Biomedical subjects

Claire Corot

Publications and source records attributed to Claire Corot.

At least 19 recordsLinked to original sources

PubMed2006

Effect of ultrasmall superparamagnetic iron oxide nanoparticles (Ferumoxtran-10) on human monocyte-macrophages in vitro.

Ferumoxtran-10, a dextran-coated ultrasmall superparamagnetic iron oxide particle, has the potential to reveal macrophages in vivo using magnetic resonance imaging potentially acting as a marker of inflammatory status. Pending clinical trials, we examined the interactions of Ferumoxtran-10 with human monocyte-macrophages (HMMs) in vitro to assess its safety and lack of pro-inflammatory activity. After 72 h, Ferumoxtran-10 was not toxic at 1 mg/ml and may be only mildly toxic at 10 mg/ml. Viability in cells with a high intracellular Ferumoxtran-10 load was not affected over 14 days. Ferumoxtran-10 did not interfere with baseline or stimulated cytokine (interleukin-12, interleukin-6, tumour necrosis factor-alpha or interleukin-1beta) or superoxide anion production or with Fc-receptor-mediated phagocytosis. Similarly, Ferumoxtran-10 did not induce cytokine production and was not chemotactic. High-resolution electron microscopy and selected-area electron diffraction confirmed the core of Ferumoxtran-10 is composed of crystalline magnetite. Bright field transmission electron microscopy of thin sections demonstrated that Ferumoxtran-10 was retained in lysosomes of HMM for several days. Ferumoxtran-10 is not toxic to HMMs in vitro, does not activate them to produce pro-inflammatory cytokines or superoxide anions, is not chemotactic and does not interfere with Fc-receptor-mediated phagocytosis. Furthermore, extremely high intracellular Ferumoxtran-10 concentrations had only slight or no effects on these key activities.

Cells, Cultured↗

PubMed2006

Discrimination of myocardial acute and chronic (scar) infarctions on delayed contrast enhanced magnetic resonance imaging with intravascular magnetic resonance contrast media.

OBJECTIVES: The purpose of this study was to examine the potential of intravascular gadolinium (Gd)-chelates in discriminating acute from chronic myocardial infarctions (MIs). BACKGROUND: A potential limitation of delayed contrast enhanced magnetic resonance imaging with standard extracellular Gd-chelates is its inability to distinguish acute from chronic MIs. METHODS: Eight pigs with MIs were studied at 3 days and 8 weeks. Inversion recovery gradient echo (IR-GRE), T(1)-turbo spin echo (TSE), and T(2)-TSE images were acquired before and after administration of intravascular and extracellular Gd-chelates. Triphenyltetrazolium chloride (TTC) was used to delineate infarctions at postmortem. Masson's trichrome and Biotinylated Bandeiria simplicifolia Isolectin B4 stains were used to characterize scarred myocardium. Analysis of variance was used to compare signal intensity (SI) ratios and determine differences in infarct extent. RESULTS: The intravascular agent produced differential enhancement of acute infarctions at 3 days (SI ratio 5.8 +/- 1.3) but not at 8 weeks (1.6 +/- 0.4, p < 0.01). The extracellular agent provided differential enhancement of both acute (SI ratio 7.7 +/- 1.4) and chronic (7.5 +/- 0.9) infarctions. The extents of enhanced regions in acute infarctions were not different after intravascular (16.0 +/- 1.3%) or extracellular (17.1 +/- 1.7%) agents; at 8 weeks the extent of extracellular enhanced and TTC regions were smaller (13.2 +/- 1.4% and 12.0 +/- 1.5%, respectively). Masson's trichrome stain demonstrated dense scar tissue, signaling the complete healing of infarction. The vascular stain showed that scar tissue contained fewer microvessels oriented in a haphazard array. CONCLUSIONS: The combination of intravascular and extracellular Gd-chelates discriminates acute from chronic infarctions on delayed images. This double contrast agent approach can be used to determine the age and extent of infarctions.

Animals↗

PubMed2006

Recent advances in iron oxide nanocrystal technology for medical imaging.

