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Le Touquet – Paris-Plage, France

Sigovan M.,University of Lyon | Sigovan M.,University of California at San Francisco | Kaye E.,Stanford University | Lancelot E.,Guerbet Group | And 5 more authors.
Investigative Radiology | Year: 2012

OBJECTIVES: The renin-angiotensin system and local phagocytic activity play a major role in atherosclerotic plaque development. Treatment with irbesartan, an antagonist of angiotensin II receptor, can decrease atherosclerotic lesion formation. Iron oxide-enhanced magnetic resonance imaging (MRI) can be successfully used to evaluate the phagocytic activity in the atherosclerotic plaque in mice. In this study, we used 2 iron oxide-enhanced MRI strategies, in vivo labeling by injection of iron oxide particles and injection of in vitro labeled macrophages, to investigate the effect of irbesartan on both atherosclerotic plaque size and macrophage content in apolipoprotein (Apo) E-deficient mice. MATERIALS AND METHODS: ApoE-/-female mice (C57BL/6 background; Charles-River, France) were divided into 2 groups (irbesartan treated [TG] or not treated [NTG]) and started on a high-fat diet (Harlan TD88137 Western Diet, 21% fat, 0.2% cholesterol). Animals underwent magnetic resonance examinations on a 7-T scanner at baseline and at 14 and 28 weeks of treatment. At each time point, 2 MRI sessions were performed, before and 48 hours after administration of an iron oxide agent (P904; Guerbet, France) or magnetically labeled macrophages (MΦΦ). At the end of the follow-up, blood samples were taken for plasma lipid dosing and aorta samples for histology. The study was approved by the animal experimentation ethic committee of our institution.Vessel wall area measurements were performed on high-resolution spin echo transverse images. Multiecho gradient echo images acquired with the same geometry were used to calculate T2* maps of the vessel wall using a pixel-by-pixel monoexponential fit. Irbesartan effect on vessel wall area over time was assessed using a factorial analysis of variance test. T2* values of the vessel wall at pre-and post-ultrasmall superparamagnetic iron oxide (USPIO) administration were analyzed with a 1-way analysis of variance test with Bonferroni post hoc. RESULTS: Irbesartan treatment resulted in significantly smaller vessel wall areas at 28 weeks of treatment (P = 0.04). Postinjection values varied significantly over time for both the NTG-P904 (P = 0.02) and the TG-P904 (P = 0.01) groups. Furthermore, when comparing the TG-P904 with the NTG-P904 group at 28 weeks of treatment, a significant difference was obtained for both pre-and post-USPIO administration values (P = 0.01). In the labeled-macrophage group, postinjection T2* values were smaller than the preinjection ones for the NTG animals at 14 weeks of treatment. No T2* changes were observed in the TG-MΦ group.The difference between pre-and post-USPIO administration T2* values (ΔT2*) was significantly smaller in the TG-P904 group compared with the NTG-P904 group at 28 weeks of treatment. At this point, a good correlation (R = 0.7, P = 0.03) was found between the ΔT2* values in the P904 imaging group and the macrophage-covered area by immunohistological analysis. CONCLUSIONS: The present study illustrates an MRI follow-up of intraplaque macrophages using in vivo labeling by iron oxide particle injection and macrophage injection after in vitro USPIO labeling in the assessment of a therapeutic effect in a mouse model of atherosclerosis. Even though in vivo labeling is not fully specific of macrophage uptake, it enabled the detection of a treatment-related reduction in the macrophage content of atherosclerotic plaques in ApoE-/-mice. ©2012 by Lippincott Williams & Wilkins. Source

Peldschus K.,University of Hamburg | Hamdorf M.,University of Hamburg | Robert P.,Guerbet Group | Port M.,Guerbet Group | And 2 more authors.
Journal of Magnetic Resonance Imaging | Year: 2010

