Mingqian Tan^1,2, and Zheng-Rong Lu^1
1Case Western Reserve University, Cleveland, Ohio, United States, ²National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian, Liaoning, China, People's Republic of

A cyclic peptide CLT1-targeted nanoglobular Gd(III)-based contrast agent was evaluated in male mice bearing orthotopic xenograft tumor with MRI. The r1 and r2 relaxivities of the CLT1 targeted agent were 11.63 and 15.73 mM-1s-1 per Gd(III) chelate at 1.5T, respectively. Peptide CLT1 has shown significant accumulation in tumor as compared to a control peptide. The CLT1 targeted contrast agent resulted in strong contrast enhancement in the orthotopic prostate tumor for in vivo MR molecular imaging, while little enhancement was observed in the tumor with the control agent. The results demonstrated that the CLT1-targted nanoglobular contrast agent is effective for in vivo cancer MR molecular imaging in an orthotopic mouse tumor model.

Chiao-Yun Chen^1,2, Twei-Shiun Jaw^1,2, Hua-Lin Wu³, Guey-Yueh Shi³, Yun-Ming Wang⁴, Gin-Chung Liu^1,2, and Yu-Ting Kuo^1,2
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 biochemistry & Molecular Biology, College of Medicine & cardiovascular Research Cancer, National Cheng Kung Univerisity, Taiwan, ⁴Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan

We have successfully synthesized and characterized a novel gadolinium-based MR contrast agent, Gd-NBCB-TTDA-MMP-2, formed of a peptide with a high affinity for MMP-2 .Our study demonstrated that Gd-NBCB-TTDA-MMP-2 can be a useful MR contrast agent for in vivo detection of MMP-2 activity in atherosclerosis at a molecular pathologic level. Because evaluation of the MMP-2 content and activity may aid in the prediction of the vulnerability of atherosclerotic plaques to rupture and thrombosis, using Gd-NBCB-TTDA-MMP-2 enhanced MR imaging to assess MMP-2 activity may allow identification of unstable plaques and contribute substantially to preclinical and clinical evaluation of atherosclerosis.

Benjamin Marty¹, Françoise Geffroy¹, Boucif Djemai¹, Benoit Theze², Aline Perrin¹, Caroline Robic³, Marc Port³, Philippe Robert³, Denis Le Bihan¹, Franck Lethimonnier¹, and Sébastien Mériaux^1
1CEA/DSV/I2BM/Neurospin, Gif-sur-Yvette, France, ²CEA/DSV/I2BM/SHFJ, Orsay, France, ³Research Division, Guerbet, Roissy Charles de Gaulle, France

Molecular magnetic resonance imaging is an increasingly used tool to investigate tumors angiogenic activity. Here we used a high relaxivity Gadolinium based (Gd-based) emulsion grafted with RGD peptides to target αvβ3 protein over-expressed during tumor angiogenesis induced in mice brain. This study proposes to quantify the Gd-based emulsion concentration by acquiring dynamic T1 maps. Thanks to this methodology we are able to detect and quantify the accumulation of contrast agent in the tumor after its intravenous injection. A proof of concept of its binding was obtained in vivo with brain tumors induced in nude mice, and was confirmed by histology.

David C Zhu¹, Kheireddine El-Boubbou², George S Abela³, Ruiping Huang³, Medha Kamat², and Xuefei Huang^2
1Radiology and Psychology, Michigan State University, East Lansing, MI, United States, ²Chemistry, Michigan State University, ³Medicine, Michigan State University

Atherosclerotic plaques are formed through the accumulation of macrophages, lipids, and fibrous connective tissue underneath the endothelium lining in arterial walls. CD44 is a cell surface receptor at macrophages which tend to accumulate at atherosclerotic plaques. In this work, hyaluronic acid (HA) was bonded to dextran coated SPIO nanoparticles (DESPIONs). The synthesized HA-DESPIONs were used to target CD44 at macrophages and were able to highlight atherosclerotic plaques in MRI. With HA-DESPION as an example, here we summarize our molecular imaging strategy of a rabbit model on a human clinical scanner.

