-Cheng Weng^1,4
1School of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan, ²Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan, ³Department of Psychiatry, Chung Shan Medical University Hospital, Taichung, Taiwan, ⁴Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan

The spontaneously hypertensive rat (SHR) is the best-validated animal model of attention-deficit hyperactivity disorder (ADHD) based on behavioral, genetic, and neurobiological data. The symptoms of this common disorder include difficulty controlling behavior and over-activity. Manganese-enhanced MRI (MEMRI) uses manganese ion (Mn2+) as the contrast agents by shortening the spin-lattice relaxation time constant (T1) and entering the voltage-gated calcium channels in active neurons. It enables visualization of neuronal tracks, and enhance the capacity of MRI to provide functional information of the localization of brain activity. In the study, we tried to establish a working protocol to map the motor cortex of ADHD rats, and compared the functional brain mapping between ADHD and normal Wistar-Kyoto (WKY) rats by MEMRI method. In the results, we have mapped ADHD motor cortex using MEMRI and have shown the difference of the manganese enhanced cortical and thalamic regions between ADHD and WKY rats.

Chien-Lin Yeh^1,2, Eric Ward¹, Sandy Snyder¹, Frank Rosenthal¹, and Ulrike Dydak^1,2
1School of Health Sciences, Purdue University, West Lafayette, Indiana, United States, ²Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, United States

High exposure to manganese (Mn) causes motor impairments closely resembling Parkinson’s disease. Using R1 relaxation rate mapping we investigated the relationship between Mn deposition in the brain of welders with Mn accumulation in toenails. A significant correlation was found between R1 and Mn exposure in the past 3 months, but no correlation was found between toenail Mn and R1. Since toenail Mn is known to best reflect exposure 7-12 months ago, our results demonstrate that R1 in certain brain regions and toenail Mn accumulation may both serve as biomarkers of exposure to Mn, reflecting different time periods of exposure.

Nikorn Pothayee¹, Diana Cummings², Timothy Schoenfeld³, Heather Cameron³, Leonardo Belluscio², and Alan Koretsky^1
1Laboratory of functional and molecular imaging, NINDS, NIH, Bethesda, MD, United States, ²Developmental neural plasticity section, NINDS, NIH, Bethesda, MD, United States,³Neuroplasticity Section, NIMH, NIH, Bethesda, MD, United States

Olfactory bulb displays remarkable plasticity and its volume changes have been implicated in many CNS pathologies such as Alzheimer’s and Parkinson’s diseases. Understanding factors that play role in regulating the OB and its size may yield insights into the OB plasticity. In this work, we utilize longitudinal cellular MRI in combination with transgenic animal model of adult neurogenesis to study interplaying effects of olfactory input level and neurogenesis on the dynamic volume changes of the olfactory bulb.

Wassef Khaled¹, Benjamin Leporq¹, Jing Hong Wan¹, Philippe Garteiser¹, Simon Auguste Lambert¹, Nathalie Mignet², Bich-Thuy Doan², Simona Manta², Sophie Lotersztajn¹, and Bernard Edgar Van Beers^1
1Center of research on inflammation, Paris 7 University; INSERM U1044, Paris, France, ²Chemical, Genetic and Imaging Pharmacology Laboratory; CNRS UMR 8151; INSERM U1022, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Chimie-ParisTech, Paris, France

This work aims at distinguishing pro and anti-inflammatory (M1 and M2) macrophages with relaxometry and QSM using the degree of phagocytosis of gadolinium liposomes and superparamagnetic iron oxide particles as imaging biomarker. At relaxometry and QSM, M1 macrophages showed higher R2*and susceptibility, indicating higher particle uptake, as confirmed by confocal microscopy. These results show that it is feasible to distinguish between M1 and M2 macrophages with relaxometry and QSM, making phagocytosis of magnetic particles a potential MRI biomarker of inflammation.