Purpose: To compare signal-enhancing properties of the high relaxivity Gd chelates P1152 and Gd-BOPTA for contrast-enhanced MR angiography (CE-MRA) in rabbits at 1.5 Tesla (T) and 3.0T. Materials and Methods: Three-dimensional CE-MRA of the abdominal vasculature was performed in six rabbits using both contrast agents at a dose of 0.1 mmol/kg. Data acquisition was carried out during first pass and up to 10 min after contrast material administration. CNR was determined in aorta, vena cava, and renal cortex. Image quality (5-point scale, 5 = best) of first pass MR angiograms was rated by two radiologists. Results: During first pass CNR of the aorta was 55.1 ± 5.8 (P1152) and 40.3 ± 3.9 (Gd-BOPTA) at 1.5T (P < 0.05), and 114.9 ± 9.9 (P1152) and 73.5 ± 8.1 (Gd-BOPTA) at 3.0T (P < 0.05). Both contrast agents showed a comparable decline of CNR within 10 min. Image quality was rated 4.8 ± 0.40 (P1152) and 4.5 ± 0.50 (Gd-BOPTA) at 1.5T (P = 0.17), and 4.8 6 0.37 (P1152) and 4.7 6 0.47 (Gd-BOPTA) at 3.0T (P = 0.61). Conclusion: The high relaxivity Gd-chelate P1152 offers potential to improve image contrast for CE-MRA compared with a clinically approved high relaxivity contrast agent. © 2010 Wiley-Liss, Inc. Source

Daldrup-Link H.E.,Stanford University | Golovko D.,University of Massachusetts Medical School | Ruffell B.,University of California at San Francisco | DeNardo D.G.,University of California at San Francisco | And 7 more authors.
Clinical Cancer Research | Year: 2011

Purpose: The presence of tumor-associated macrophages (TAM) in breast cancer correlates strongly with poor outcome. The purpose of this study was to develop a clinically applicable, noninvasive diagnostic assay for selective targeting and visualization of TAMs in breast cancer, based on magnetic resonanceI and clinically applicable iron oxide nanoparticles. Experimental Design: F4/80-negative mammary carcinoma cells and F4/80-positive TAMs were incubated with iron oxide nanoparticles and were compared with respect to magnetic resonance signal changes and iron uptake. MMTV-PyMT transgenic mice harboring mammary carcinomas underwent nanoparticle-enhanced magnetic resonance imaging (MRI) up to 1 hour and 24 hours after injection.The tumor enhancement on MRIs was correlated with the presence and location of TAMs and nanoparticles by confocal microscopy. Results: In vitro studies revealed that iron oxide nanoparticles are preferentially phagocytosed by TAMs but not by malignant tumor cells. In vivo, all tumors showed an initial contrast agent perfusion on immediate postcontrast MRIs with gradual transendothelial leakage into the tumor interstitium. Twenty-four hours after injection, all tumors showed a persistent signal decline on MRIs. TAM depletion via αCSF1 monoclonal antibodies led to significant inhibition of tumor nanoparticle enhancement. Detection of iron using 3,3′-diaminobenzidine-enhanced Prussian Blue staining, combined with immunodetection of CD68, localized iron oxide nanoparticles to TAMs, showing that the signal effects on delayed MRIs were largely due to TAM-mediated uptake of contrast agent. Conclusion: These data indicate that tumor enhancement with clinically applicable iron oxide nanoparticles may serve as a new biomarker for long-term prognosis, related treatment decisions, and the evaluation of new immune-targeted therapies. ©2011 AACR. Source

Sigovan M.,CNRS Research Center for Image Acquisition and Processing for Health | Bessaad A.,CNRS Research Center for Image Acquisition and Processing for Health | Alsaid H.,CNRS Research Center for Image Acquisition and Processing for Health | Lancelot E.,Guerbet Group | And 6 more authors.
Investigative Radiology | Year: 2010

