Novel Contrast Agents & Reporters

Monday 22 April 2013

Maja Cassidy¹, Henry Chan², Pratip Bhattacharya^2,3, and Charles Marcus^1,4
1Harvard University, Cambridge, MA, United States, ²Huntington Medical Research Institutes, Pasadena, CA, United States, ³Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States, ⁴University of Copenhagen, Copenhagen, Denmark

We report direct in-vivo imaging of hyperpolarized silicon microparticles by ²⁹Si MRI. Hyperpolarization of the ²⁹Si nuclei is generated by dynamic nuclear polarization using electronic defects that naturally occur at the particle surface, and so no additional radical is required. Applications to gastrointestinal, intravascular, and tumor perfusion imaging at sub-picomolar concentrations are presented.

Amnon Bar-Shir^1,2, Assaf A. Gilad^1,2, Kannie W.Y. Chan^1,3, Guanshu Liu^1,3, Peter C.M. van Zijl^1,3, Michael T. McMahon^1,3, and Jeff W.M. Bulte^1,2
1Department of Radiology, Johns Hopkins University, Baltimore, MD, United States, ²Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, United States, ³F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, MD, United States

Although Ca²⁺ ions are involved in a myriad of biological signaling processes, a non-invasive means of detecting micromolar Ca²⁺ levels remains a formidable challenge. We present an approach for specifically sensing the presence of Ca²⁺ ions through its substrate binding kinetics by exploiting the chemical shift change of ¹⁹F upon binding of Ca²⁺ to the fluorinated chelator 1,2-Bis-[2-bis(carboxymethyl)amino-5-¹⁹fluorophenoxy]ethane (5-¹⁹FBAPTA). Using RF labeling at the bound-¹⁹F frequency and detection of label transfer to the free-¹⁹F frequency (Δω=5.8ppm) in millimolar concentration substrate, we were able to amplify the signal of Ca²⁺ with supreme specificity over other divalent cations.

Firas Moosvi¹, Jennifer H.E. Baker^1,2, Andrew Yung¹, Kenneth Curry³, and Stefan A. Reinsberg^1
1Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada, ²Radiation Biology, BC Cancer Research Institute, Vancouver, BC, Canada, ³RF Therapeutics, Vancouver, BC, Canada

We validate an MR-visible, necrosis-avid contrast agent(RF1101) using TUNEL staining and DCEMRI. The agent is injected and binds to areas of apoptosis/necrosis and unbound agent is excreted from the systemic circulation. T1-weighted imaging is performed after approximately 24h to identify areas of contrast agent uptake. Data from a preclinical cancer model is shown with spectacular agreement between histologically identified areas of necrosis and RF1106 uptake.

Devkumar Mustafi¹, Jesse Ward², Urszula Dougherty³, Erica Markiewicz¹, Marc Bissonnette³, Stefan Vogt², and Gregory S. Karczmar^1
1Radiology, The University of Chicago, Chicago, Illinois, United States, ²Advanced Photon Source - Sector 2, Argonne National Laboratory, Lemont, Illinois, United States, ³Medicine, The University of Chicago, Chicago, Illinois, United States

Targeted contrast agents that specifically enhance early cancers could significantly improve diagnostic accuracy. Here we compare a new vanadium-based (VC) MRI contrast agent that is sensitive to glycolysis to a conventional Gd-based agent in a mouse model of colorectal cancer. A novel method is developed for co-registrations of in vivo MR images with ex vivo histological images using agar-based phantoms. X-ray fluorescence microscopy (XFM) imaging was used to quantify contrast uptake directly and to determine cellular and sub-cellular distributions in situ. Results revealed that VC-based agents preferentially accumulate in cancer cells, offering an advantage over less selective Gd-based agents.

Maria Veronica Clavijo Jordan¹ and Kevin M. Bennett^1
1School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona, United States

Chemical doping is implemented in order to disrupt magnetic moment coupling within a crystal and render a paramagnetic nanoparticle. Tunstate is introduced inside the apoferritin cavity as a dopant of the iron oxide core. The crystal surface un-coupled moments are in close contact with the surrounding water protons to reduce overall longitudinal relaxation. The paramagnetic apoferritin composite resulted in a particle r₁ of 4870mM^-1s^-1 and r₂/r₁ of 1.86 making them a sensitive nanoparticle agent for in vivo molecular MRI.