Mirko Meißner¹, Daniel Dürschmied², Irene Neudorfer², Constantin von zur Mühlen², and Dominik von Elverfeldt^1
1Dept. of Radiology / Medical Physics, University Medical Center Freiburg, Freiburg, Germany, ²Dept. of Cardiology and Angiology, University Medical Center Freiburg, Freiburg, Germany

The final event leading to myocardial infarction is adhesion and activation of platelets after rupture of an atherosclerotic plaque. Platelets then aggregate, culminating in thrombotic occlusion of the coronary artery. We examined the feasibility of molecular MRI for the detection of non-occluding coronary artery thrombosis in mice, by using MPIOs targeted to activated platelets. Hypointense regions in the MR images were co-localised with MPIO accumulation in thrombi, as confirmed by histology.

Siranush Anna Sargsyan¹, Kendra M. Hasebroock², Brandon Renner², Brian Larsen³, Conrad Stoldt³, V. Michael Holers², Joshua M. Thurman², and Natalie Serkova^2
1Medicine, University of Colorado Denver, Aurora, Colorado, United States, ²University of Colorado Denver, ³University of Colorado Boulder

Lupus nephritis is characterized by immune-complex deposition as well as complement C3 activation within the glomeruli of the kidney. Percutaneous renal biopsy is the gold standard for monitoring disease activity, yet less invasive methods of obtaining biopsy information are needed. We have developed a non-invasive method for detecting tissue-bound iC3b/C3d using MRI and superparamagnetic iron oxide (SPIO) nanoparticles linked to the iC3b/C3d binding region of complement receptor type 2 (CR2). We found that CR2-targeted SPIO nanoparticles caused a reduction in the T2-relaxation time in nephritic kidneys corresponding to the peak glomerular iC3b deposition and disease severity.

Chiwei Hung¹, Yuan-Chia Kuo^1,2, Jiachen Zhuo³, Srinivasa R Raghavan^2,4, Janet E Baulch¹, Rao Gullapalli³, Mohan Suntharalingam¹, and Warren D D'souza^1,2
1Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, United States, ²Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States, ³Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland Medical Center, Baltimore, MD, United States, ⁴Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, MD, United States

A multifuctional molecular probe was investigated for the targeting and imaging of the epidermal growth factor receptors on head and neck tumor cells by combining a paramagnetic contrast agent, Gadolinium, with a monoclonal EGFR targeting antibody. Our research showed that this probe was able to target EGFR on the cancer cell and showed an increase in contrast under MR imaging. It may be used to provide the diagnostic feedback of the ongoing targeted therapy with concurrent RT.

Janaki Raman Rangarajan¹, Greetje Vande Velde², Caroline Guglielmetti³, Ruth Vreys³, Marleen Verhoye³, Tom Dresselaers², Annemie Van Der Linden³, Uwe Himmelreich², and Frederik Maes^1
1Medical Image Computing - ESAT/PSI, K.U. Leuven, Leuven, Belgium, ²Biomedical NMR unit, K.U. Leuven, Belgium, ³Bio-Imaging Lab, University of Antwerp, Belgium

Iron-oxide based particles or MRI reporter genes (e.g. ferritin) can be used for labeling and visualization of endogenous stem cells in the rodent brain. While the quantification of hypo-intense contrast induced by these MRI reporters using parametric T2-maps is often constrained by their low resolution and are sensitive to B1 inhomogeneity, we have developed an image analysis pipeline for regional quantification from 3D T2*-weighted MRI. We demonstrate its potential for in vivo assessment of both iron-oxide particle based and gene based MRI reporters, which creates new opportunities for large scale in vivo imaging studies, including longitudinal follow-up within the same animal.

