Catechol derivatives-coated Fe3O4 and gamma-Fe2O3 nanoparticles as potential MRI contrast agents.

Superparamagnetic iron oxide nanoparticles, Fe(3)O(4) and gamma-Fe(2)O(3), were produced by the so-called polyol process. In order to stabilize the particles in a physiological environment as potential contrast agents for Magnetic Resonance Imaging (MRI), the as-prepared particles were successfully transferred to an aqueous medium through ligand exchange chemistry of the adsorbed polyol species with the dopamine or the catechaldehyde. The ligands were able to participate in bidentate binding to the nanoparticles surface and to improve the stability of aqueous suspensions of the nanoparticles. Analysis was performed by various techniques including X-ray diffraction, transmission electron microscopy, infrared spectroscopy and thermal analysis. The results of magnetic measurements and initial in vitro magnetic resonance imaging essays are presented for the pre- and post-surface modified nanoparticles, respectively and discussed in relation with their structure and microstructure.

A new gadolinium-based contrast agent for magnetic resonance imaging of brain tumors: kinetic study on a C6 rat glioma model.

T1-weighted magnetic resonance imaging (MRI) was used to evaluate the potential interest of a new Gd-based contrast agent, termed P760, to characterize brain tumor heterogeneity and vascularization and to delineate regions containing permeable vessels. The C6 rat glioma model was used as a model of high-grade glioblastoma. The signal enhancement was measured as a function of time in the vascular compartment and in different regions of interest (ROIs) within the tumor after the injection of 0.02 mmol x kg(-1) of P760. The results were compared to those obtained after the injection of 0.1 mmol x kg(-1) of Gd-DOTA. We showed that P760, in spite of a Gd concentration five times smaller, produces an enhancement in the blood pool similar to that produced by Gd-DOTA. It was shown that P760 makes possible an excellent delineation of regions containing vessels with a damaged blood-brain barrier (BBB). Images acquired 5-10 minutes after P760 injection showed the location of permeable vessels more accurately than Gd-DOTA-enhanced images. The enhancement produced in the tumor by P760 was, however, less than that produced by Gd-DOTA. The extravasation and/or diffusion rate of P760 in the interstitial medium were found to be strongly reduced, compared to those found with Gd-DOTA. This study suggests that the new contrast agent has promising capabilities in clinical imaging of brain tumors.

Preclinical profile of the monodisperse iodinated macromolecular blood pool agent P743.

RATIONALE AND OBJECTIVES: To summarize the chemical synthesis, physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P743, a new macromolecular iodinated contrast medium. METHODS: The synthesis and molecular modeling of the iodinated macromolecule P743 are described. The pharmacokinetic profile was established in rabbits and rats. Acute toxicity in mice, renal tolerance in normal rabbits, and renal tolerance in uninephrectomized, dehydrated rats undergoing selective intrarenal injection was evaluated. In vitro permeability effects on isolated mastocytes and on the coagulation pathways were carried out. Computed tomography vascular imaging was performed after intravenous injection of P743 (300 mg I/kg) in rabbits and compared with the nonspecific nonionic agent iobitridol. RESULTS: P743 is a monodisperse, macromolecular iodinated contrast medium. In both rabbits and rats, P743 showed a pharmacokinetic profile consistent with that of a rapid-clearance blood-pool agent. Its diffusion through the endothelium was found to be low in vitro, thus confirming early confinement of this macromolecule, unlike nonspecific contrast media. In both species, P743 was excreted by glomerular filtration. Acute toxicity disclosed no mortality at the highest volume that could be injected into mice, leading to a median lethal dose greater than 8.9 g I/kg. Renal tolerance was found to be good in both euvolemic rabbits and uninephrectomized, dehydrated rats. No histamine or leukotriene B4 release was found on RBL-2H3 isolated mastocytes. P743 did not interfere with the coagulation pathways. Imaging experiments confirmed that P743 remains in the vascular compartment for a longer time than does iobitridol, thus allowing vascular enhancement that is twice as high as that of iobitridol in the recirculation phase. CONCLUSIONS: The pharmacokinetic and imaging profiles of P743, a new, monodisperse, macromolecular blood-pool iodinated contrast medium, were consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Further experimental imaging studies are required to define the clinical interest in such molecules.

Reversibility of experimental acute renal failure in rats: assessment with USPIO-enhanced MR imaging.