Superparamagnetic iron oxide particles (SPIO and USPIO) have a variety of applications in molecular and cellular imaging. Most of the recent research has concerned cellular imaging with imaging of in vivo macrophage activity. According to the iron oxide nanoparticle composition and size which influence their biodistribution, several clinical applications are possible: detection liver metastases, metastatic lymph nodes, inflammatory and/or degenerative diseases. USPIO are investigated as blood pool agents with T1 weighted sequence for angiography, tumour permeability and tumour blood volume or steady-state cerebral blood volume and vessel size index measurements using T2 weighted sequences. Stem cell migration and immune cell trafficking, as well as targeted iron oxide nanoparticles for molecular imaging studies, are at the stage of proof of concept, mainly in animal models.

Animals↗

PubMed2006

Interaction of functionalized superparamagnetic iron oxide nanoparticles with brain structures.

Super Paramagnetic Iron Oxide Nanoparticles (SPIONs) combined with magnetic resonance imaging (MRI) are under clinical evaluation to enhance detection of neurodegenerative diseases. A major improvement would be to link therapeutic drugs to the SPIONs to achieve targeted drug delivery, either at the cell surface or intracellularly, together with active disease detection, without inducing cell reaction. Our objectives were to define the characteristics of SPIONS able to achieve cell-specific interaction with brain-derived structures. Our system consisted in an iron oxide core (9-10 nm diameter) coated either with dextran (Sinerem and Endorem) or various functionalized polyvinyl alcohols (PVAs) (PVA-SPIONs). We investigated the cellular uptake, cytotoxicity, and interaction of these various nanoparticles with brain-derived endothelial cells, microglial cells, and differentiating three-dimensional aggregates. None of the nanoparticles coated with dextran or the various PVAs was cytotoxic or induced the production of the inflammatory mediator NO used as a reporter for cell activation. AminoPVA-SPIONs were taken up by isolated brain-derived endothelial and microglial cells at a much higher level than the other SPIONs, and no inflammatory activation of these cells was observed. AminoPVA-SPIONs did not invade brain cells aggregates lower than the first cell layer and did not induce inflammatory reaction in the aggregates. Fluorescent aminoPVA-SPIONs derivatized with a fluorescent reporter molecule and confocal microscopy demonstrated intracellular uptake by microglial cells. Fluorescent aminoPVA-SPIONs were well tolerated by mice. Therefore, functionalized aminoPVA-SPIONs represent biocompatible potential vector systems for drug delivery to the brain that may be combined with MRI detection of active lesions in neurodegenerative diseases.

Animals↗

PubMed2006

Multi-slice DCE-MRI data using P760 distinguishes between metastatic and non-metastatic rodent prostate tumors.

An intermediate molecular weight contrast agent P760 was used to investigate the ability of multi-slice dynamic contrast-enhanced MRI (DCE-MRI) to distinguish metastatic from non-metastatic rodent prostate tumors. Non-metastatic AT2.1 and metastatic AT3.1 prostate tumors originally derived from the Dunning prostate cancer model were implanted on the hind leg of Copenhagen rats. Multi-sliced DCE-MRI data were acquired on a SIGNA 1.5 T scanner and analyzed using a recently developed empirical mathematical model. The P760 multi-slice DCE-MRI data in combination with the empirical mathematical model successfully distinguished between metastatic and non-metastatic rodent prostate tumors. Specifically, fitting the data with the empirical model showed that metastatic tumors had significantly faster contrast media uptake (p<0.001) and slower washout rates (p<0.01) than non-metastatic tumors.

Algorithms↗

PubMed2006

Magnetic resonance imaging of experimental atherosclerotic plaque: comparison of two ultrasmall superparamagnetic particles of iron oxide.

