|Methods & Applications of Molecular Imaging|
Time-Resolved Molecular Imaging of the “Angiogenic Switch” in Animal Models of Cancer
Anne H. Schmieder1, Todd A. Williams1, John S. Allen1, Grace Hu1, Huiying Zhang1, Shelton D. Caruthers1, 2, Samuel A. Wickline1, Gregory M. Lanza1
1Washington University School of Medicine, St Louis, Missouri, USA; 2Philips Medical Systems, Andover, Massachusetts, USA
α v β3 targeted paramagnetic nanoparticles provide a powerful tool to noninvasively interrogate tumors and characterize angiogenesis. Time-resolved 3D neovascular maps illustrated the “angiogenic switch” between days 8 and 14 in the Vx2 tumor, revealing densely coalesced regions of neovasculature interspersed with a sparse reticular pattern of enhanced voxels. In contradistinction, angiogenesis in the MDA435 tumor model was minimal at 14 and 21 days. Characterization of tumor neovasculature could support individualized stratification of patients into anti-angiogenic based treatment regimens and their longitudinal monitoring.
Avidin-Induced Clearance of Non-Bound RGD-Biotin-Liposomes for
Target-Specific MR Molecular Imaging of Tumor Angiogenesis
Geralda A.F. van Tilborg1, Willem j.m. Mulder2, Chris P.M. Reutelingsperger3, Arjan W. Griffioen3, Daisy W.J. van der Schaft1, Gustav J. Strijkers1, Klaas Nicolay1
1Eindhoven University of Technology, Eindhoven, Netherlands; 2Mount Sinai School of Medicine, New York, USA; 3University of Maastricht, Maastricht, Netherlands
The α v β 3 integrin is strongly expressed in angiogenic vessels and has been used as a target for RGD-functionalized MR contrast agents to enable visualization of angiogenesis in vivo. Little difference in contrast enhancement between the targeted and the non-targeted control contrast agent was observed in the MR images, which was attributed to differences in the circulation half-life between both agents. This study shows that avidin-induced blood clearance can be used to investigate the relative contribution of target-associated and circulating non-bound contrast agent to the MRI contrast enhancement, which opens exciting opportunities for the improvement of MR molecular imaging protocols.
In-Vivo Assessments of Mucus Dynamics in the Lungs Using a
Gd-Cy5.5-Bilabeled Contrast Agent
François-Xavier Blé1, 2, Philipp Schmidt1, Rainer Kneuer1, Catherine Cannet1, Harry Karmouty-Quintana1, Stefan Zurbruegg1, Hans-Ulrich Gremlich1, Nicolau Beckmann1
1Novartis Institutes for BioMedical Research, Basel, Switzerland; 2University Louis Pasteur-Strasbourg-1, Illkirch, France
A Gd- and Cy5.5-bilabeled aminodextran contrast agent was developed with the aim of marking specifically the mucus in the lung. Administration of the contrast agent either as solution (BCR249) or powder (BCR250) led to a significant increase of signals in the rat lung 24 h after lipopolysaccharide (LPS). The signals remained increased for about 24 h after the probe administration. At this time point, near-infrared fluorescence (NIRF) imaging confirmed the presence of the contrast agent in the isolated lungs from the same animal, and histology revealed that BCR249/250 was bound specifically to mucus.
In Vivo Quantification of 19F Molecluar Imaging
Agents with Improved Accuracy and Sensitivity Using Motion Correcting,
Simultaneous 19F/1H Radial MRI
Jochen Keupp1, Jürgen Rahmer1, Emily A. Waters2, Shelton D. Caruthers2, 3, Gregory M. Lanza2, Samuel A. Wickline2
1Philips Research Europe, Hamburg, Germany; 2Washington University, St. Louis, Missouri, USA; 3Philips Medical Systems, Andover, Massachusetts, USA
Simultaneous 19F/1H MRI has a high potential for precise anatomical location and quantification of fluorine labeled diagnostic or therapeutic agents. However, during the measurement time (10 minutes) which is necessary to detect targeted agents in vivo, physiological motion leads to signal blurring and systematic underestimation of concentrations. It is shown in a mouse model, that motion correction for 19F is feasible using the 1H signal in simultaneous radial image acquisitions (2D or 3D stack-of-stars). Statistical analysis of measurements with and without motion demonstrates the improvement for in vivo 19F signal quantification.