The purpose of this study was to evaluate the potential reversibility of kidney lesions in an experimental model of acute renal failure using ultra-small particles of iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging. This study was conducted in 21 uninephrectomized rats using a model of iodinated contrast media-induced renal failure. Thirteen rats received selective intraarterial renal administration of diatrizoate (370 mg/ml) and were compared with two control groups, including six animals injected with saline and two noninjected animals. MR imaging was performed 28 hours, 8 days, and 22 days after the procedure. Each MR session included axial and coronal T1- and coronal T2-weighted images before and after intravenous administration of 60 micromol Fe/kg of USPIO. The rats were sacrificed immediately after the last MR session for pathologic evaluation. MR images were qualitatively and quantitatively interpreted with respect to pathologic data, and differences were statistically studied. At day 22, histology showed 4 severely diseased kidneys with focal areas of necrosis, 5 mildly diseased kidneys with tubular vacuolization, and 12 normal kidneys. On quantitative data, a high correlation between the percentage of negative enhancement and histologic data was observed (P < 0.05). Qualitative interpretation showed a sensitivity and specificity of USPIO-enhanced T2-weighted MR images of 88% and 91%, respectively. Follow-up enhancement curves showed a constant increase of intrarenal USPIO negative enhancement in normal kidneys between day 1 and day 22, whereas all severely involved kidneys displayed higher USPIO negative enhancement at day 1 without significant changes over time until day 22. USPIO may be useful for in vivo follow-up of the reversibility of experimentally induced iodinated contrast media renal impairment in animals.

Pilot MR evaluation of pharmacokinetics and relaxivity of specific blood pool agents for MR angiography.

RATIONALE AND OBJECTIVES: To evaluate the use of two new blood pool contrast agents (P760, P775) compared with a low-molecular-weight gadolinium chelate in MR angiography. METHODS: The r1 efficiency of P760 was evaluated in vitro at 1.5 T; 3D abdominal contrast-enhanced MR angiography with qualitative analysis was compared in four rabbits after injection of incremental doses of P760 and in one rabbit after Gd-DOTA. A dynamic MR study was performed using a 2D T1-weighted turbo-flash MR sequence after injection of P760, P775, and Gd-DOTA. Each compound was tested at equivalent doses in three rabbits to assess r1 efficiency. Quantitative analysis of signal intensity in the aorta, the inferior vena cava, the renal cortex, and the medulla was performed. RESULTS: In vitro, the r1 efficiency of P760 was 23.3 mmol(-1) x L x sec(-1) at 1.5 T. Injection of a dose of P760 10 times less than Gd-DOTA allowed similar vessel visualization. The signal intensity peak and first-pass contrast kinetics in the aorta and the inferior vena cava were similar with the three products. Compared with P760 and Gd-DOTA, P775 allowed a greater renal cortex signal intensity at the first pass and a faster decrease on delayed images. CONCLUSIONS: The superior r1 efficiency of P760 and P775 was confirmed in vitro and in vivo at 1.5 T compared with Gd-DOTA, and P775 proved to be a rapid-clearance blood pool agent.

P760 and P775: MRI contrast agents characterized by new pharmacokinetic properties.

RATIONALE AND OBJECTIVES: In this paper we discuss novel MR imaging blood pool agents characterized by new pharmacokinetic properties. METHODS: The pharmacokinetics of the products were studied in a rabbit model. The potential of these new products was demonstrated in experimental MR imaging. RESULTS AND CONCLUSION: Three main classes of blood pool agents have been defined and characterized according to their pharmacokinetic properties: low diffusion agents, rapid clearance blood pool agents, slow clearance blood pool agents. Each kind of blood pool agent is expected to have different diagnostic applications.

Infarcted myocardium in pigs: MR imaging enhanced with slow-interstitial-diffusion gadolinium compound P760.

PURPOSE: To assess the value of P760, a gadolinium chelate with slow interstitial diffusion and high relaxivity, for magnetic resonance (MR) imaging of acute myocardial infarction in pigs. MATERIALS AND METHODS: First-pass gradient-echo MR imaging and spin-echo MR imaging were performed with P760 and then with gadoterate meglumine in eight pigs with occlusive acute myocardial infarction. P760 signal intensity enhancement and clearance were compared with those of gadoterate meglumine. RESULTS: The first-pass enhancement ratio of P760 in normal myocardium was higher than that in infarcted myocardium (1.37 +/- 0.06 [SEM] vs 1.05 +/- 0.03, P = .03). The myocardial first pass showed a blood pool-like curve for P760. The blood pool enhancement ratio 40 seconds after injection was higher for P760 than for gadoterate meglumine (left ventricular cavity, 1.75 +/- 0.06 vs 1.45 +/- 0.06, P = .009). Spin-echo MR imaging showed improved contrast between normal and infarcted myocardium after P760 administration: The ratio before contrast material administration was 0.21 +/- 0.03, that at 15 minutes was 0.48 +/- 0.05 (P = .002), and that at 25 minutes was 0.47 +/- 0.07 (P = .003). CONCLUSION: P760 is an MR imaging contrast agent characterized by low diffusion, a blood pool effect soon after low-dose administration, and fast elimination. This agent is useful for improved myocardial perfusion MR imaging of acute myocardial infarction.