PURPOSE: To evaluate a new ultrasmall superparamagnetic particles of iron oxide (USPIO) compound, ferumoxytol, as a marker of macrophage activity in atherosclerotic plaques and to compare it to ferumoxtran-10. MATERIALS AND METHODS: Ten mature heritable hyperlipidemic (WHHL) female Watanabe rabbits served as the animal model for atherosclerosis, four coeval female New Zealand White (NZW) rabbits were the control group. Five WHHL and two NZW received a single intravenous injection (250 micromol/kg) of either ferumoxtran-10 or ferumoxytol and were subjected to daily MR examinations on a 1.5T whole body scanner for the next five days. Development of signal intensity changes and susceptibility effects was assessed. Statistical analysis was based on a nonparametric Wilcoxon-Mann-Whitney-U test by using a P value at the 0.05 significance level. On day 5, the rabbits were sacrificed and the aorta was referred to histopathology, distribution of iron particles in the vessel wall was analyzed. RESULTS: MRI was feasible in all animals. Three days after injection of ferumoxytol the highest luminal signal intensity measurements were observed in the ferumoxytol group; the highest measurements were five days after injection in the ferumoxtran-10 group (P < 0.05). In the WHHL, susceptibility effects presented as homogeneous dark lines parallel to the aortic wall after ferumoxytol and spotted areas void of signal after ferumoxtran-10. None of these findings were observed in the NZW control groups. CONCLUSION: Ferumoxtran-10 and ferumoxytol at a respective dose of 250 mumol/kg appear well suited for atherosclerotic plaque detection with MRI in experimental atherosclerosis. Ferumoxytol warrants further analysis in humans.

Animals↗

PubMed2006

Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review.

Gadolinium-based contrast agents (CAs) are widely used to enhance the contrast of images in magnetic resonance imaging procedures. Two categories of gadolinium chelates exist: the macrocyclic molecules where Gd3+ is caged in the pre-organized cavity of the ligand and the linear molecules. Gadolinium chelates differ in their thermodynamic stability constants and in their kinetic stability. In general, macrocyclic chelates such as Gd-DOTA or Gd-HP-DO3A are more stable than linear molecules. Even among linear agents, differences can be found. There is increasing evidence that transmetallation can be found in vivo, in the case of certain CAs (especially linear chelates), with body cations such as zinc, calcium or iron. Furthermore, analytical interference with colorimetric determination of calcium has been clinically evidenced with two linear chelates, Gd-DTPA-BMA and Gd-DTPA-BMEA. Clinical cases of spurious hypocalcaemia have been reported with these molecules. Such interference with some colorimetric assays for calcium is clinically relevant in that it can lead to unnecessary and potentially harmful treatment for hypocalcaemia.

Biomarkers↗

PubMed2005

T1 and T2 relaxivity of intracellular and extracellular USPIO at 1.5T and 3T clinical MR scanning.

In this study we evaluated the effects of intracellular compartmentalization of the ultrasmall superparamagnetic iron oxide (USPIO) ferumoxtran-10 on its proton T1 and T2 relaxivities at 1.5 and 3T. Monocytes were labeled with ferumoxtran-10 by simple incubation. Decreasing quantities of ferumoxtran-10-labeled cells (2.5x10(7)-0.3x10(7) cells/ml) and decreasing concentrations of free ferumoxtran-10 (without cells) in Ficoll solution were evaluated with 1.5 and 3T clinical magnetic resonance (MR) scanners. Pulse sequences comprised axial spin echo (SE) sequences with multiple TRs and fixed TE and SE sequences with fixed TR and increasing TEs. Signal intensity measurements were used to calculate T1 and T2 relaxation times of all samples, assuming a monoexponential signal decay. The iron content in all samples was determined by inductively coupled plasma atomic emission spectrometry and used for calculating relaxivities. Measurements at 1.5T and 3T showed higher T1 and T2 relaxivity values of free extracellular ferumoxtran-10 as opposed to intracellularly compartmentalized ferumoxtran-10, under the evaluated conditions of homogeneously dispersed contrast agents/cells in Ficoll solution and a cell density of up to 2.5x10(7) cells/ml. At 3T, differences in T1-relaxivities between intra- and extracellular USPIO were smaller, while differences in USPIO T2-relaxivities were similar compared with 1.5T. In conclusion, cellular compartmentalization of ferumoxtran-10 changes proton relaxivity.

