Albumin-bound MRI contrast agents: the dilemma of the rotational correlation time

Human serum albumin (HSA) binds numerous molecules, among which are suitably designed MRI contrast agents. The rotational tumbling of the protein is thus one of the parameters likely to affect the in vivo relaxivity of these agents. Literature unveils discrepancies about the value of the rotational correlation time (τ_R) of HSA. In the present work, the τ_R of this protein has been determined by studying the deuterium relaxation rate of small molecules known for their strong binding to HSA (warfarin and 4-hydroxycoumarin). Values of approx. 20–22 ns are obtained at 310 K in a 4% HSA solution and are in good agreement with the theoretical predictions.     

Clinical assessment of myocardial viability using MRI during a constant infusion of Gd-DTPA

This study assessed the accuracy and feasibility of magnetic resonance imaging (MRI) during a constant infusion of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) for the determination of myocardial viability in patients with recent acute myocardial infarction (AMI). Nine patients were studied within 10 days of AMI. Rest-redistribution²⁰¹Thallium (²⁰¹Tl) single photon emission computed tomography (SPECT) was used as a gold standard for viability. Using MRI, regional perfusion was assessed using dynamic imaging during a bolus injection of Gd-DTPA and viability was assessed during a continuous infusion. Finally, cine MR images were acquired at baseline, during low-dose dobutamine infusion and after recovery. To assess viability, the left ventricle was divided into 16 segments and signal intensity in corresponding MRI and redistribution SPECT segments were compared. Wall thickening index (WTI) was determined at each step during the dobutamine study. The results revealed that in five patients, reduced perfusion in infarcted regions was observed qualitatively during dynamic first pass imaging. There was a significant inverse correlation between²⁰¹Tl uptake and MRI signal intensity, i.e. infarcted tissue (low²⁰¹Tl uptake) had increased MR signal intensity. Segments were separated into normal (²⁰¹Tl uptake >90%) and infarcted (<60%). Infarcted MRI segments had greater signal intensity than normal segments (179±50 vs. 102±14%;P<0.0001). WTI in normal segments increased by 18±8.5% (P<0.0001) from baseline to 10 μg/kg per min of dobutamine while infarcted tissue WTI decreased 2.8±7.2% (P=0.17). Thus regions of myocardium that were infarcted as defined by reduced²⁰¹Tl uptake and absent contractile reserve showed greatly increased MRI signal intensity during a constant infusion of Gd-DTPA. The use of MRI during a constant infusion of Gd-DTPA is accurate and feasible for the determination of myocardial necrosis in a clinical setting.     

Relaxivity of liposomal paramagnetic MRI contrast agents

Paramagnetic liposomes, spherical particles formed by a lipid bilayer, are able to accommodate a high payload of Gd-containing lipid and therefore can serve as a highly potent magnetic resonance imaging contrast agent. In this paper the relaxation properties of paramagnetic liposomes were studied as a function of composition, temperature and magnetic field strength. The pegylated liposomes with a diameter of approximately 100 nm were designed for favorable pharmacokinetic properties in vivo. The proton relaxivity, i.e. the T₁ relaxation rate per mmol of Gd(III) ions, of liposomes with unsaturated DOPC phospholipids was higher than those with saturated DSPC lipids. Addition of cholesterol was essential to obtain monodisperse liposomes and led to a further, although smaller, increase of the relaxivity. Nuclear magnetic relaxation dispersion measurements showed that the relaxivity was limited by water exchange. These results show that these paramagnetic liposomes are very effective contrast agents, making them excellent candidates for many applications in magnetic resonance imaging.     

Synthesis and characterization of polyethylenimine-based iron oxide composites as novel contrast agents for MRI

OBJECT: Use of polyethylenimines (PEIs) of different molecular weight and selected carboxylated-PEI derivatives (PEI-COOH) in the synthesis and stabilization of iron oxide nanoparticles, to obtain possible multifunctional contrast agents. MATERIALS AND METHODS: Oxidation of Fe(II) at slightly elevated pH and temperature resulted in the formation of highly soluble and stable nanocomposites of iron oxides and polymer. Composites were characterized and studied by atomic force microscopy (AFM), transmission electron microscopy (TEM), X-ray diffractometry, AC and DC magnetometry, NMR relaxometry and magnetic resonance imaging (MRI). RESULTS: From AFM the dimensions of the aggregates were found to be in the ~150-250 nm size region; the mean diameter of the magnetic core of the compounds named PEI-25, PEI-500 and PEI-COOH60 resulted d approximately 20 +/- 5 nm for PEI-25, d approximately 9.5 +/- 1.0 nm for PEI-500 and d approximately 6.8 +/- 1.0 nm for PEI-COOH60. In PEI-COOH60 TEM and X-ray diffractometry revealed small assemblies of mineral magnetic cores with clear indications that the main constituents are maghemite and/or magnetite as confirmed by AC and DC SQUID magnetometry. For PEI-COOH60, the study of NMR-dispersion profiles revealed r (1) and r (2) relaxivities comparable to superparamagnetic iron-oxide commercial compounds in the whole investigated frequency range 7 < or = nu < or = 212 MHz. CONCLUSION: PEI-25 was studied as possible MRI contrast agent (CA) to map the cerebral blood volume (CBV) and cerebral blood flow (CBF) in an animal model obtaining promising results. The reported compounds may be further functionalized to afford novel multifunctional systems for biomedical applications.     