Pramod Kumar Avti¹, Henry Bryant², Youssef Zaim Wadghiri³, Joseph Frank², Kenneth Shroyer⁴, and Balaji Sitharaman^5
1Biomedical Engineering, Stony Brook University, Stony Brook, New York, United States, ²Frank Laboratory, Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD 20892, United States, ³Radiology, New York University, Langone Medical Center, New York, New York 10016, United States, ⁴Pathology, Stony Brook University Medical Center, Stony Brook, New York 11794-8691, United States, ⁵Biomedical Engineering, Stony Brook University Medical Center, Stony Brook, New York 11794-5281, United States

We report the in vitro cell labeling and in vivo biological response of novel water-solubilized gadolinium-catalyzed single-walled carbon nanotubes (Gd-SWCNTs). The Gd-SWCNT show 25-fold greater relaxivities (at 1.5 T, r1 (Gd-SWCNT) = 126 mM-1s-1 vs. r1(Magnevist) = 4.5 mM-1s-1, [Gd3+] = 0.2 mM), and are uptaken by NIH 3T3 cells at Gd-SWCNT concentrations upto 25 ìg/ml without inducing cytotoxicity. Intravenous injection of the Gd-SWCNT into rats (dosage = 0.5 mg/kg) reveal distribution into various organs with no signs of inflammation or tissue architectural damage. In conclusion, Gd-SWCNTs show potential for future development as magnetic labels for cellular MRI.

Marc-André Fortin^1,2, Mélanie Tremblay¹, Jean Lagueux², Mathieu Létourneau¹, Luc Faucher¹, and Dario Rojas^1
1Engineering Materials, Université Laval, Québec, Québec, Canada, ²Axe métabolisme, santé vasculaire et rénale, Centre hospitalier universitaire de Québec (CHUQ), Québec, Québec, Canada

Ultra-small MnO nanocrystals were used to label cancer cells. To enhance the ingestion efficiency, the particles were coated with thiol-containing molecules. This strategy also allowed to tune the contrast agent from agglomerates (SPMnO) to individual nanoparticles (USPMnO). For both products, the cell labeling efficiency and MR contrast effect were compared with Mn2+. Labeling cells with (U)SPMnO is efficient, while preserving the viability of cells. Pellets containing as low as 10000 cells were visualized in 1T MRI. The strong positive contrast enhancement effect, normalized to the amount of Mn internalized in the cells, could be preserved over many division cycles.

Volker Sturm¹, Tobias Hertlein², Thomas Christian Basse-Lüsebrink¹, Knut Ohlsen², and Peter Michael Jakob^1
1Experimental Physics 5, University of Würzburg, Würzburg, Germany, ²Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany

In the last few years, several methods have been developed to non-invasively monitor the time course of bacterial infections. In this context, MRI has proven its potential to image edema and infections by utilization of MR-markers. Perfluorocarbon (PFC) markers internalized by macrophages migrating to the site of inflammation allow background-free inflammation localization. The present study examined PFC markers to evaluate the efficacy of therapeutic measures in time course.

Thomas Christian Basse-Luesebrink¹, Gesa Weise², Carsten Wessig², Peter Michael Jakob¹, and Guido Stoll^2
1Experimental Physics 5, University of Wuerzburg, Wuerzburg, Bavaria, Germany, ²Neurology, University of Wuerzburg, Wuerzburg, Bavaria, Germany

Inflammatory cells play an important role in the pathophysiology disorders of the nervous system. Iron oxide-based contrast agents are commonly used to visualize neuroinflammation by magnetic resonance imaging (MRI). Unfortunately, local hemorrhages, blood pool effects and passive diffusion of iron oxide particles through a defective blood-nerve barrier can hamper the information gained. In contrast to iron oxide contrast agents, ¹⁹F markers have shown their potential in unambiguous imaging of labeled cells. In the present study, 3D ¹⁹F chemical shift imaging (CSI) was applied in- and ex vivo to visualize macrophage infiltration in focal peripheral nerve demyelination using a lysolecithin model.