Cell Culture Techniques↗

PubMed2005

Magnetic resonance characterization of tumor microvessels in experimental breast tumors using a slow clearance blood pool contrast agent (carboxymethyldextran-A2-Gd-DOTA) with histopathological correlation.

Carboxymethyldextran (CMD)-A2-Gd-DOTA, a slow clearance blood pool contrast agent with a molecular weight of 52.1 kDa, designed to have intravascular residence for more than 1 h, was evaluated for its potential to characterize and differentiate the microvessels of malignant and benign breast tumors. Precontrast single-slice inversion-recovery snapshot FLASH and dynamic contrast-enhanced MRI using an axial T1-weighted three-dimensional spoiled gradient recalled sequence was performed in 30 Sprague-Dawley rats with chemically induced breast tumors. Endothelial transfer coefficient and fractional plasma volume of the breast tumors were estimated from MRI data acquired with CMD-A2-Gd-DOTA enhancement injected at a dose of 0.1 mmol Gd/kg body weight using a two-compartment bidirectional model of the tumor tissue. The correlation between MRI microvessel characteristics and histopathological tumor grade was determined using the Scarff-Bloom-Richardson method. Using CMD-A2-Gd-DOTA, no significant correlations were found between the MR-estimated endothelial transfer coefficient or plasma volumes with histological tumor grade. Analysis of CMD-A2-Gd-DOTA-enhanced MR kinetic data failed to demonstrate feasibility for the differentiation of benign from malignant tumors or for image-based tumor grading.

Animals↗

PubMed2005

Optimization of a blood pool contrast agent injection protocol for MR angiography.

PURPOSE: To design an ideal first-pass profile for MR angiography (MRA) by optimizing a multiphasic injection protocol based on two experimental animal models. MATERIALS AND METHODS: An equivalent contrast-enhanced (CE) MRA injection protocol was developed with controlled injection modalities (injection rate, volume, and dose) in rabbits and pigs. P792, a blood pool contrast agent, was injected in 17 male New Zealand rabbits and five farm pigs with variable injection schemes (mono- and multiphasic). From the gadolinium (Gd) blood concentration data, a simulation of an MR acquisition was performed to evaluate the impact of such an injection protocol on MR arterial signal and to select the best injection protocol. RESULTS: An empirical relationship between the arterial peak concentration and the injection parameters was found in the rabbits and pigs, allowing precise prediction of the first-pass profile. Of the four injection scheme strategies tested (standard bolus and bi-, tri-, and multiphasic injection protocols), the multiphasic "ramp" injection protocol provided the most optimal contrast agent pharmacokinetics with a durable plateau of concentration. CONCLUSION: Ramp injection protocol provides an optimized first-pass profile for CE-MRA.

Animals↗

PubMed2005

Renal functional contrast-enhanced magnetic resonance imaging: evaluation of a new rapid-clearance blood pool agent (p792) in sprague-dawley rats.

OBJECTIVES: The objective of the present study was to compare P792, a new rapid clearance blood pool agent characterized by negligible interstitial diffusion but unrestricted glomerular filtration, with Gd-DOTA in both qualitative and quantitative aspects of renal functional magnetic resonance imaging. MATERIALS AND METHODS: Dynamic imaging was performed with a fast T1-weighted gradient-echo sequence on a 1.5-T magnet in 25 Sprague-Dawley rats, after injection of 13 micromol Gd/kg-1 of P792 (n = 10), 100 (n = 10), or 50 micromol Gd/kg-1 of Gd-DOTA (n = 5). Signal-time curves from 6 regions of interest (ROIs), including renal parenchyma and contents, were analyzed. RESULTS: Qualitative analysis depicted a typical pattern of temporal enhancement as previously described with extracellular gadolinium chelates, including early and brief enhancement of the aorta, renal vessels and cortex, quickly followed by enhancement of the medulla and then renal pelvis. However, a decrease in signal intensity was noted in the inner medulla and the renal pelvis approximately 90 seconds after bolus injection, being more marked when using the full dose of Gd-DOTA. Curve analysis showed a similar vascular phase within each parenchymal ROI, confirmed by similar upslopes, which ranged from 0.015 +/- 0.007 to 0.019 +/- 0.005. Following this initial phase, T1-enhancement appeared greater and longer within the medulla and renal pelvis, and subsequently in the whole kidney ROI with P792 (time to maximal enhancement (sec)/ enhancement rate: 85.5 +/- 15.9/3.1 +/- 0.4) as compared with Gd-DOTA full (53.0 +/- 18.9/ 2.7 +/- 0.3) or half dosage (65.2 +/- 20.1/ 2.2 +/- 0.2). The subsequent decrease in signal intensity, characterized by a downslope during the minute following maximal enhancement, was faster with Gd-DOTA (0.006 +/- 0.002) as compared either to P792 or half dosage Gd-DOTA (0.003 +/- 0.001). CONCLUSIONS: Due to its physicochemical and pharmacokinetic properties, P792 allows the use of a reduced dosage of gadolinium, resulting in less T2* effect without compromising T1 enhancement. Thus, P792 appears suitable for renal functional MR imaging.

