Molecular Imaging: New Agents & New Targets

Monday 12 May 2014

Nikorn Pothayee¹, Der-Yow Chen¹, Maria Aronovo², Chunqi Qian¹, Richard Leapman², and Alan Koretsky^1
1Laboratory of Functional and Molecular Imaging, NINDS, NIH, Bethesda, MD, United States, ²Laboratory of Cellular Imaging and Macromolecular Biophysics, NIBIB, NIH, Bethesda, MD, United States

In this work,we describe a ‘one-pot’ and aqueous-based preparation of paramagnetic metal ion-block copolymer complexes for potential use as MRIcontrast agent. The pH-sensitive nature of soft particles was exploited in response to neuronal uptake and subsequent transport of Mn ions, which can be visualized by MRI.

Jingzhe Hu¹, Maja Cassidy², Nicholas Whiting¹, Pamela Constantinou³, Niki Zacharias Millward¹, David Volk⁴, David Gorenstein⁴, Daniel Carson³, Charles Marcus⁵, and Pratip Bhattacharya^1
1Cancer Systems Imaging, The University of Texas, MD Anderson Cancer Center, Houston, TX, United States, ²Kavli Institute of Nanoscience, Delft University of Technology, Delft, Netherlands, ³Biochemistry and Cell Biology, Rice University, Houston, TX, United States, ⁴Institute of Molecular Medicine and Department of NanoMedicine and Biomedical Engineering, The University of Texas Health Science Center at Houston, Houston, TX, United States, ⁵Center for Quantum Devices, Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark

Nanomedicine is an emerging field that offers great promise in the development of non-invasive strategies for the diagnosis and treatment of disease. Hyperpolarized silicon nanoparticles are one such material that has emerged as a platform technology for targeting that may suit a wide range of potential applications. They can be easily surface functionalized, are biocompatible and biodegradable and has opened up the possibility of performing in vivo targeted MRI in real time with over 10,000 fold sensitivity enhancement via dynamic nuclear polarization (DNP).

Neha Koonjoo¹, Elodie Parzy¹, Philippe Massot¹, Matthieu Lepetit-Coiffé^1,2, Sylvain R.A Marque³, Jean-Michel Franconi¹, Eric Thiaudiere¹, and Philippe Mellet^1,4
1Centre de Résonance Magnétique des Systèmes Biologiques, UMR 5536, CNRS, University Bordeaux Segalen, Bordeaux, France, Metropolitan, ²Siemens France, Saint-Denis, France, Metropolitan, ³UMR 7273 Aix-Marseille Université, Marseille, France, Metropolitan, ⁴University Bordeaux Segalen, INSERM, France, Metropolitan

Proteolysis of a nitroxide-labeled macromolecule was detected in the intestinal tract of living mice by Overhauser-enhanced MRI. Using an Overhauser-effect switch, namely a nitroxide with an unpaired electron bound to the macromolecule, here elastin, Overhauser enhancement was generated only after the protein carrier was digested. A high signal enhancement indicated elastin proteolysis by pancreatic elastase secreted in the duodenum. Highly resolved 3D keyhole OMRI images of resolution 0.5mm^{3 were acquired with a fully balanced steady state sequence – TrueFISP at 0.2T (Magnetom Open Viva Siemens) in 18 seconds. This current research is a step towards in vivo pathology-related proteolysis detection.}

Alexander B. Sigalov^1
1SignaBlok, Inc., Shrewsbury, MA, United States

Macrophage imaging has important diagnostic and prognostic value in cardiology, oncology and other diseases. Nanoparticles that mimic native high density lipoproteins (HDL) are a versatile delivery platform for Gd-based MRI contrast agents (GBCA) but require targeting moieties to direct the particles to macrophages. In this study, using in vivo MRI, immunohistology and confocal fluorescence microscopy, we show that a naturally occurring modification of apo A-I in GBCA-HDL targets the particles to intraplaque macrophages in an apo E-deficient atherosclerotic mouse. Synthetic apo A-I peptides were demonstrated to functionally replace native apo A-I in these contrast agents, encouraging their further development.

Kimberly Brewer¹, Rehan Ali², James A Rioux¹, Sui Seng Tee¹, Alexey Bazarov², Suleyman Felek², Caleb Bell², and Brian K Rutt^1
1Radiology, Molecular Imaging Program, Stanford University, Stanford, California, United States, ²Bell Biosystems Inc, Palo Alto, California, United States

Bacterial-derived pseudo-organelles, “Magnelles®”, were recently developed as a novel, magnetite-based MRI contrast agent. Since Magnelles were derived from magnetotactic bacteria, they have the ability to self-replicate, making them interesting candidates for labeling and longitudinal evaluation of cells. This is crucial for applications such as evaluation of stem cell and other cell-based therapies. We characterized the MRI relaxivity properties (both r1 and r2) of Magnelles, their cell loading and ex vivo imaging characteristics using a model breast cancer cell line. Magnelles were found to have similar r2 relaxivity values to conventional SPIO agents and demonstrated strong MR contrast for implanted cells.

