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Background-Based on the observation that ultrasmall superparamagnetic particles of iron oxides (USPIOs) are phagocytosed by cells of the mononuclear phagocytic system, the purpose of this study was to evaluate their use as a marker of atherosclerosis-associated inflammatory changes in the vessel wall before luminal narrowing is present. Methods and Results-Experiments were conducted on 6 heritable hyperlipidemic and 3 New Zealand White rabbits. 3DMR angiography (MRA) of the thoracic aorta was performed on all rabbits by use of a conventional paramagnetic contrast agent that failed to reveal any abnormalities. One week later, all rabbits except 1 of the hyperlipidemic animals were injected with a USPIO contrast agent (Sinerem, Guerbet) at a dose of 1 mmol Fe/kg. 3D MRA data sets collected over the subsequent 5 days showed increasing signal in the aortic lumen. Whereas the aortic wall of the control rabbits remained smooth and bright, marked susceptibility effects became evident on day 4 within the aortic walls of hyperlipidemic rabbits. Ex vivo imaging of aortic specimens confirmed the in vivo results. Histopathology documented marked Fe uptake in macrophages embedded in atherosclerotic plaque of the hyperlipidemic rabbits. Electron microscopy showed multiple cytoplasmic Fe particles in macrophages. No such changes were seen in control rabbits or in the hyperlipidemic rabbit that had not received Sinerem. Conclusions-USPIOs

Gadolinium-based contrast agents are widely used to enhance image contrast in magnetic resonance imaging (MRI) procedures. Over recent years, there has been a renewed interest in the physicochemical properties of gadolinium chelates used as contrast agents for MRI procedures, as it has been suggested that dechelation of these molecules could be involved in the mechanism of a recently described disease, namely nephrogenic systemic fibrosis (NSF). The aim of this paper is to discuss the structure-physicochemical properties relationships of marketed gadolinium chelates in regards to their biological consequences. Marketed gadolinium chelates can be classified according to key molecular design parameters: (a) nature of the chelating moiety: macrocyclic molecules in which Gd3+ is caged in the pre-organized cavity of the ligand, or linear open-chain molecules, (b) ionicity: the ionicity of the complex varies from neutral to tri-anionic agents, and (c) the presence or absence of an aromatic lipophilic residue responsible for protein binding. All these molecular characteristics have a profound impact on the physicochemical characteristics of the pharmaceutical solution such as osmolality, viscosity but also on their efficiency in relaxing water protons (relaxivity) and their biodistribution. These key molecular parameters can also explain why gadolinium chelates differ in terms of their thermodynamic stability constants and kinetic stability, as demonstrated by numerous in vitro and in vivo studies, resulting in various formulations of pharmaceutical solutions of marketed contrast agents. The concept of kinetic and thermodynamic stability is critically discussed as it remains a somewhat controversial topic, especially in predicting the amount of free gadolinium which may result from dechelation of chelates in physiological or pathological situations. A high kinetic stability provided by the macrocyclic structure combined with a high thermodynamic stability (reinforced by ionicity for macrocyclic chelates) will minimize the amount of free gadolinium released in tissue parenchymas.

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.

Purpose The presence of tumor-associated macrophages (TAMs) in breast cancer correlates strongly with poor outcome. The purpose of this study was to develop a clinically applicable, non-invasive diagnostic assay for selective targeting and visualization of TAMs in breast cancer, based on magnetic resonance (MR) imaging 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 regarding MR signal changes and iron uptake. MMTV-PyMT transgenic mice harboring mammary carcinomas underwent nanoparticle-enhanced MR up to 1 hour (h) and at 24 h post injection (p.i.). The tumor enhancement on MR images was correlated with the presence and location of TAMs and nanoparticles on 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 demonstrated an initial contrast agent perfusion on immediate postcontrast MR images with gradual transendothelial leakage into the tumor interstitium. At 24 h p.i., all tumors demonstrated a persistent signal decline on MR scans. TAM-depletion via αCSF1 mAb lead to significant inhibition of tumor nanoparticle enhancement. Detection of iron using DAB-enhanced Prussian Blue staining, and immunodetection of CD68 localized iron oxide nanoparticles to TAMs, indicating that the MR signal effects on delayed MR images 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.

ObjectivesTo prospectively compare in healthy rats the effect of multiple injections of macrocyclic (gadoterate meglumine) and linear (gadodiamide) gadolinium-based contrast agents (GBCAs) on T1-weighted signal intensity in the deep cerebellar nuclei (DCN), including the dentate nucleus.Materials and MethodsHealthy rats (n = 7/group) received 20 intravenous injections of 0.6 mmol of gadolinium (Gd) per kilogram (4 injections per week during 5 weeks) of gadodiamide, gadoterate meglumine, or hyperosmolar saline (control group). Brain T1-weighted magnetic resonance imaging was performed before and once a week during the 5 weeks of injections and during 5 additional weeks (treatment-free period). Gadolinium concentrations were measured with inductively coupled plasma mass spectrometry in plasma and brain. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data.ResultsA significant and persistent T1 signal hyperintensity in DCN was observed only in gadodiamide-treated rats. The DCN-to-cerebellar cortex signal ratio was significantly increased from the 12th injection of gadodiamide (1.070 ± 0.024) compared to the gadoterate meglumine group (1.000 ± 0.033; P < 0.001) and control group (1.019 ± 0.022; P < 0.001) and did not significantly decrease during the treatment-free period. Total Gd concentrations in the gadodiamide group were significantly higher in the cerebellum (3.66 ± 0.91 nmol/g) compared with the gadoterate meglumine (0.26 ± 0.12 nmol/g; P < 0.05) and control (0.06 ± 0.10 nmol/g; P < 0.05) groups.ConclusionsRepeated administrations of the linear GBCA gadodiamide to healthy rats are associated with progressive and persistent T1 signal hyperintensity in the DCN, with Gd deposition in the cerebellum in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

ObjectivesThe aim of this study was to evaluate Gd retention in the deep cerebellar nuclei (DCN) of linear gadolinium-based contrast agents (GBCAs) compared with a macrocyclic contrast agent.Materials and MethodsThe brain tissue retention of Gd of 3 linear GBCAs (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) and a macrocyclic GBCA (gadoterate meglumine) was compared in healthy rats (n = 8 per group) that received 20 intravenous injections of 0.6 mmol Gd/kg (4 injections per week for 5 weeks). An additional control group with saline was included. T1-weighted magnetic resonance imaging was performed before injection and once a week during the 5 weeks of injections and for another 4 additional weeks after contrast period. Total gadolinium concentration was measured with inductively coupled plasma mass spectrometry. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data.ResultsAt completion of the injection period, all the linear contrast agents (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) induced a significant increase in signal intensity in DCN, unlike the macrocyclic GBCA (gadoterate meglumine) or saline. The T1 hypersignal enhancement kinetic was fast for gadodiamide. Total Gd concentrations for the 3 linear GBCAs groups at week 10 were significantly higher in the cerebellum (1.21 ± 0.48, 1.67 ± 0.17, and 3.75 ± 0.18 nmol/g for gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide, respectively) than with the gadoterate meglumine (0.27 ± 0.16 nmol/g, P < 0.05) and saline (0.09 ± 0.12 nmol/g, P < 0.05). No significant difference was observed between the macrocyclic agent and saline.ConclusionsRepeated administrations of the linear GBCAs gadodiamide, gadobenate dimeglumine, and gadopentetate dimeglumine to healthy rats were associated with progressive and significant T1 signal hyperintensity in the DCN, along with Gd deposition in the cerebellum. This is in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

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