Gary Stinnett¹, Kelly Ann Moore¹, Errol Loïc Samuel², Ming Ge³, Brett Graham³, James Tour², and Robia G Pautler^1
1Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States, ²Department of Chemistry, Rice University, Houston, Texas, United States,³Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States

Due to their paramagnetic properties, increased production of superoxide and hydroxyl radicals can cause decreases in T1 relaxation. Animals with increased superoxide and hydroxyl radical production will have lower T1 values in the liver compared to wild type controls. To determine that T1 reduction is due specifically to increased superoxide and hydroxyl radicals, animals were then treated with superoxide scavenging PEG-HCCs. These particles rendered the superoxide and hydroxyl anions inert, increasing T1 values to that of wild type controls. We therefore demonstrate that it is possible to use MRI in conjunction with PEG-HCCs to measure in vivo ROS levels.

Hyeyoung Moon¹, Jongeun Kang², Hyunseung Lee¹, and Kwan Soo Hong^1,2
1Division of MR research, Korea Basic Science Institute, Cheongju, Chungcheongbuk-do, Korea, ²Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea

In our study, we investigated whether MNP-enhanced MRI could distinguish between the severe inflammatory sites, weak inflammatory sites, and normal tissues within 12 h after injection of MNPs having long blood-circulation time using myocardial inflammation induced rat models.

Wen Hong¹, Qun He², Hongda Shao², and Jiang Du^2
1Radiology, China-Japan friendship hospital, Beijing, Beijing, China, ²Radiology, UC, San Diego, San Diego, CA, United States

The purpose of this study was to compare 3D-MP-RAGE and UTE sequences for morphological and quantitative imaging of iron.3D MP-RAGE sequence can be used to generate high contrast for lower iron concentration (0.1 to 10 mM), while IR-UTE, especially 3D IR-Cones sequences can be used to imaging iron with higher concentration (0.1 to 30 mM) .

Roberto Colotti^1,2, Christine Gonzales³, Juerg Schwitter³, and Ruud B. van Heeswijk^1,2
1Department of Radiology, University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland, ²Center for Biomedical Imaging (CIBM), Lausanne, Switzerland,³Division of Cardiology and Cardiac MR Center, Department of Internal Medicine, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

The relaxation times of a perfluoropolyether perfluorocarbon (PFC) that is used for fluorine-19 MRI were determined on a 3T clinical scanner under different physiological conditions. The results were used in Bloch equation simulations to optimize a turbo spin echo (TSE) pulse sequence and to evaluate the loss of acquisition efficiency due to the varying relaxation times observed under different physiological conditions.

Allegra Conti¹, Massimo Caulo^1,2, Angelo Galante³, Vittorio Pizzella^1,2, Gian Luca Romani^1,2, and Stefania Della Penna^1,2
1Department of Neuroscience, Imaging and Clinical Sciences, G. D'Annunzio Univ. of Chieti and Pescara, Chieti, CH, Italy, ²Institute for Advanced Biomedical Technologies (ITAB), G. D'Annunzio Univ. of Chieti and Pescara, Chieti, CH, Italy, ³MESVA, Department of Life, Health & Environmental Sciences, L'Aquila University, L'Aquila, AQ, Italy

Gadolinium based Contrast Agents are routinely used in MRI to improve the diagnostic accuracy of brain pathologies. Recently, Very and Ultra Low Field-MRI scanners have been developed, and the advantages of these system in the study of tissue contrast have been suggested. Here we show how the contrast of T1-weighted images of different concentrations of MultiHance and Gadovist changes varying the applied field (8.9 mT, 0.2 T, 1. 5 T ,3 T). Results demonstrate that signal contrast does not improve at high field strengths, and that longitudinal relaxation rate-maps at ULF are the best instruments to distinguish different Gd-concentrations.

Nikita Oskolkov^1,2, Xiaolei Song^1,2, Kannie W.Y. Chan^1,2, Jeff W.M. Bulte^1,2, and Michael T. McMahon^1,2
1The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, Maryland, United States, ²F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, United States

Cell transplantation is an important strategy for treating otherwise incurable diseases, with numerous clinical trials now ongoing all over the world. Various biocompatible materials have been designed to support transplanted cells and protect them from the immune system. Our previous study showed that alginate-based hydrogels could be used for non-invasive monitoring of hepatocytes cell death in vivo using pH sensitive CEST magnetic resonance imaging (MRI) technique. In this study we were interested in redesigning these for use on lower field scanners, through incorporating salicylic acid (SA)-based pH-nanosensors into the biomaterial through dispersing SA-liposomes through alginate capsules. These SA agents display CEST contrast at high-frequency-offsets. In this abstract we show how these can be used for non-invasive MRI imaging of encapsulated cells.