Xiaolei Song^1,2, Xing Yang¹, Sangeeta Ray Banerjee¹, Martin G Pomper^1,3, and Michael T McMahon^1,2
1The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, Baltimore, Maryland, United States, ²F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, United States, ³Institute for Nanobiotechnology, The Johns Hopkins University, Baltimore, Maryland, United States

Diamagnetic chemical exchange saturation transfer (diaCEST) agents form a new class of imaging agents with unique magnetic resonance properties. Here we present a series of anthranilic acid analogues as examples of Uncommonly Shifted HYdrogen-bonded (U SHY) diaCEST agents, which produce significant and tunable contrast between 4.8 - 9.3 ppm from water. Five of these analogues, N-sulfonyl anthranilic acids, are highly soluble and produce strong CEST contrast. We also discovered that flufenamic acid, a commercial non-steroidal anti-inflammatory drug, displays CEST contrast at 4.8 ppm. These N-H U SHY agents, with contrast insensitive to pH, are complementary to existing diaCEST probes.

Zhuxian Zhou¹, Mohammed Qutaish¹, David L. Wilson¹, and Zheng-Rong Lu^1
1Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States

MRI is a powerful medical imaging modality for the detection and characterization of diseased soft tissues such as solid tumors. MR molecular imaging has a great potential for detection and characterization of metastatic breast cancer if a suitable molecular target can be identified. However, currently available targeted contrast agents could not generate sufficient contrast enhancement for molecular MRI of the biomarkers on cancer cell surface due to low concentration of the biomarkers and low sensitivity of MRI. The extracellular matrix of malignant tumors has abundant accumulation of fibrin-fibronectin complexes that can be used as a suitable biomarker for effective molecular MRI of small breast cancer metastases. CREKA is a tumor-homing pentapeptide (Cys-Arg-Glu-Lys-Ala) specifically homes to tumors by binding to fibrin and fibronectin associated plasma protein clots in tumor stroma. Here, we synthesized and evaluated a tumor-targeted contrast agent CREKA-Tris(Gd-DOTA)3 for MR molecular imaging of breast cancer metastases.

Zhao Li¹, Chaohsiung Hsu¹, Vay Liang W. Go², and Yung-Ya Lin^1
1Chemistry and Biochemistry, UCLA, Los Angeles, CA, United States, ²UCLA Center for Excellence in Pancreatic Diseases, UCLA, Los Angeles, CA, United States

Early detection of pancreatic cancers using enhanced MRI techniques increases not only the treatment options available, but also the patients’ survival rate. This can be achieved with antibody-conjugated superparamagnetic iron oxide (SPIO) nanoparticles capable of binding to early stage pancreatic cancer cells to improve imaging specificity and innovation methods that can sensitively detect SPIO to improve imaging sensitivity. The enhanced contrast from SPIO can then be used to visually assess the distribution and magnitude of SPIO-targeted tumor cells. In vivo subcutaneous and orthotopic xenografts mouse models validated the superior contrast/sensitivity and robustness of this approach towards early pancreatic cancers detection.

Ian Wilson¹, Peter Harvey², Katie-Lousie Finney², Alexander M Funk², P Kanthi Senanayake², Ross J Maxwell¹, David Parker², and Andrew M Blamire^3
1Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom, ²Dept of Chemistry, Durham University, Durham, United Kingdom, ³Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

A new class of contrast agents are demonstrated which present new opportunities for molecular imaging by MRI. By placing a tert-Butyl reporter group at a controlled distance from a lanthanide ion, the dipolar interaction gives rise to a frequency shifted reporter resonance with short T1 which can bedirectly detected in vivo without contamination from endogenous water or fat signal and with good sensitivity. These agents are denoted PARASHIFT agents. An example of in vivo detection of a dysprosium based agent is presented. Comparison of in vivo spectral peak areas against a reference standard suggested that a tissue concentration of 1 micromolar was detectable in a scan duration of only ~3 mins.

Amnon Bar-Shir^1,2, Nirbhay N Yadav^1,3, Assaf A Gilad^1,2, Peter CM van Zijl^1,3, Michael T McMahon^1,3, and Jeff WM Bulte^1,2
1Russell H. Morgan Department of Radiology and Radiological Science, the Johns Hopkins University School of Medicine, Baltimore, MD, United States,²Cellular Imaging Section, Institute for Cell Engineering, the Johns Hopkins University School of Medicine, Baltimore, MD, United States, ³F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States

Metal ion levels in biological systems have been extensively studied using optical probes. However, specific detection of low levels of metal ions in vivousing non-invasive methodologies remains a formidable challenge. We present an approach for specifically sensing the presence of Zn²⁺ and Fe²⁺ using the single fluorinated chelate TF-BAPTA. By exploiting the dynamic exchange between the ion-bound and free TF-BAPTA, and capitalizing on the different chemical shifts of ¹⁹F upon binding of Zn²⁺ or Fe²⁺, we were able to detect both ions simultaneously using ion CEST (iCEST) ¹⁹F MRI.