Equilibrium phase MR angiography of the aortic arch and abdominal vasculature with the blood pool contrast agent CMD-A2-Gd-DOTA in pigs.

Meglumine-carboxymethyldextran-ethylenediamino-gadoterate (CMD-A2-Gd-DOTA) was evaluated as a blood pool contrast agent for magnetic resonance angiography (MRA). MRA of large body vasculature was performed in seven pigs using a gradient-echo sequence at 1.5 T before and after 0.05 mmol/kg CMD-A2-Gd-DOTA injection. The signal- and contrast-to-noise ratios (SNRs, CNRs) were measured, as well as the pharmacokinetic clearance pattern. CMD-A2-Gd-DOTA visualized the vasculature with a high SNR and CNR for over 110 minutes after injection, but for the renal arteries the CNR was only significant within 15 minutes. Image quality was maximum within 15 minutes, producing enhancement (mean +/- SD) as follows: aortic arch 738 +/- 272%, abdominal aorta 393 +/- 123%, left renal artery 202 +/- 95%, right renal artery 248 +/- 107%, inferior vena cava 371 +/- 129%, and portal vein 513 +/- 145%, all P values < or =0.001. The clearance pattern was triphasic. Due to the excellent enhancement of vasculature without background enhancement, CMD-A2-Gd-DOTA is potentially a useful MR blood pool contrast agent for equilibrium phase MRA.

Ultrasmall superparamagnetic iron oxide particles (AMI 227) as a blood pool contrast agent for MR angiography: experimental study in rabbits.

The purpose of this study was to evaluate the contribution of an ultrasmall superparamagnetic iron oxide particles (USPIOs) based contrast agent (AMI 227), in a transverse three-dimensional time-of-flight TONE MR angiography sequence of abdominal aorta in rabbits. The main goal was to assess improvement in the visualization of small arteries such as renal arteries, when using such a sequence. Imaging experiments were performed on a 1.5 T magnet, using a transverse 3D time-of-flight (TOF) tilted optimized nonsaturating excitation (TONE) sequence with magnetization transfer suppression. The contrast media used were composed of a USPIO core surrounded by a dextran-surfactant (AMI 227). Different concentrations of AMI 227 were evaluated in 12 rabbits. Concentrations varied within the range 8.5-34 micromol Fe/kg - bw: 8.5 micromol Fe/kg (three rabbits); 17 micromol Fe/kg (three rabbits); 25.5 micromol Fe/kg (three rabbits); 34 micromol Fe/kg (three rabbits). A visual analysis based on the improvement of visualization of small arteries (renal arteries) on MIP images and a quantitative analysis based on the percentage of contrast enhancement of the aorta plotted against distance in the slab from the top edge of the acquisition volume were obtained. A signal-to-noise ratio enhancement of the distal part of the aorta and only improvement in the delineation of the renal arteries were noted when using low concentrations of the contrast media. A loss of signal-to-noise ratio of the aorta and a decrease in arterial visualization were respectively noted with higher concentration of contrast media. In this experimental study, using a transverse three-dimensional TOF TONE MR angiography sequence of renal arteries, in which sequence the saturation effect is minimized, the use of AMI 227 allows only improvement in the delineation of small arteries when using low concentrations of contrast media.

MR assessment of iodinated contrast-medium-induced nephropathy in rats using ultrasmall particles of iron oxide.