Donna H Murrell^1,2, Fiona Dickson¹, Amanda M Hamilton¹, and Paula J Foster^1,2
1Imaging, Robarts Research Institute, London, Ontario, Canada, ²Medical Biophysics, Western University, London, Ontario, Canada

Monitoring the fate of dormant cancer cells is important because these provide a reservoir of viable cells that contribute to relapse, even after treatment appears successful. Here, we demonstrate that iron-based MRI cell tracking can be used to study nonproliferative cancer cells in metastatic and primary cancer models. We present 3D MRI of the mouse brain illustrating persisting signal voids over time and show these represent nonproliferative cancer cells. This work shows varying dormancy profiles in cancer, and the ability for nonproliferative cells to persist through therapy. Understanding this dormant cell population is vital to prevent tumor recurrence in patients.

Jinjin Zhang¹, Sidath C. Kumarapperuma², Katie Hurley³, Hattie L. Ring³, and Michael Garwood^1
1Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States, ²Department of Medicinal Chemistry, University of Minnesota, MN, United States, ³Department of Chemistry, University of Minnesota, MN, United States

Cell-based therapies have received much attention as novel therapeutics for the treatment of cancer and autoimmune disease. In this study, T-cells labeled with superparamgnetic iron oxide nanoparticles (SPION) at different concentrations were quantified using the SWIFT Look-Locker T1 mapping method. The longitudinal relaxation rate constant (R1) measured by SWIFT showed a linear dependence on the concentration of SPION in T-cells. These preliminary results indicate a potential role for positive contrast from SWIFT as a means to quantify the distribution of SPION-labeled cells, provided the cells are incubated at a constant SPION concentration.

Corby Fink^1,2, Jeffrey Gaudet^2,3, Paula Foster^2,3, and Gregory Dekaban^1,2
1Microbiology and Immunology, Western University, London, Ontario, Canada, ²Robarts Research Institute, London, ON, Canada, ³Medical Biophysics, Western University, London, ON, Canada

A critical aspect of cell-based therapies involving engineered primary cells is knowledge of the location, number and persistence of therapeutic cells following injection. With respect to antigen presenting cell-based cancer vaccines, tracking and quantification of their in vivo migration to a secondary lymphoid organ can be used to not only assess the effectiveness of the vaccine, but also to compare the effectiveness of different vaccine formulations. Our laboratory has efficiently labeled human peripheral blood mononuclear cells with a Fluorine-19 perfluorocarbon cell-labeling agent, which permits their in vivo detection and quantification in a mouse model.

Dan Mu¹, Hong Ming Yu², Bin Zhu³, Biao Xu⁴, and Wei Bo Chen^5
1Drum Tower Hospital, Nanjing, Jiangsu, China, ²Drum Tower Hospital, Jiangsu, China, ³Radiology, Drum Tower Hospital, Nanjing, Jiangsu, China, ⁴cardiology, Drum Tower Hospital, Jiangsu, China, ⁵Philips Healthcare, Shanghai, China

The present study in vivo detect the homing and migration ability of MSCs overexpressing ILK (ILK-MSCs) after transplantation via coronary in swine model of AMI using MR molecular imaging technique.

Emily Alexandria Waters¹, Luke Vistain², Liang Mu³, Madhavi Puchalapalli⁴, Chad Haney¹, Basma El Haddad⁴, Brandon Parker³, Thomas Meade⁵, and Jennifer Koblinski^4
1Center for Advanced Molecular Imaging, Northwestern University, Evanston, IL, United States, ²Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL, United States, ³Northwestern University, IL, United States, ⁴Pathology, Virginia Commonwealth University, Richmond, VA, United States, ⁵Chemistry, Northwestern University, Evanston, IL, United States

Though improved treatment of primary breast cancers has increased patient survival, those diagnosed with brain metastases typically survive only 2-16 months. Understanding mechanisms of breast cancer metastasis to the brain should improve patient outcomes. We modeled metastasis in mice with intracardiac injection of bioluminescent breast cancer cells that had been labeled with iron oxide nanoflowers. We used IVIS to screen for successful cell delivery to the brain and then MRI to track the labeled cells for 7 days after their arrival in the brain.