A Three-Compartment T1-Relaxation Model for Intracellular
Contrast Agents: Implications for Molecular MR Imaging
Gustav Jacob Strijkers1, Sjoerd Hak1, Maarten B. Kok1, Charles S. Springer, Jr. 2, Klaas Nicolay1
1Eindhoven University of Technology, Eindhoven, Netherlands; 2Oregon Health & Science University, Portland, Oregon, USA
The goal of this work is to develop a model describing the effective longitudinal relaxation rate constant (R1) for H2O in three compartments experiencing possible exchange, and to apply this model to explain the effective R1 [CA]-dependence of internalized contrast agents into cells. The quenching of H2O R1 due to limited water exchange could be simulated and the model matched experimental in vitro data very well.
Four-Pool Modeling of Proton Exchange Processes in Biological Systems
in the Presence of MRI-PARACEST Agents
Alex Xuexin Li1, 2, Robert H.E. Hudson2, John Barrett1, Robert Bartha1, 2
1Robarts Research Institute, London, Canada; 2The University of Western Ontario, London, Canada
The inherent magnetization transfer from endogenous macromolecules significantly limits the detection sensitivity of current PARACEST agents. A four-pool model of the proton exchange processes in biological systems in the presence of a PARACEST contrast agent is presented based on the modified Bloch equations with exchange terms. The model was applied to estimate the bound water chemical shift and the transverse relaxation time of an agent-labeled (Eu3+-DOTAM-Gly-Phe) biological system consisting of Vero cells.
Microfabricated Magnetic Structures for Multi-Spectral Contrast
Gary Zabow1, 2, Stephen Dodd1, John Moreland2, Alan Koretsky1
1National Institutes of Health, Bethesda, USA; 2National Institute of Standards and Technology, Boulder, USA
We demonstrate a new form of multi-spectral MRI contrast agent constructed via microfabrication instead of traditional chemical synthesis. The spectral shifts of these agents can be tailored through fabrication process parameter control and, even for small MRI fields, can span a range far exceeding that of chemical exchange agents. We show how such micro-engineered structures allow increased functionality and sensitivity compared to existing chemically-synthesized contrast agents.
Core HDL Applied for Macrophage Imaging
David Peter Cormode1, Torjus Skajaa1, Mark E. Lobatto1, Karen C. Briley-Saebo1, Alessandra Barazza1, 2, Edward A. Fisher2, Zahi Adel Fayad1, Willem J. Mulder1
1Mount Sinai School of Medicine, New York, USA; 2New York University, New York, USA
Imaging atherosclerosis is a topic of great current interest and HDL is naturally targeted to this disease. We have replaced the triglyceride/cholesterol ester core of HDL with inorganic nanoparticles such as gold for CT, iron oxide for MRI or quantum dots for optical imaging, forming novel molecular imaging contrast agents for atherosclerosis. Rhodamine and gadolinium were incorporated into the phospholipid coating for the gold and quantum dots, creating multifunctional particles. We have incubated these particles with macrophage cells and shown uptake by confocal microscopy, TEM, MRI and CT imaging. In addition, we have carried out preliminary in vivo imaging studies.
Vivo MR Imaging of Acute Thrombus Formation Using a Bimodal Contrast
Robbert-Jan J.H.M. Miserus1, 2, Lenneke Prinzen2, M V. Herias1, Tilman M. Hackeng2, Anouk Dirksen2, Wencke Adriaens2, Marc A.M.J. van Zandvoort2, Marc B.I. Lobbes1, Mat J.A.P. Daemen1, Jos J.M.A. van Engelshoven1, Sylvia Heeneman1, Marianne Eline Kooi1
1Maastricht University Hospital, Maastricht, Netherlands; 2Maastricht University, Maastricht, Netherlands
Thrombus formation plays a central role in several cardiovascular diseases. Since the resistance of thrombi against fibrinolytic therapy is achieved within hours, early detection of thrombus formation is vital. During these early stages of thrombus formation, activated factor XIII cross-links α 2-antiplasmin to the fibrin network. A bimodal α 2-antiplasmin-based contrast agent (CA) and a non-specific bimodal control CA were synthesized. A feasibility study was performed in vitro and in vivo which showed that the α 2-antiplasmin-based bimodal CA enables in vivo MR imaging of acute thrombus formation. Specific binding of this CA to the fibrin network was confirmed by TPLSM.
MntR, an MRI Reporter Provides Cellular T1 Contrast
Without Mn Supplementation
Benjamin B. Bartelle1, Daniel H. Turnbull1
1Skirball Institute of Biomolecular Medicine, New York, New York, USA
MntR is an MRI reporter gene that localizes Mn within cells. In this work we show cellular T1w contrast in cells stably expressing MntR and our progress towards in vivo MntR expression.