The purpose of this study was to determine the diagnostic value of ultrasmall particles of iron oxide (USPIO)-enhanced MR imaging at different concentrations to evaluate experimental nephropathy. This study was conducted in 23 uninephrectomized rats using a model of iodinated contrast media-induced renal failure. Eleven rats received selective intra-arterial renal administration of diatrizoate (370 mg I/ml) and were compared to two control groups, including five animals injected with isotonic saline and seven noninjected animals. MR imaging was performed 28 hours after the procedure, including T1- and T2-weighted images before and after intravenous administration of successively 5 mumol Fe/kg and 60 mumol/kg of USPIO. Results were interpreted qualitatively and quantitatively with respect to pathologic data, and differences were studied statistically. The maximal signal intensity decrease was noted in normal kidneys in cortex (-65 +/- 4%) and medulla (-84 +/- 5%) on T2-weighted images after injection of 60 mumol/kg of USPIO. At this dose, diseased kidneys displayed less signal intensity decrease than normal kidneys on T2-weighted images (p = .05). Moreover, qualitative analysis showed that the highest sensitivity and specificity to diagnose kidney involvement were obtained with T2-weighted MR images (75% and 91%, respectively) when 60 mumol/kg of USPIO were used (p < .01). USPIO should be useful for in vivo evaluation of the severity of experimentally induced iodinated contrast media renal impairment in animals.

Contribution of Sinerem used as blood-pool contrast agent: detection of cerebral blood volume changes during apnea in the rabbit.

The authors suggest that ultra-small paramagnetic iron oxide (USPIO) particles used as blood pool contrast agents may increase the sensitivity of midfield MRI (i.e., less than 1.5 Tesla) to physiological variations in cerebral blood volume. This hypothesis was tested on a rabbit model of apnea which increases pCO2 and cerebral blood volume. Using Sinerern as the USPIO at a blood concentration of 60 mumol Iron/kg body weight, an 8% T2*-weighted signal decrease could be observed at 1.0 T with 25-33% increase in pCO2. Comparatively, in the absence of USPIO, T2*-weighted signal dropped only 4% during apnea and after mild hyperoxygenation beforehand, due to increased deoxyhemoglobin content. These preliminary data suggest that USPIOs could play an important role in functional MRI at midfield strength, by sensitizing the signal to cerebral blood volume changes.

Carboxymethyl-dextran-gadolinium-DTPA as a blood-pool contrast agent for magnetic resonance angiography. Experimental study in rabbits.

RATIONALE AND OBJECTIVES: The authors evaluate the efficiency of various doses of a paramagnetic macromolecular contrast agent, a gadolinium (Gd)-DTPA-dextran conjugate, as a blood-pool contrast media, in a transverse three-dimensional time-of-flight (TOF) magnetic resonance (MR) angiography sequence of the abdominal aorta in rabbits. METHODS: Imaging experiments were performed on a 1.5-T magnet, using a transverse three-dimensional TOF tilted optimized nonsaturating excitation (TONE) sequence. The macromolecular contrast media used was a carboxymethyl-dextran-Gd-DTPA (CMD-Gd-DTPA). Different concentrations of CMD-Gd-DTPA (0.005, 0.01, 0.03, 0.05 mmol Gd/kg) were evaluated. A comparative study using Gd-DOTA (0.01 and 0.1 mmol/kg) was performed. A visual analysis based on the gain in the visualized length of small arteries (renal arteries), and a quantitative analysis based on the percent contrast enhancement of the aorta plotted against distance in the slab from the top edge of the acquisition volume were obtained. RESULTS: A signal-to-noise ratio enhancement of the distal part of the aorta and an improvement in the visualized length of the renal arteries were noted for concentrations of CMD-Gd-DTPA ranging form 0.01 to 0.05 mmol Gd/kg. Venous enhancement was noted for concentrations greater than 0.01 mmol Gd/kg when using CMD-Gd-DTPA or Gd-DOTA. CONCLUSION: Carboxymethyl-dextran-Gd-DTPA reduced, in part, the saturation effect in a three-dimensional transverse TOF TONE MR angiography in rabbits. To prevent venous enhancement, observed with the higher concentrations used in this study, a decrease in the polydispersity of the polymer should be a goal in the future. Rapid extravasation of the low-molecular weight fraction of the polymer could explain the venous enhancement.

Time course of biodistribution and changes in density following administration of iobitridol in rabbits. A comparative study vs iohexol.

PURPOSE: A new nonionic low-osmolality contrast medium, iobitridol (Xenetix 350) was compared with iohexol (Omnipaque) after i.v. injection in anesthetized rabbits to assess efficacy in CT examinations and biodistribution. MATERIAL AND METHODS: The densities in test tubes and the pharmacogenetics and biodistribution of iobitridol 350 and iohexol were compared in rabbits. CT of the brain, liver, the abdominal aorta and the kidneys was performed before and after injection of the contrast media. RESULTS: In aqueous medium, iobitridol absorbed roentgen rays in a manner exactly identical to that of iohexol. Within 15 min following injection of iohexol and iobitridol at a dose of 300 mg I/kg, both contrast agents resulted in aortic enhancement which decreased with time. An increased attenuation of the liver also occurred, decreasing with time. There was no significant enhancement in the brain but enhancement was found in the renal pelvocalyceal cavities 10 min postinjection. No significant difference was found between the 2 contrast agents under the study conditions. CONCLUSION: As could be expected from its behavior as a tracer of extracellular fluid, iobitridol resulted in significant changes in the signal, corresponding to its vascular, hepatic and renal pharmacokinetics in rabbits.