Animals↗

PubMed2005

How to compare the efficiency of albumin-bound and nonalbumin-bound contrast agents in vivo: the concept of dynamic relaxivity.

RATIONALE AND OBJECTIVES: The objective of this study was to compare, in a rabbit experimental model that mimics a magnetic resonance (MR) angiographic protocol, the efficiency of the following types of compound on the MR signal: (1) a nonalbumin-bound blood pool contrast agent: P792; (2) a weak albumin-bound extracellular contrast agent: Gd-BOPTA; and (3) a strong albumin-bound blood pool contrast agent: MS325. METHODS: The 2 main phases of early distribution after contrast agent injection, ie, the bolus phase (0-15 seconds postinjection) and the postbolus phase (1-5 minutes postinjection) were investigated by measuring Gd blood concentrations in the first 5 minutes postinjection. In the case of MS325 and Gd-BOPTA, the percentage of the free and bound forms were calculated throughout the pharmacokinetic profile. The dynamic relaxivity at 60 MHz in plasma of each contrast agent was determined in the 2 phases after contrast agent injection, ie, the bolus phase and the postbolus phase. RESULTS: Injected under similar conditions, the 3 contrast agents had a comparable profile during the bolus phase (0-15 seconds postinjection). At 1 minute postinjection, only 38% of Gd-BOPTA remained in the blood, whereas 85% of P792 was still present in the blood. MS-325 had an intermediate position with 61% remaining in the blood. During the postbolus phase, the various compounds demonstrated similar behavior: the plasma concentration of P792 was higher than that of MS325 and Gd-BOPTA, ie, Ci/C0 (P792)>Ci/C0 (MS325)>Ci/C0 (Gd-BOPTA). At the peak of the bolus, 75% of MS325 and 93% of Gd-BOPTA was present in free form. This proportion decreased progressively during the postbolus phase, because 5 minutes postinjection, 23% of the free form remained for MS325 and 82% for Gd BOPTA. A significant decrease in dynamic r1 relaxivity was observed at 60 MHz for the products that bind to albumin (Gd-BOPTA and MS325) during the bolus phase. The dynamic relaxivity for MS325 at the bolus phase was 8.6 mMs and 5.2 mMs for Gd-BOPTA. At the postbolus phase, the dynamic relaxivity increased (17.3 mMs for MS325 and 6.7 mMs for Gd-BOPTA). The dynamic relaxivity of P792, which does not bind to albumin, was constantly equal to 26 mMs at each time point of the pharmacokinetic profile (bolus and postbolus phase). CONCLUSIONS: The physicochemical measurements of relaxivity in plasma are made in vitro at a fixed concentration of gadolinium and the value of relaxivity is not necessarily an accurate reflection of the efficiency of the contrast agent in vivo, especially for contrast agents that bind to albumin. Indeed, in vivo, the proportion of free and bound forms of albumin-binding contrast agents varies according to the pharmacokinetic profile, and the relaxivities of albumin-bound and free contrast agents are different. Consequently, the concept of dynamic relaxivity was introduced to compare the efficiency of MS325, Gd-BOPTA, and P792 in vivo. The variation of the dynamic relaxivity of MS325 and Gd-BOPTA between the bolus and postbolus phase is significant (101% for MS325 and 29% for Gd-BOPTA) as a result of the variation in the quantity of bound and free forms during the pharmacokinetic profile. The blood pool agent P792 has different properties, which result from its intravascular retention and its lack of albumin binding. Indeed, contrary to Gd-BOPTA and MS325, the dynamic relaxivity of P792 is higher at the bolus phase (26 mMs) and does not vary during the pharmacokinetic profile. The impact of these different dynamic relaxivities should be integrated in the analysis of the performance of the different classes of contrast agents in clinical MRA protocols.