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.     

Interaction of Gd(III) MRI contrast agents with membranes: a review of recent EPR studies

Rational development of new selective paramagnetic contrast agents (PCAs) requires a detailed understanding of their interactions with biological macromolecules. This report shows how some of these interactions can be studied with electron paramagnetic resonance (EPR) through examples of Gd³⁺ complexes interactions with model phospholipid membranes. It is shown that the spin label EPR method can be used to detect: (i) presence and possible location of lipophilic contrast agents in the model membranes, (ii) changes and distortions in membrane organization upon interaction with the PCAs, and (iii) changes in the local polarity of the bilayer and its phase behavior due to addition of Gd³⁺ complexes. This work demonstrates that interaction of Gd³⁺ complexes with phospholipid bilayers can be observed directly from changes in their continuous wave (CW) EPR spectra obtained at frequencies higher than X-band (9.5 GHz), where signals arising from aqueous and lipid-bound Gd³⁺ complexes become resolved. Analysis of frequency dependence of the effectiveg-factors of the EPR signal provides estimates of zero-field splitting (ZFS) parameter for these complexes at physiological conditions and information on how this parameter is affected by interaction with lipids. Multifrequency EPR experiments at high magnetic fields are also useful in providing data on the frequency dispersion of electronic relaxation caused mainly by a modulation of the electron-electron dipolar interaction (ZFS) of these high spin ions.     

Volumetric assessment of myocardial viability in rats using 3D double contrast enhanced T1 and T2-weighted MRI

Objective: Volumetric evaluation of the myocardial viability post-infarction in rats using 3D in vivo MR imaging at 7 T using injection of an extracellular paramagnetic contrast agent and intravascular superparamagnetic iron oxide nanoparticles in the same imaging session. Materials and methods: Five hours after induction of permanent myocardial infarction in rats (n=6), 3D in vivo T1- and T2-weighted MR Imaging was performed prior to and after Gd-DOTA injection (0.2 mmol/kg) and prior to and after nanoparticle injection (5 mg Fe/kg) to assess infarct size and myocardial viability. Results: 3D MR Imaging using a successive contrast agent injection showed a difference of infarct size after Gd-DOTA injection on T1-weighted images compared to the one measured on T2-weighted images after Gd-DOTA and nanoparticle injection. Conclusion: The use of 3D T1- and T2-weighted MR Imaging using a double contrast agents protocol made possible the accurate characterization of myocardial infarction volume and allowed the detection of myocardial viability post-infarction in rats     

Roles for paramagnetic substances in MRI: contrast agents,molecular amplifiers,and indicators for redox and pH mapping

A molecular amplifier is a substance which at high dilution can significantly influence the magnetic resonance (MR) properties of water; its gain can be controlled by varying either its chemical or magnetic properties. If the gain of that amplifier is sensitive to the chemical potential of its molecular environment, then it can be used as an MRI-active chemical indicator. Three examples are described: (a) the use of the ethylenediaminetetraacetic acid-copper(II) complex to map the spatial distribution of pH; (b) the use of Fe(II)/Fe(III) ions to map redox potential and thereby reducing species such as ascorbic acid or oxidants such as perbromate ion; (c) similar use of a stable nitroxide free radical to map reducing agents. The mass transport diffusion of those species can be visualized in hydrocolloid gels and in articular cartilage by MR imaging and the diffusion coefficients measured quantitatively using the null-point MR imaging method.     

Standardized MR protocol for the evaluation of MRA sequences and/or contrast agents effects in high-degree arterial stenosis analysis

Purpose To investigate the relative role of high resolution (spatial or temporal) magnetic resonance angiography (MRA) sequence and of contrast agent properties in the evaluation of high-degree arterial stenosis. Methods We qualitatively and quantitatively studied both 50 and 95% (300 μm diameter) stenosis of a 6 mm arterial phantom with two contrast agents (CA), Gd-DOTA (r₁ =2.9 mM⁻¹ s⁻¹) versus P760 (r₁ =25 mM⁻¹ s⁻¹) at several CA concentrations, including arterial peak concentration after injection of either a single or double dose of CA, using either a high temporal (booster) or high spatial (HR) resolution 3D MRA sequences. Experimental data were then compared to theoretical data. Results With the 3D HR sequence, both visual and quantitative analysis were significantly better compared to the 3D booster sequence, at each phantom diameter. Quantitative analysis was significantly improved by injection of a double versus a single dose of each CA (Gd-DOTA or P760), primarily in high degree stenosis. Conclusion Combined MRA spatial resolution and high CA efficiency are mandatory to correctly evaluate high degree stenosis.     