Kai D. Ludwig¹, Myriam Bouchlaka², Jeremy Gordon¹, Christian Capitini², and Sean B. Fain^1,3
1Medical Physics, University of Wisconsin-Madison, Madison, WI, United States, ²Pediatrics and Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States, ³Radiology and Biomedical Engineering, University of Wisconsin-Madison, WI, United States

A current unmet need in cellular-based immunotherapies is longitudinal tracking and quantification of cells after infusion into a patient. Previously, human natural killer (hNK) cells have successfully been intracellularly labeled with a perfluoropolyether (PFPE) enabling in vivo detection and longitudinal tracking by ¹⁹F MRI. Here, a labeling concentration of 4mg/mL PFPE resulted in hNKs with 3.60.510^11 19F/cell. A minimum detection limit was extrapolated to be 1.210⁵ hNKs/voxel at 4.7 T. In vivo quantification on a tumor-bearing mouse showed intratumorally localized ¹⁹F signal over 7 days with 60-70% of the initially injected hNK cells being detected at all time points.

May A Taha¹, Roman Krawetz², Derrick E Rancourt², John R Matyas³, and Jeff F Dunn^1
1Department of Radiology, Calgary, Alberta, Canada, ²Department of Biochemistry & Molecular Biology, Alberta, Canada, ³Department of Comparative Biology and Experimental Medicine, Faculties of Medicine and Veterinary Medicine, University of Calgary, Alberta, Canada

Stem cell therapies show significant promise for stimulating healing of bone injury, but nothing is known of how stem cells migrate after implant. We developed a successful iron labeling protocol for embryonic stem cells. We proved it is possible to track ESC’s using 9.4T MRI in a mouse bone injury model and showed that cells migrated to the marrow and to a second injury site. We are the first to image ESC migration in bone injury and, as we did this in mice, it opens the possibility of using the range of mouse models available to study bone injury

Linshan Liu^1,2, Neil Gelman^1,2, Rebecca McGirr¹, R. Terry Thompson^1,2, Frank S Prato^1,2, Lisa Hoffman^1,2, and Donna E Goldhawk^1,2
1Imaging program, Lawson Health Research Institute, London, Ontario, Canada, ²Medical Biophysics, Western University, London, Ontario, Canada

MRI-based cell tracking techniques play an important role in developing cellular therapy. To improve these detection methods, we have examined MR measures of iron contrast in the P19 cell model. We measured the changes in apparent susceptibility (χa) and transverse relaxation rates (R2*, R2', R2) in cells cultured in the presence and absence of iron supplementation. Cellular iron content was determined using inductively-coupled plasma mass spectrometry and normalized to the amount of protein. The change in transverse relaxation rates showed a stronger correlation to iron levels than did the change in apparent susceptibility.

Laura C Rose¹, Guan Wang¹, Brooke M Helfer², Charles F O'Hanlon², Amnon Bar-Shir¹, Dara L Kraitchman¹, Ricardo L Rodriguez³, and Jeff WM Bulte^1
1Johns Hopkins University, Baltimore, MD, United States, ²Research & Development, Celsense Inc, PA, United States, ³CosmeticSurg LLC, Luthersville, MD, United States

Labeling cells with perfluorinated carbons allows tracking with ¹⁹F-MRI in vivo. As part of clinical trial NCT02035085 and FDA IND submission, we labeled adipose-derived stromal vascular fraction (SVF) cells and determined uptake in cell subtypes. The majority (87-92%) of CD31+ and CD34+ stem cells were labeled but only 47% of CD45+ cells, highlighting SVF cell heterogeneity. With a 3T clinical set-up and ¹⁹F content of 10¹² atoms/cell, 2x10⁶ cells were detected in a breast phantom 5mm below the surface. With 1x10⁸ SVF cells for breast reconstruction, this sensitivity will be sufficient to track transplanted SVF cells in breast cancer survivors.