Animals↗

PubMed2005

Allergy-like reactions to iodinated contrast agents. A critical analysis.

Allergy-like reactions may occur following administration of iodinated contrast media (CM), mostly in at-risk patients (patients with history of previous reaction, history of allergy, co-treated with interleukin-2 or beta-blockers, etc.) but remain generally unpredictable. Severe and fatal reactions are very rare events. All categories of CM may induce such reactions, although first generation (high osmolar CM) have been found to induce a higher rate of adverse events than low osmolar CM. However, no differences were found between the two categories of CM with respect to mortality. Delayed reactions can also occur. There are no differences between the various categories of CM except for non-ionic dimers, which are more likely to induce such effect. Numerous clinical studies have evaluated the prophylactic value of drugs (mostly antihistamines and corticosteroids). Results are unclear and highly variable. Any prevention depends upon the mechanism involved. However, the mechanism of CM-induced allergy-like reaction remains disputed. Relatively recent data revived the hypothesis of a type-I hypersensitivity mechanism. Positive skin tests to CM have been reported. However, the affinity of IgE towards CM has been found to be very low in the only study which actually evaluated it. Other pathophysiological mechanisms (involving direct secretory effects on mast cells or basophils, or activation of the complement system associated or not with the plasma contact system) are also much debated. Anaphylaxis and anaphylactoid reactions are, in the end, clinically undistinguishable.

Anaphylaxis↗

PubMed2005

Migration of iron oxide-labeled human hematopoietic progenitor cells in a mouse model: in vivo monitoring with 1.5-T MR imaging equipment.

PURPOSE: To evaluate the use of clinical 1.5-T magnetic resonance (MR) imaging equipment to depict the in vivo distribution of iron oxide-labeled human hematopoietic progenitor cells in athymic mice. MATERIALS AND METHODS: This study was approved by the ethical committee, and all women had given consent to donate umbilical cord blood for research. Twenty athymic female Balb/c mice underwent MR imaging before and 1, 4, 24, and 48 hours after intravenous injection of (1-3) x 10(7) human hematopoietic progenitor cells labeled with the superparamagnetic iron oxide particles ferumoxides through simple incubation (n = 10) or P7228 through lipofection (n = 10). Fifteen female Balb/c control mice were examined after intravenous injection of the pure contrast agents (n = 6 for both probes) or nonlabeled cells (n = 3). Signal intensities of liver, spleen, and bone marrow on MR images obtained before and after injection were measured and compared for significant differences by using the t test. MR imaging data were compared with the results of immunostaining against human CD31(+) cells and against the coating of the contrast agents; these results served as the standard of reference. RESULTS: Ferumoxides was internalized into more mature CD34(-) cells but not into CD34(+) stem cells, while P7228 liposomes were internalized into both CD34(-) and CD34(+) cells. After injection of iron oxide-labeled hematopoietic cells, a significant decrease in MR signal intensity was observed in liver and spleen at 1, 4, 24, and 48 hours after injection (P < .05) and in the bone marrow at 24 and 48 hours after injection (P < .05). The signal intensity decrease in bone marrow was significantly stronger after injection of iron oxide-labeled cells compared to controls that received injections of the pure contrast agent (P < .05). Results of histopathologic examination confirmed homing of iron oxide-labeled human progenitor cells in the murine recipient organs. CONCLUSION: The in vivo distribution of intravenously administered iron oxide-labeled hematopoietic progenitor cells can be monitored with 1.5-T MR imaging equipment.