Kannie W.Y. Chan^1,2, Guanshu Liu^1,3, Peter C.M. van Zijl^1,3, Jeff W.M. Bulte^2,4, and Michael T. McMahon^1,3
1Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Baltimore, MD, United States, ³F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, ⁴Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States

Hydrogels are used to enhance cell transplantation therapies by providing immunoprotection and physical support. A non-invasive imaging technique that allows monitoring of successful engraftment and lack of fibrosis is needed. In particular at an early stage where cell infiltration is commonly found, imaging is necessary to assess if adjustments are required to enhance cell survival. Here, we are interested in monitoring if cell infiltration is occurring in the region of the transplanted hydrogels using magnetization transfer imaging. We found that the MTR values increased with cell infiltration, which can be used as a surrogate marker for the occurrence of FBR.

Cornelius Faber¹, Rebecca Schmidt¹, Nadine Nippe², Klaus Strobel¹, Max Masthoff¹, Carsten Höltke¹, Olga Reifschneider³, Daniela Delli Castelli⁴, Silvio Aime⁴, and Christoph Bremer^1
1Department of Clinical Radiology, University Hospital Münster, Münster, NRW, Germany, ²Department of Dermatology, University Hospital Münster, Münster, NRW, Germany, ³Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, NRW, Germany, ⁴Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy

We have used Tm-DOTMA to label bone marrow-derived macrophages and track their migration after i.v. administration in a mouse model of local inflammation. The strongly shifted methyl resonance of Tm-DOTMA can be detected efficiently with short-TR 3D UTE MRI, avoiding signal losses due to fast relaxation. Labeled cells were detectable over eight days and the detection limit was estimated to be below 10,000 cells. Our approach may be an alternative to fluorine cell tracking, which does not require a dedicated rf coil.

Christian Thomas Farrar¹, Jason S. Buhrman², Guanshu Liu^3,4, Assaf A. Gilad^3,4, Michael T. McMahon^3,4, and Giulia Fulci^2
1Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States, ²Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States, ³F. M. Kirby Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, ⁴Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

One of the major challenges in treating glioblastoma is the poor efficiency of drug delivery. Oncolytic viruses (OVs) that can selectively replicate in tumor cells and target the infiltrating margins of the tumor represent a promising new tool in cancer therapy. However, the lack of a means to detect the OV in a non-invasive fashion limits the evaluation of such treatments. Here we demonstrate the use of a lysine-rich protein reporter for imaging oncolytic viral delivery using chemical exchange saturation transfer (CEST) MRI that may for the first time provide a tool for the in vivo monitoring of oncolytic virotherapy.

Amnon Bar-Shir^1,2, Yoshinori Kato¹, Arvind P. Pathak¹, Jeff W.M. Bulte^1,2, and Assaf A. Gilad^1,2
1Department of Radiology, Johns Hopkins University, Baltimore, MD, United States, ²Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, United States

The Drosophila melanogaster 2’-deoxynucleoside kinase (Dm-dNK) enzyme phosphorylates a wide range of nucleoside analogs, including the fluorescent nucleoside pyrrolo-2’-deoxycytidine (pyrrolo-dC). We show here that the NH proton of the pyrrolo-dC generates high CEST contrast when a saturation pulse is applied at 5.8ppm from the water protons. The formation of the pyrrolo-dC monophosphate by recombinant Dm-dNK resulted in accumulation of the probe selectively in the cytoplasm of Dm-dNK-expressing cells since its negative charge prevents cellular export. Hence, pyrrolo-dC can be used for monitoring the reporter gene Dm-dNK expression with CEST MRI.

P. Stephen Patrick^1,2, Jayne Hammersley², Louiza Loizou², Mikko I. Kettunen¹, Tiago B. Rodrigues¹, De-En Hu², Sui Seng Tee^2,3, Robin Hesketh², Scott K. Lyons¹, Silvio Aime⁴, Sandra M. Fulton², and Kevin M. Brindle^1,2
1Cancer Research UK, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom, ²Department of Biochemistry, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom, ³School of Medicine, University of Stanford, Palo Alto, California, United States, ⁴Molecular Biotechnology Centre, University of Turin, Turin, Piedmont, Italy

A new reporter gene for MRI is described that gives rapid, intense, and reversible T₁-weighted contrast enhancement. We have achieved this through the expression of Oatp1, which is a transporter for the clinically approved contrast agent gadoxetate. R₁ was enhanced by over four fold in reporter expressing tissue 5 hours post intravenous gadoxetate injection, while R₁ for control tissue was not significantly different than before injection. This system therefore has the potential to allow detection of gene expression with higher sensitivity and resolution than was previously possible using MRI.