Natarajan Raghunand¹, Jan Scicinski², Bryan Oronsky², Bhumasamudram Jagadish³, Eugene A Mash³, and Ronald L Korn^4
1Cancer Imaging & Metabolism, Moffitt Cancer Center, Tampa, Florida, United States, ²RadioRx Pharmaceuticals, Mountain View, California, United States, ³Dept. of Chemistry & Biochemistry, The University of Arizona, Tucson, Arizona, United States, ⁴Imaging Endpoints LLC, Scottsdale, Arizona, United States

We have investigated the kinetics of T1-shortening produced in 3 pre-clinical tumor xenograft models by Gd-LC7-SH, a DOTA-thiol complex of gadolinium. Mice were imaged before and at multiple time points following treatment with RRx-001, a novel anticancer agent that perturbs tumor redox status. Gd-LC7-SH spontaneously binds to macromolecular thiol targets following i.v. administration, producing prolonged shortening of tumor T1 in untreated animals. Following treatment with RRx-001 the washout of Gd-LC7-SH from tumors was markedly faster, consistent with the proposed glutathione-depleting mechanism of action of the drug. Use of Gd-LC7-SH-enhanced MRI as a pharmacodynamic marker of RRx-001 action is discussed.

Nadia Rose Ayat¹, Rebecca Schur¹, and Zheng-Rong Lu^1
1Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States

Utilizing mild hyperthermia (40-42°C ) has the potential to increase blood flow into tumors, and thus overcome some of the barriers to drug delivery. This study utilizes MRI to determine the effect of ultrasound-induced mild hyperthermia on the uptake of a paramagentically labeled polymer conjugate. The results of this study show that contrast enhancement increased two-fold upon the induction of hyperthermia in the tumor periphery. A five-fold increase in contrast enhancement was also seen in the tumor intersitium. This work suggests that mild hyperthermia has the potential to enhance the therapeutic efficacy of drugs in development for cancer treatment.

Yiyi Ji¹, Helmar Waiczies^1,2, Lukas Winter¹, Pavla Neumanova¹, Daniela Hofmann¹, Jan Rieger^1,2, Ralf Mekle³, Sonia Waiczies¹, and Thoralf Niendorf^1,4
1Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Germany, ²MRI.TOOLS GmbH, Berlin, Germany, ³Medical Physics, Physikalisch-Technische Bundesanstalt, Berlin, Germany, ⁴Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center, Berlin, Germany

The sensitivity limit for ¹⁹F detection constitutes an impediment for translational research and clinical applications of in vivo ¹⁹F MR. This limitation could be overcome by sensitivity gain at UHF. This work proposes a double-tuned ¹H/¹⁹F Tx/Rx RF coil array tailored for knee imaging to examine the feasibility of human ¹H/¹⁹F MR at 7.0 T. The suitability of the proposed approach for ¹⁹F MR following topical application of a fluorinated drug is demonstrated.

Matthew Tarasek¹, Amanda Aleong^2,3, Jinzi Zheng^2,3, Yannan Dou⁴, Christine Allen^3,4, David Jaffray^3,4, Tom Foo¹, and Desmond T.B. Yeo^1
1MRI, GE Global Research, Niskayuna, NY, United States, ²Princess Margaret Cancer Centre, Toronto, Canada, ³Techna Institute, University Health Network, Toronto, Canada,⁴University of Toronto, Toronto, Canada

Current innovations in the field of advanced drug delivery are focused on the development of new systems that can (i) trigger drug release at the tumor sites, (ii) avoid drug deposition in non-target tissues, and (iii) allow for quantitative measurement of drug dose to the target tissue. Here we report a pilot evaluation of a novel MR image-guided radiofrequency (RF) hyperthermia-mediated drug delivery platform. Results indicate that the MR body coil provides adequate image quality for monitoring drug release in the current setup, despite its inherent limitations in image acquisition speed and SNR when compared to surface-coil arrays.