Objective: Inflammation within atherosclerotic lesions increases the risk for plaque rupture and thrombosis. A functional approach to plaque analysis is the intravenous administration of ultrasmall superparamagnetic particles of iron oxide (USPIO) that enables visualization of macrophages residing in the plaques. In this study, we sought to characterize the age-related inflammatory status associated with atherosclerosis lesion progression in ApoE-/- mice using USPIO-enhanced magnetic resonance imaging (MRI). Materials and Methods: A total of 24 ApoE mice were divided in 4 groups (N = 6) and were given a high cholesterol diet from 6 weeks of age to the end of the protocol. One group per MR time point was investigated at 10, 16, 24, and 34 weeks of age. Each MR examination was performed on a 4.7 T scanner and consisted of baseline and 48 hours post-USPIO administration imaging sessions. P904, a USPIO contrast agent (Guerbet, Paris, France) with a potential for plaque macrophage targeting, was used.Vessel wall area measurements were performed on high resolution spin echo transverse images. Multi-echo gradient-echo images acquired with the same geometry were used to calculate T2* maps of the vessel wall using a pixel-by-pixel monoexponential fit. A one-way analysis of variance was performed to characterize the temporal variation of vessel wall area, susceptibility artifact area, baseline, and post-USPIO T2* values. MR measurements were correlated with the histologic findings. Results: A significant increase was found in the aortic wall area from 1.4 ± 0.2 at 10 weeks to 2.0 ± 0.3 mm at 34 weeks of age (P < 0.05). Concerning the post-USPIO MRI, signal loss regions, with patterns spanning from focal to the complete disappearance of the vessel wall, were observed on all postcontrast images. A significant increase in the size of the susceptibility artifact was observed from 0.5 ± 0.2 to 2.4 ± 1.0 at 24 weeks (P < 0.05) and to 2.0 ± 0.9 mm at 34 weeks (P < 0.05).The T2* values calculated on the 48 hours post-USPIO images were shorter compared with baseline. The decrease was 34% ± 16% at 10 weeks, 57% ± 11% at 16 weeks, 57% ± 16% at 24 weeks, and 48% ± 13% at 34 weeks.The Pearson's correlation test between measurement of aortic wall area performed on both MR images and histologic analysis showed a statistically significant correlation (r = 0.695 and P < 0.05). A correlation was also obtained between the signal loss area and the macrophages covered area (r = 0.68 and P < 0.05). Conclusions: This study demonstrated the feasibility of USPIO-enhanced MRI in assessing the inflammatory status related to the temporal progression of the atherosclerosis plaque in ApoE transgenic mice model of atherosclerosis. In our experimental conditions, the vascular inflammation peak, for the ApoE-/-mice feeding high-fat/high-cholesterol diet is measured between 16 and 24 weeks of age. Copyright © 2010 by Lippincott Williams and Wilkins. Source

Kinner S.,University of Duisburg - Essen | Maderwald S.,University of Duisburg - Essen | Parohl N.,University of Duisburg - Essen | Albert J.,University of Duisburg - Essen | And 6 more authors.
Investigative Radiology | Year: 2011

Objectives: To evaluate the performance of a gadolinium-based contrast compound (P846) as well as an ultra-small particle of iron oxide agent (P904) in contrast-enhanced magnetic resonance angiography (MRA) in rabbits and to compare those agents with gadoterate meglumine (Gd-DOTA) for first pass and steady state imaging. Materials and methods: A total of 6 rabbits underwent contrast-enhanced MRA of the aorta and its branches at 3 different time points. All examinations were performed on a 1.5T MR (Siemens HealthCare, Magnetom Espree), and the contrast agents were applied in random order. Image data were acquired using a time-resolved MRA sequence (time-resolved angiography with stochastic trajectories) during the first pass to assess the bolus phase and a high-resolution MRA sequence followed by repetitive measurements over the next 10 minutes for all 3 agents to evaluate the postbolus phase. Two radiologists reviewed the images in consensus blinded to the contrast agent used. Signal-to-noise ratio and contrast-to-noise ratio for three-dimensional high-resolution MRA were calculated for each time point and agent. Image quality was consensually evaluated on a 4-point Likert scale. A Wilcoxon-Mann-Whitney U test was used for comparison with P < 0.05 as level of statistical significance. Results: All agents led to diagnostic MR angiograms in all 6 rabbits. The time-resolved angiography with stochastic trajectories datasets provided detailed information about the bolus phase for all the 3 agents. During the first pass, P904 and P846 proved to be superior to Gd-DOTA with the highest peak enhancement for P846. In the postbolus phase up to 10 minutes postcontrast injection, P904 proved to be superior to the other agents. All the agents led to excellent image quality, with no statistical difference to a maximum of 3 minutes postinjection, whereas thereafter images with Gd-DOTA and P846 were assessed as nondiagnostic. Conclusions: P846 and P904 proved to be superior to Gd-DOTA for time-resolved MRA. The ultra-small particle of iron oxide compound P904 showed continuous high signal over 10 minutes and seems to be best suited for first pass and steady-state imaging. © 2011 Lippincott Williams & Wilkins. Source

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