Animals↗

PubMed2004

Detection of synovial macrophages in an experimental rabbit model of antigen-induced arthritis: ultrasmall superparamagnetic iron oxide-enhanced MR imaging.

PURPOSE: To evaluate intravenously administered ultrasmall superparamagnetic iron oxide (USPIO) as a marker of macrophage activity in an experimental rabbit model of antigen-induced arthritis. MATERIALS AND METHODS: Unilateral arthritis was induced by means of intraarticular injection of methylated bovine serum albumin in 10 knees of 10 rabbits that had been presensitized to the same antigen. The contralateral knees in these rabbits, as well as six knees in three other rabbits, served as controls. After onset of arthritis, all knees were imaged prior to and 24 hours after administration of USPIO. The magnetic resonance (MR) imaging protocol included T1-weighted spin-echo, T2-weighted fast spin-echo, T2*-weighted gradient-echo, and short inversion time inversion-recovery sequences. Images were analyzed quantitatively and qualitatively with regard to signal characteristics and pattern. MR findings were correlated with histopathologic findings. Wilcoxon signed rank test was used to compare results of signal-to-noise ratio calculations before and after USPIO administration. RESULTS: All knees with intraarticular injection of antigen suspension developed unilateral arthritis, whereas no signs of arthritis occurred in the control knees. On USPIO-enhanced images obtained 24 hours after contrast agent administration, significant T1 (P =.03) and more predominantly T2* (P =.02) and T2 effects (P =.01) were evident in the synovium of all 10 arthritic knees, which reflected USPIO uptake by macrophages in the synovial tissue. To a lesser extent, T2* effects were present also within the joint effusion (P =.01). No significant changes in signal characteristics were detected in the 10 nonarthritic knees in the antigen-injected group or the six knees in the control group (P =.06-.91). Histologic examination confirmed uptake of iron in the macrophages of arthritic knees. Changes in MR signal characteristics within the arthritic synovium and synovial effusion were visually detectable after intravenous administration of USPIO. CONCLUSION: MR imaging at 1.5 T can depict USPIO uptake in phagocytic-active macrophages in an antigen-induced arthritis animal model.

Adjuvants, Immunologic↗

PubMed2004

New model for analysis of dynamic contrast-enhanced MRI data distinguishes metastatic from nonmetastatic transplanted rodent prostate tumors.

Dynamic contrast-enhanced MRI (DCEMRI) data were acquired from metastatic and nonmetastatic tumors in rodents to follow the uptake and washout of a low-molecular-weight contrast agent (Gd-DTPA) and a contrast agent with higher molecular weight (P792). The concentration vs. time curves calculated for the tumor rims and centers were analyzed using the two-compartment model (TCM) and a newly developed empirical mathematical model (EMM). The EMM provided improved fits to the experimental data compared to the TCM. Parameters derived from the empirical model showed that the contrast agent washout rate was significantly slower in metastatic tumors than in nonmetastatic tumors for both Gd-DTPA (P < 0.03) and P792 (P < 0.04). The effects of the tumor on blood flow in "normal" tissue immediately adjacent to the tumors were evident: Gd-DTPA uptake and washout rates were much lower in muscle near the tumor (P < 0.05) than normal muscle farther from the tumor. The results suggest that accurate fits of DCEMRI data provide kinetic parameters that distinguish between metastatic and relatively benign cancers. In addition, a comparison of the dynamics of Gd-DTPA and P792 provides information regarding the microenvironment of tumors.

Animals↗

PubMed2004

Dark lumen magnetic resonance colonography in a rodent polyp model: initial experience and demonstration of feasibility.