Tumor microvasculature observed using different contrast agents: a comparison between Gd-DTPA-Albumin and B-22956/1 in an experimental model of mammary carcinoma

OBJECTIVE: The aim of this study was to compare a pure macromolecular contrast agent (Gd-DTPA-albumin) with a new protein-binding blood pool contrast agent (B22956/1) in terms of their capacity to investigate the microvasculature in an experimental model of mammary carcinoma. MATERIALS AND METHODS: Tumors were induced by subcutaneous injection of 5 x 10(5) BB1 cells into the backs of 5-7 week-old female FVB/neuNT233 mice. The animals were observed using DCE-MRI when the longest diameter of the tumor was 10.2+/-2.0 mm. DCE-MRI experiments were carried out using B22956/1 and (24 h later) Gd-DTPA-albumin. RESULTS: DCE-MRI data showed that vasculature in the tumor rim was characterized by greater fractional plasma volume and transendothelial permeability than vasculature in the tumor core as measured by both contrast agents. Permeability to Gd-DTPA-albumin in the tumor core was hardly measurable while permeability to B22956/1 was substantial. Histologically the tumor core showed areas of well vascularized, viable tissue surrounded by necrotic regions. CONCLUSIONS: DCE-MRI experiments performed with B22956/1 are useful in the investigation of vasculature in those tumor regions that are characterized by low permeability to macromolecules.     

Effect of new manganese contrast agent on tissue intensities in human volunteers: comparison of 0.23, 0.6 and 1.5 T MRI,a part of a phase I trial

To evaluate the effect of a new oral manganese contrast agent (CMC-001) on magnetic resonance imaging (MRI) intensities at different magnetic field strengths. Twelve healthy volunteers underwent abdominal MRI 1 week before and within 2.5–4.5 h after CMC-001 (MnCl₂ and absorption promoters dissolved in water) intake at three different MR scanners of 0.23, 0.6 and 1.5 T. Image contrast and intensity enhancement of liver and pancreas were analysed relatively to muscle and fat intensities. Manganese blood levels were followed for 24 h. Whole-blood manganese concentration levels stayed within the normal range. The liver intensities on T2w images decreased about 10% for the 1/2 contrast dose and about 20% for the full contrast dose independent of the field strength. The liver intensities on T1w images increased more than 30% for 1/2 contrast dose and over 40% for full contrast dose. The maximum T1 enhancement was achieved at the highest field. Pancreas intensities were not affected. Contrast between liver, muscle and fat intensities increased with magnetic field, as well as standard errors of the volunteer-averaged intensities. Oral intake of CMC-001 influences liver intensities and does not affect pancreas intensities at different magnetic field strengths.     

人民币汇率浮动对电池业的影响

讨论了人民币汇率浮动对电池业的影响,提出了相关的措施.     

A method for the design of MRI radiofrequency coils based on triangular and pulse basis functions

This paper presents a numerical technique for the design of an RF coil for asymmetric magnetic resonance imaging (MRI) systems. The formulation is based on an inverse approach where the cylindrical surface currents are expressed in terms of a combination of sub-domain basis functions: triangular and pulse functions. With the homogeneous transverse magnetic field specified in a spherical region, a functional method is applied to obtain the unknown current coefficients. The current distribution is then transformed to a conductor pattern by use of a stream function technique. Preliminary MR images acquired using a prototype RF coil are presented and validate the design method.     

1H-NMRD and17O-NMR assessment of water exchange and rotational dynamics of two potential MRI agents: MP-1177 (an extracellular agent) and MP-2269 (a blood pool agent)

The parameters that govern water proton magnetic relaxation (e.g. water exchange rates, and rotational and electronic correlation times) of representatives of two classes of Gd(III) complexes have been estimated, using two different approaches and the results compared with those derived for known analogs. The complexes studied are: (i) the non-ionic GdDTPA-bis(methoxyethyl-amide) [Gd(DTPA-BMEA)], a typical small-molecule extracellular MR agent, and (ii) the ionic Gd(III) complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-l-aspartyl-lysine-derived-DTPA [GdL]⁴⁻, a prototype MR blood pool agent, which binds to serum albumin in vivo through non-covalent hydrophobic interactions. An¹⁷O-NMR study of [Gd(DTPA-BMEA)] gives a water exchange rate constant ofk _ex ²⁹⁸ =(0.39±0.02)×10⁶ s⁻¹, identical to that for the bismethylamide analog [Gd(DTPA-BMA)]. Both approaches yield longer rotational correlation times for [Gd(DTPA-BMEA)], consistent with its higher molecular weight. An¹⁷O-NMR study of [GdL]⁴⁻ gives a water exchange rate constant ofk _ex ²⁹⁸ =(4.2±0.1)×10⁶ s⁻¹, identical to that for [Gd(DTPA)]²⁻. The water exchange rate on [GdL]⁴⁻ did not decrease considerably when bound to albumin, the lowest limit isk _ex,GdL-BSA=k _ex,GdL/2. Both approaches yield identical rotational correlation times for [GdL]⁴⁻, however, it was difficult to derive a consistent rotational constant for the albumin-bound [GdL]⁴⁻ using the different approaches (values ranged between 1.0 and 23.0 ns).