P. Jallet

Iron oxide nanoparticles for use as an MRI contrast agent: Pharmacokinetics and metabolism☆

The pharmacokinetics and metabolism of a new preparation of superparamagnetic iron oxide nanoparticles were evaluated by 59Fe radiotracer studies and histologic examination of mice liver and spleen tissues (light and transmission electron microscopy). In the first 30 min following IV injection of the product half of the dose injected remains in the blood, the other part being sequestered mainly by the mononuclear phagocyte system (MPS). In the first five days following IV administration of the nanoparticles, early metabolization of the iron oxide cores occurs, revealed by modification of their aspect in the lysosomes of Kupffer cells and macrophages of the splenic red pulp. The incorporation of 59Fe is then observed in RBC of the mice. These results are discussed in relation with the physicochemical properties of this new preparation of nanoparticles, and compared with current pharmacokinetic data concerning injectable particle systems.

In vivo quantitative microimaging of rat spinal cord at 7T.

In vivo T2, ADC, and MT properties of the GM and WM of the rat spinal cord were measured at 7T in the cervical region. The GM T2, T2GM = 43.2 ± 1.0 msec is significantly reduced compared to the WM T2, T2WM = 57.0 ± 1.6 msec. Diffusion is anisotropic for both GM and WM, with a larger ADC value along the cord axis (ADCGM// = 1.05 ± 0.09 10−9 m2sec−1 and ADCWM// = 1.85 ± 0.18 10−9 m2sec−1) than perpendicular to this plane (ADCGM⊥ ∼ 0.50 * 10−9 m2sec−1 and ADCWM⊥ ∼ 0.18 * 10−9 m2sec−1). The MT properties do not significantly differ between the WM and the GM, but allow one to distinguish the thin CSF layer from the WM. DWI with the sensitizing gradient perpendicular to the cord axis leads to the best contrast between GM and WM in the cervical region. Magn Reson Med 44:893–898, 2000.

Superparamagnetic iron oxide nanoparticles as a liver MRI contrast agent: Contribution of microencapsulation to improved biodistribution☆

We have developed a new method of synthetizing superparamagnetic iron oxide nanoparticles, consisting in the modifications of Moldays method, which ensures high relaxivity (2.4 10(5) s-1.M-1.L), good chemical stability, singular biodistribution and a considerable safety margin. The ED (Efficace Dose) to LD50 ratio is 1/2400 instead of 1/50 for Gd-DTPA. In order to develop a magnetite-delivery system to the liver we have incorporated the nanoparticles into biodegradable synthetic microcapsules. Encapsulated 59Fe oxide nanoparticles are injected into rats; in these conditions the sequestration is 9-fold greater in liver and 6 and 5 times lower in blood and carcase, respectively. This modification of the biodistribution enables the use of magnetite containing microcapsules at only 0.3 mg/kg iron to obtain an improved contrast in liver.

Regional assessment of wall curvature and wall stress in left ventricle with magnetic resonance imaging

Left ventricular functional abnormalities are associated with regional increases of wall stress and modifications of wall curvature. This study describes the integration of the short-axis and long-axis wall curvatures for determining peak systolic wall stress. Quantification was realized with cine magnetic resonance imaging (MRI) from the location of the endocardial and epicardial borders of the left ventricle on pairs of consecutive short-axis sections. Fifteen normal volunteers were subjected to cine MRI, and different methods of calculating peak systolic wall stress were compared. A short-axis analysis showed a 55 +/- 13% increase of the circumferential mean of the peak systolic wall stress between apical and basal sections. Regarding the curvature, no significant increase of wall stress was observed except on the septal wall (31 +/- 18%). Short-axis studies proved to be insufficient for determining the regional variations of left ventricular wall stress and for providing normal reference values for the location of abnormal regions in patients.

High‐field quantitative transverse relaxation time, magnetization transfer and apparent water diffusion in experimental rat brain tumour

The potential of quantitative parameter images of transverse relaxation time T2, apparent diffusion coefficient (ADC) and magnetization transfer ratio (MTR) to characterize experimental brain tumours was studied. Necrosis or haemorrhage can be detected using either MTR, ADC or T2 (necrosis—MTR reduced by 35%, ADC and T2 increased respectively by 170% and 100% compared with normal brain tissue; haemorrhage—MTR increased by 60%, ADC and T2 decreased by 40% and 20%, respectively). Normal brain tissue can only be distinguished from tumour on T2 and MTR parameter images. However, for small tumours (10 µl), the best contrast is observed with MTR, ca. 30%, whereas for T2 the contrast is ca. 10%. Copyright

Three-dimensional coronary artery mr imaging using prospective real-time respiratory navigator and linear phase shift processing : Comparison with conventional coronary angiography

Respiratory gating with navigator echo is a recent technique to detect diaphragm position in 3D magnetic resonance (MR) coronary angiography. The purpose of our study was to image proximal coronary arteries and to detect significant stenoses in patients with coronary artery diseases and to compare with contrast enhanced angiography results. Twenty patients with coronary artery diseases who were referred for conventional angiography underwent magnetic resonance angiography (MRA). Three-dimensional gradient echo volumes were acquired using cardiac and respiratory gating and fat suppression. Using reformatted oblique planes and maximum intensity projection technique, visualization coronary segments and detection of significant coronary stenoses were made. Eighty-three coronary segments were analyzed. The sensitivity and specificity were 65% and 93%, respectively. The corresponding positive and negative predictive values were 69% and 91%. This study shows the ability to image correctly coronary arteries and to identify proximal stenoses, but image quality need to be improved for an efficiency detection of coronary artery stenoses in clinical practice.