[Magnetic resonance contract agents and perfusion imaging]. / Produits de contraste IRM et imagerie de perfusion.

Contrast agents may be categorised as non-specific or specific agents. Non-specific agents are freely diffusible in the extracellular and extravascular compartment with the exception of the brain where only blood brain barrier lesions enables the contrast agent to pass. In the specific agent group, a new class of products has been developed, that of blood pool contrast agent, which are distributed in the total intravascular volume and are slowly cleared from the blood. Crossing the healthy capillary wall is limited and depends both on the pathological state of the endothelial permeability tissue of the organ under interest and on the characteristics of the contrast agent (size, charge, molecular shape...). The diagnostic efficacy in perfusion imaging including cerebral perfusion is modulated by the pharmacokinetic profile of the blood pool contrast agent. One way to improve the vascular residence time, consists in binding a vector such as synthetic polymer or a biological macromolecule and a lanthanide like Gd3+, Mn2+, Dy3+ or metal ions. A second way is the synthesis of ultrasmall iron oxide nanoparticles which could escape rapid recognition by the monocyte macrophage phagocytic system mainly of liver and spleen. Because of their cristalline structure and the large number of non-paired spins, five electrons for the iron metal, the nanoparticles behave as magnetic domain when an external field is applied. They consequently have a high dipolar magnetic moment, and can produce a T2 effect in vivo, resulting in a drop in the magnetic resonance signal. Possible interests and developments toward perfusion imaging are demonstrated in experimental models studies.

Capillary leakage of a macromolecular MRI agent, carboxymethyldextran-Gd-DTPA, in the liver: pharmacokinetics and imaging implications.

Capillary leakage of a macromolecular contrast agent, Carboxymethyl Dextran-Gd-DTPA (CMD-Gd-DTPA) was characterized in a highly permeable system, the liver, to assess its potential as a blood pool marker. Its elimination kinetics in hepatic lymph were compared in nephrectomized rabbits with that of a tracer of extra cellular fluid space, Gd-DOTA. Four parameters were defined: volume of distribution, normalized initial leakage rate (ILRn), maximum ratio of lymph and plasma concentrations (max Cl/Cp), and the time to obtain this maximum ratio. The effect of this leakage was studied on MR images by comparing liver contrast enhancement after injection and after almost total removal of the contrast agent from the blood by exchange transfusion. Capillary leakage of CMD-Gd-DTPA was detected in lymph. Compared to Gd-DOTA, it was slower (ILRn = 0.36 10(-5) l min-1 for CMD-Gd-DTPA and ILRn = 2.6 10(-5) l min-1 for Gd-DOTA), less abundant (max Cl/Cp was 80% for CMD-Gd-DTPA and 100% for Gd-DOTA). Liver enhancement remained stable, which indicated that the leakage did not modify the enhancement induced by the intravascular fraction of the contrast agent. These results obtained in a highly permeable capillary model indicate that this agent can be used as a selective blood pool enhancer.

USPIO-enhanced MR imaging of glycerol-induced acute renal failure in the rabbit.

Enhanced-MR imaging in combination with ultrasmall superparamagnetic iron oxide (USPIO) was used in the glycerol-induced model of acute renal failure (ARF) in the rabbit to detect renal perfusion abnormalities. A control group (n = 5) and an ARF group (n = 5) were studied after intramuscular injection of glycerol (10 ml/kg) with T2-weighted spin-echo sequence at 1.5 T and a 27 mumol/kg IV dose of iron. The signal intensity (SI) was quantified in the cortex, the outer medulla (OM), and the inner medulla (IM). In control rabbits, the maximum SI decrease after USPIO injection was in the OM (76% +/- 3.6), as this is the region of maximal vascular density, then in the IM (73.4% +/- 2.9). In the glycerol group, SI loss in the OM (61% +/- 12.6) and the IM (45.2% +/- 16.24) was significant less than in the control group (p < .05). Pathology results showed fibrinous thrombus in the efferent arterioles and congestive aspect of the vasa recta in the medulla. We argue that a reduced medullary concentration of USPIO in the renal failure group is indicative of medullary hypoperfusion.