ting liu¹, Haiju Zhou², Rui Xia¹, Jichun Liao¹, Hui Wang¹, Hua Ai³, Feng Bi², and Fabao Gao^1
1Department of Radiology, West China Hospital£¬Sichuan University, CHENGDU, SICHUAN, China, People's Republic of, ²Department of Oncology, West China Hospital£¬Sichuan University, CHENGDU, SICHUAN, China, People's Republic of, ³National Engineering Research Center for Biomaterials£¬Sichuan University, CHENGDU, SICHUAN, China, People's Republic of

To investigate the mechanism of tumor lymphatic metastases, we inoculated subcutaneously with USPIO labeled and unlabeled LOVO cells in foot pad, groin or axillary area of nude mice, respectively, to develop a model system for tracking metastatic tumor cells in lymphatic system with MR cellular imaging in live mice. MR T2/ T2* weighted image showed the primary tumor growth and the draining lymphatic architecture, as well as the USPIO labeled tumor cells metastasized into regional lymph node at 8 days P.I. And histological finding confirmed MR imaging results and revealed a close relationship between tumor lymphatic metastasis with lymphangiogenesis.

Halima Chahboune^1,2, Jamie Harrington³, Jason Criscione², Ragy Ragheb², Narutoshi Hibino³, Toshiharu Shinoka³, Christopher Breuer Breuer³, and Tarek Fahmy^4
1Diagnostic Radiology, Yale University, New HAven, CT, United States, ²Biomedical Engineering, Yale University, New HAven, CT, United States, ³Interdepartmental Program in Vascular Biology and Therapeutic, Yale University, New HAven, CT, United States, ⁴Biomedical Engineering, Yale University, New HAven, United States

Magnetic Resonance Imaging (MRI) is a non-invasive method potentially well suited for monitoring cells grafts to identify and map the fate of transplanted cells. This study reports the use of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles to noninvasively monitor and map the fate of labeled macrophages seeded onto a biodegradable scaffold used as venous conduit. The results demonstrate that the seeded cells do not actually become incorporated into the neovessel, but instead are important for inciting an inflammatory remodeling process, through the recruitment of host cells, that is critical for the development of the neovessel.

Olivier M Girard¹, Rose Ramirez¹, Stephanie McCarty^1,2, Elamprakash N Savariar³, and Robert F Mattrey^1
1Department of Radiology, University of California, San Diego, CA, United States, ²New York Medical College, Valhalla, NY, United States, ³Department of Pharmacology, University of California, San Diego, CA, United States

Iron oxide nanoparticles (IONPs) are widely used in cellular MRI because of their strong magnetic properties. However quantification of absolute concentration still remains a challenge because relaxivities depend on IONP distribution within a given sample. Recent works on susceptibility mapping have suggested that susceptibility measurements could be used for IONP quantification. Here we study IONP samples that contain a mixture of free- and cell-internalized- IONPs. We investigate multiple MR characteristic parameters (T₁, T₂, T₂* and ) in order to extract absolute IONP concentration as well as free vs. internalized IONP fractions.

Yi-Xiang Wang¹, K C Leung², T Quercy-Jouvet², H H Wang³, C P Chak², S Lin³, D F Wang³, D W Au⁴, P C Leung⁵, and K P Fung^5
1Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, ²Center of Novel Functional Molecules, Department of Chemistry, The Chinese University of Hong Kong, Hong Kong, ³Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong,⁴4Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong, ⁵Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong

Silica has good biocompatility and hydrophilicity. When silica is coated outside the SPIO core, the silica shell may be able to act as a stabilizer, limiting the effect of intracellular enzymes and acids on the core particles. In this study, an attempt was made to compare the transfecting agent-free mesenchymal stem cell (MSCs) labeling using SPIO with different coatings, with a view to study the durability and retainability of these SPIOs in MSCs. The preliminary results in this study suggest silica coating offers better protection to its SPIO core compared with biodegradable PEG coating when the nanomaterials are within MSCs.