PURPOSE: We sought to assess dark lumen magnetic resonance (MR) colonography for the detection of colon polyps in a rodent model with histology as the gold standard. MATERIAL AND METHODS: Fourteen male Wistar rats were subjected to carcinogenic N-methyl-N'-nitro-N-nitrosoguanidine at the age of 4 months to induce colon neoplasms. MR imaging was performed after a time interval of 1 year. Preparation and data acquisition was performed with the animals under full anesthesia. After a body-warm saline enema images were acquired on a clinical 1.5-T whole-body MR system using a standard extremity coil. Plain and contrast-enhanced (0.3 mmol/kg; Gd-DOTA; Dotarem, Guerbet, France) 3-dimensional T1-weighted gradient recall echo images were acquired. Two radiologists analyzed the MR data sets in consensus for lesion depiction. Contrast uptake in colonic wall and polyps was quantitatively assessed by signal-to-noise ratio and contrast-to-noise ratio measurements and compared using a Wilcoxon-Mann-Whitney U test with statistical significance at a P value < 0.05. Finally, all animals were killed, and the MR imaging results were compared with pathologic findings. Sensitivity and specificity were calculated. RESULTS: By pathology, a total of 15 polyps were found in 9 of 14 rats. MR colonography detected 13 of 15 polyps measuring between 4 and 11 mm (mean 7 +/- 0.6 mm) in 8 of 9 animals, resulting in a sensitivity and specificity of 0.87 and 1.0, respectively. Compared with the precontrast data, all polyps showed a statistically significant increase in signal-to-noise ratio (78.2 +/- 6.3 to 167.4 +/- 17.7) and contrast-to-noise ratio (45.4 +/- 5.2 to 124.6 +/- 11.2). CONCLUSION: MR colonography with a dark colon lumen and a bright, contrast-enhanced colon wall appears well suited for the detection of colonic lesions in a rodent model.

Animals↗

PubMed2004

Macrophage endocytosis of superparamagnetic iron oxide nanoparticles: mechanisms and comparison of ferumoxides and ferumoxtran-10.

RATIONALE AND OBJECTIVES: Superparamagnetic iron oxides (SPIO) used as magnetic resonance (MR) contrast agents undergo specific uptake by macrophages. The purpose of this study was first to determine the mechanism of macrophage uptake for Ferumoxides by using competition experiments with specific ligands of scavenger receptors SR-A (I/II) and second, to evaluate and compare the internalization of 2 different contrast agents, Ferumoxides (SPIO) and Ferumoxtran-10 (USPIO: ultrasmall superparamagnetic iron oxide) using macrophages obtained by chemical activation of human monocytic cells. METHODS: Ferumoxides and Ferumoxtran-10 are 2 MR contrast agents, composed of dextran-coated iron oxide nanoparticles. The endocytosis pathway of Ferumoxides was studied using competition experiments on mouse peritoneal macrophages in the presence of specific ligands of scavenger receptors SR-A (types I and II): polyinosinic acid and fucoidan. In vitro assays using THP-1 (human promonocyte) cells activated into macrophages were performed in the presence of the 2 superparamagnetic nanoparticles. The cellular uptake was determined by measuring the iron content using ICP-AES (inductively coupled plasma-atomic emission spectrometry) and by Prussian blue staining. RESULTS: In the presence of polyinosinic acid or fucoidan, the endocytosis of Ferumoxides by mouse peritoneal macrophages was inhibited. This inhibition was obtained using 10 microg/mL of scavenger receptor ligands at a concentration of 62.5 microg Fe/mL of SPIO, and a dose-dependent relationship was observed. Without competitors, the percentage of uptake of Ferumoxides by mouse peritoneal macrophages ranged between 3 and 8%. On the human activated monocyte THP-1 cell assay, Ferumoxides underwent a higher macrophage uptake (between 1.1 and 3%) compared with Ferumoxtran-10 (between 0.03 and 0.12%). This difference is attributed to the larger size of Ferumoxides nanoparticles. CONCLUSIONS: Competition experiments indicate that the cellular uptake of Ferumoxides involves scavenger receptor SR-A-mediated endocytosis. The comparison between Ferumoxides and Ferumoxtran-10 confirms that macrophage uptake of iron oxide nanoparticles depends mainly on the size of these contrast agents.

Animals↗