Hattie L. Ring^1,2, Katie R. Hurley², Michael Etheridge^3,4, Jinjin Zhang^1,5, Nathan D. Klein², Connie Chung^3,4, Qi Shao⁴, John C. Bischof^3,4, Christy L. Haynes², and Michael Garwood^1,6
1Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States, ²Chemistry, University of Minnesota, Minneapolis, MN, United States,³Mechanical Engineering, University of Minnesota, Minneapolis, MN, United States, ⁴Biomedical Engineering, University of Minnesota, Minneapolis, MN, United States, ⁵Physics, University of Minnesota, Minneapolis, MN, United States, ⁶Radiology, University of Minnesota, Minneapolis, MN, United States

Iron oxide nanoparticles (IONPs) have great potential as diagnostic and therapeutic agents in cancer and other diseases; however, their utility is limited by biological aggregation and a short T₂. We implement the incorporation of a functionalized mesoporous silica (ms) shell combined with sweep imaging with Fourier transform MRI. This enables the practical use of IONPs as a T₁ contrast agent in vitro and in vivo, which is demonstrated in lymph node carcinoma of prostate cells and tumors. Colloidal stability and minimal non-specific cell uptake allowed for effective heating in biological suspensions and strong signal enhancement in MRI in vivo.

Felix C Horn¹, Helen Marshall¹, Richard Kay², Christopher E Brightling³, Juan Parra-Robles¹, and Jim M Wild^1
1Academic Radiology, Sheffield University, Sheffield, South Yorkshire, United Kingdom, ²Novartis, Switzerland, ³University of Leicester, United Kingdom

Sensitive regional methods to assess efficacy of respiratory therapeutics are urgently needed. A method using hyperpolarized 3He ventilation imaging is introduced to calculate quantitative treatment response maps. Ventilation images from before and after bronchodilator treatment are used to quantify ventilation changes and are masked by a baseline variability calculated from two ventilation images acquired before treatment. The technique is compared to percentage ventilated volume (%VV) and forced expiratory volume (FEV1). In this cohort all tests showed significant differences before and after treatment, nevertheless TRM displayed a tighter clustering and clearer separation of positive from negative response.

Stephen E. Russek¹, Kathryn E. Keenan¹, Karl Stupic¹, Michael A. Boss¹, Zydrunas Gimbutas¹, Andrew M. Dienstfrey¹, and Robert J. Usselman^2
1NIST, Boulder, CO, United States, ²University of Montana, Bozeman, MT, United States

We investigated several materials for use in a nano-iron phantom including Fe chelates, hemoglobin, recombinant human ferritin, horse spleen ferritin (HSF), Feraheme, Molday ion, nanoComposix iron oxide, textured (chained) nanoparticles. The range of concentrations was selected to match brain iron concentrations in healthy and diseased tissue (100-200 ppm). A key advance was to develop recombinant human ferritin by obtaining H-chain DNA sequences, amplifying with PCR, splicing them into pET30a(+) plasmids, and transfecting E. Coli. Various mineralization techniques were applied to mimic pure phase, healthy, and pathologic forms of human ferritin. These materials were incorporated into phantoms and characterized using multiparameter mapping to assess ability to measure concentration and form in-vivo.

Muhammed Jamal Afridi¹, Matt Latourette², Margaret F Bennewitz³, Arun Ross¹, Xiaoming Liu¹, and Erik M Shapiro^2
1Department of Computer Science and Engineering, Michigan State University, East Lansing, MI, United States, ²Department of Radiology, Michigan State University, East Lansing, MI, United States, ³Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States

MRI detection of single cells is an underutilized advancement in MRI-based cell tracking. One reason for its underutilization has been a lack of methods for quantifying information in these images. For example, single cell detection enables quantification of cell numbers and accurate cell localization. To achieve single cell detection by MRI, cells are labeled with superparamagnetic iron oxide particles allowing their detection as punctate hypointensities in T2*-weighted MRI. We have developed a machine learning and computer vision based strategy for the generalizable detection and quantification of MRI-based single cell detection. Our approach can detect spots with an accuracy of 99.8%.