Publications (86) View all
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Article: Nephrogenic Systemic Fibrosis-Like Effects of Magnetic Resonance Imaging Contrast Agents in Rats with Adenine-Induced Renal Failure.
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ABSTRACT: Nephrogenic Systemic Fibrosis (NSF) is a scleroderma-like disease associated with prior administration of certain gadolinium chelates (GCs). NSF occurs in patients with severe renal failure. The purpose of this study was to set-up a rat model of GC-associated NSF to elucidate the mechanism of this devastating disease. Firstly, after characterization of the model, male Wistar rats received a 0.75% adenine-enriched diet for 8, 14 or 16 days to obtain various degrees of renal failure. Rats received 5 consecutive daily intravenous injections of saline or gadodiamide (2.5 mmol/kg/day). Secondly, the safety profile and in vivo propensity to dissociate of all categories of marketed GCs (gadoterate, gadobutrol, gadobenate, gadopentetate and gadodiamide) were compared in rats receiving adenine-enriched diet for 16 days. Serial skin biopsies were performed for blinded histopathological study. Total Gd concentration in tissues was measured by Inductively Coupled Plasma Mass Spectrometry. Relaxometry was used to evaluate the presence of dissociated Gd in skin and bone. Gadodiamide-induced high mortality and skin lesions (dermal fibrosis, calcification, inflammation) were related to adenine diet duration. No skin lesions were observed with other molecules. Unlike macrocyclic GCs, gadodiamide, gadopentetate and gadobenate gradually increased the r1 relaxivity value, consistent with in vivo dissociation and release of soluble Gd (or, in the case of gadobenate, the consequence of protein binding). Gadodiamide-induced cutaneous and systemic toxicity depended on baseline renal function. We demonstrate in vivo dissociation of linear GCs, gadodiamide and gadopentetate, whereas macrocyclic agents remained stable over the study period.Toxicological Sciences 09/2012; · 4.65 Impact Factor -
Article: Anti-inflammatory drug evaluation in ApoE-/- mice by ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging.
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ABSTRACT: 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. 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 (MФΦ). 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. 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. 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.Investigative radiology 09/2012; 47(9):546-52. · 4.85 Impact Factor -
Article: Comparison of two different iron oxide-based contrast agents for discrimination of benign and malignant lymph nodes.
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ABSTRACT: The aim of this study was to investigate the performance of 2 different ultrasmall superparamagnetic iron oxide particles-based contrast agents for intravascular magnetic resonance lymphography in normal, inflammatory, and tumor-bearing lymph nodes in rabbits. Two USPIO agents were assessed: Sinerem and P904 (both Guerbet Research, Aulnay-sous-Bois, France). Signal change of popliteal and paraaortic lymph nodes were studied in VX-2 tumor-bearing rabbits (n = 4) and rabbits in whom complete Freund adjuvant had been applied (n = 6). Image acquisition was performed before and 5 to 120 minutes and 24 hours after bolus injection of Sinerem (n = 5) and P904 (n = 5). Lymph node size was assessed and signal-to-noise ratios of lymph nodes were calculated. The contrast agents were compared regarding nodal signal changes over time. Furthermore, sensitivities, specificities, and negative and positive predictive values were calculated for both contrast agents, with histopathology serving as the standard of reference. No statistically significant size differences were detected between normal, reactively enlarged and tumor-infiltrated lymph nodes. Signal change over time showed greater differences between benign and metastatic lymph nodes for P904 especially at 24 hours after injection, whereas Sinerem showed the highest signal loss in benign nodes. After 24 hours, P904 showed a higher sensitivity (0.75 vs 0.67) and higher specificity (1 vs 0.94) compared with Sinerem. At earlier time points, sensitivity for Sinerem was lower (0.33), whereas for P904, sensitivity at 120 minutes was as good as after 24 hours (0.75). Magnetic resonance lymphography with USPIO contrast agents allows for differentiation of reactively enlarged lymph nodes compared with metastatic nodes. P904 yielded higher sensitivity and specificity values, with higher signal differences between benign and malignant enlarged lymph nodes. Furthermore, diagnosis seems to be possible earlier. This agent therefore seems to be a promising tool for staging cancer patient.Investigative radiology 09/2012; 47(9):511-5. · 4.85 Impact Factor -
Article: P792: a rapid clearance blood pool agent for magnetic resonance imaging: preliminary results
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ABSTRACT: An original MRI contrast agent, called P792, is described. P792 is a gadolinium macrocyclic compound based on a Gd-DOTA structure substituted by hydrophilic arms. The chemical structure of P792 has been optimized in order to provide (1) a high r1 relaxivity in the clinical field for MRI: 29 mM−1 x s−1 at 60 MHz. (2) a high biocompatibility profile and (3) a high molecular volume: the apparent hydrodynamic volume of P792 is 125 times greater than that of Gd-DOTA. As a result of this high molecular volume, P792 presents an unusual pharmacokinetic profile, as it is a Rapid Clearance Blood Pool Agent (RCBPA) characterized by limited diffusion across the normal endothelium. The original pharmacokinetic properties of this RCBPA are expected to be well suited to MR coronary angiography, angiography, perfusion imaging (stress and rest), and permeability imaging (detection of ischemia and tumor grading). Further experimental imaging studies are ongoing to define the clinical value of this compound.MAGMA Magnetic Resonance Materials in Physics Biology and Medicine 04/2012; 12(2):121-127. · 1.88 Impact Factor -
Article: Development of a magnetic resonance imaging protocol for the characterization of atherosclerotic plaque by using vascular cell adhesion molecule-1 and apoptosis-targeted ultrasmall superparamagnetic iron oxide derivatives.
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ABSTRACT: Acute ischemic events are often caused by the disruption of lipid-rich plaques, which are frequently not angiographically visible. Vascular cell adhesion molecule-1 and apoptotic cell-targeted peptides studied during our previous work were conjugated to ultrasmall superparamagnetic iron oxide (USPIO) (USPIO-R832 for vascular cell adhesion molecule-1 targeting; USPIO-R826 for apoptosis targeting) and assessed by magnetic resonance imaging. Apolipoprotein E knockout mice were injected with 0.1 mmol Fe/kg body weight and were imaged on a 4.7-T Bruker magnetic resonance imaging until 24 hours after contrast agent administration. Aortic samples were then harvested and examined by histochemistry, and the magnetic resonance images and histological micrographs were analyzed with ImageJ software. The plaques enhanced by USPIO-R832 contained macrophages concentrated in the cap and a large necrotic core, whereas USPIO-R826 produced a negative enhancement of plaques rich in macrophages and neutral fats concentrated inside the plaque. Both USPIO derivatives colocalized with their target on histological sections and were able to detect plaques with a vulnerable morphology, but each one is detecting a specific environment. Our vascular cell adhesion molecule-1 and apoptotic cell targeted USPIO derivatives seem to be highly promising tools for atherosclerosis imaging contributing to the detection of vulnerable plaques. They are able to attain their target in low doses and as fast as 30 minutes after administration.Arteriosclerosis Thrombosis and Vascular Biology 04/2012; 32(6):e36-48. · 6.37 Impact Factor