GLOBAL LEFT VENTRICULAR CARDIAC FUNCTION : COMPARISON BETWEEN MAGNETIC RESONANCE IMAGING, RADIONUCLIDE ANGIOGRAPHY, AND CONTRAST ANGIOGRAPHY

RATIONALE AND OBJECTIVES Cardiac magnetic resonance imaging (MRI) has been shown to be a robust and noninvasive method to assess left ventricular (LV) cardiac function. This study sought to assess volumes and mass calculated with MRI using fast techniques for acquisition and postprocessing, and to compare results in terms of cost-effectiveness with those of radionuclide angiography (RNA) or contrast angiography (CA). METHODS Thirty-five patients and 15 healthy volunteers were studied. All patients underwent an MRI examination during the same period that they underwent ventriculography (26 patients) or radiography (25 patients). From 7 to 11 short-axis slices were acquired with a breath-hold fast-gradient echo-segmented sequence from apex to base. Contours were drawn with an automated border detection software. RESULTS Ejection fraction (EF) correlated well between modalities (r = 0.77, P<0.001, for MRI and RNA; r = 0.72, P< 0.001, for MRI and CA). CONCLUSIONS Cardiac MRI is a fast and accurate technique for estimation of LV volumes, EF, and mass.

Early detection of liposome brain localization in rat experimental allergic encephalomyelitis.

Abstract Blood-brain barrier (BBB) permeability increases prior to the development of clinical signs in early-stage multiple sclerosis (MS). Detection of subtle changes would thus be helpful for diagnostic purposes and rapid therapeutic decisions before new episodes. Since multiple sclerosis and experimental allergic encephalomyelitis (EAE) have numerous common features, in particular BBB-permeability characteristics, and since we have previously shown that BBB localization is disturbed by tumors, embolism, and mannitol injection, we investigated BBB-liposome permeability in an EAE rat model. Twenty young male Lewis rats received a single intradermal inoculation of guinea-pig spinal cord. The effect of the Freund’s adjuvant and spinal cord alone on brain permeability were also assessed. In order to compare solution permeability and liposome localization, radioactive liposomes and, 1 h later, 99mTc-DTPA were injected intravenously. Scintigraphic acquisitions were obtained to follow the biodistribution of radioactivity in the whole body. Each rat was subjected to a first examination before inoculation and then every two days until completion and may be considered as its own control. EAE induced a previously unreported increase in global-body permeability, probably due to inflammation. Liposome brain localization and brain/heart ratio were significantly different between normal animals and those with early-stage EAE (before appearance of clinical signs) and distinguished between different disease stages in clinically patent EAE. The index of disease progression was modified earlier than with 99mTc-DTPA injection. One explanation may be particle pick-up by circulating macrophages, which cross the BBB during this pathology. For clinical applications, experiments must be confirmed on models more reliable for human multiple sclerosis.

Liver-directed superparamagnetic iron oxide: Quantitation of T2 relaxation effects

A new liver-directed superparamagnetic iron oxide nanoparticle preparation, MDL, is described. MDL is derived from previously developed MD particles only by modification of the characteristics of the coating:chemical structure and charge. The biodistribution, pharmacokinetics, and intratissular localization of both 59Fe-labeled MD and MDL particles were analyzed. R2 relaxivities determined in aqueous solution are compared to measurements in liver tissue and to R2 of nanoparticles incorporated into synthetic microcapsules, which represent a simplified cell pattern. T2 relaxation effects of both preparations in liver tissue are discussed relative to physical parameters such as iron oxide core dimension, total particle size, and charge, and pharmacological properties such as biodistribution, pharmacokinetics, and extra/intracellular localization.

Glomerular hyperfiltration in type I, type II, and secondary diabetes

Glomerular hyperfiltration, a risk factor for diabetic nephropathy, has been reported in type I insulin-dependent diabetics, but it is not clear if it occurs in other types of diabetes. To ascertain the prevalence of glomerular hyperfiltration in various types of diabetes, we measured glomerular filtration rate (GFR) in 158 diabetics (91 type I, 36 type II without insulin treatment, 20 type II with insulin treatment, and 11 subjects with diabetes secondary to chronic pancreatitis), and classified them as hyper-, normo-, or hypofiltration according to values measured in 36 age-match controls. After elimination of subjects with overt renal disease or hypertension, glomerular hyperfiltration was detected in 35% of the type I diabetics, 32% of the type II diabetics without insulin treatment, one subject with chronic pancreatitis, and one type II diabetics with insulin treatment. Glomerular hyperfiltration was associated with high blood glucose in type I, insulin-dependent diabetics, and with a high apolipoprotein B/A1 ratio in type II, non-insulin-dependent diabetics without insulin treatment. In all subjects with glomerular hyperfiltration, GFR values and urinary albumin excretion were positively related (r = 0.33; n = 34; p = 0.05). Glomerular hyperfiltration is detectable among all types of diabetics.