Nuclear spin relaxation study of aqueous raffinose solution in the presence of a gadolinium contrast agent

Paramagnetic enhancement of nuclear spin-lattice relaxation rates (PREs) was measured in aqueous solution of the trisaccharide raffinose in the presence of a gadolinium(III) complex, GdDTPA-BMA, used as a magnetic resonance imaging contrast agent. The relaxation enhancement of aqueous protons was measured over a broad range of magnetic fields, using field-cycling apparatus in addition to conventional spectrometers. The nuclear magnetic relaxation dispersion profile thus obtained was interpreted with a recently developed model, allowing for both inner- and outer-sphere relaxation. The relaxation enhancement for the carbon-13 nuclei in raffinose was studied under high-resolution conditions at three magnetic fields, whereas the sugar proton PRE was measured at two fields. The PRE of the sugar nuclei could be interpreted in a consistent way, assuming that it was caused by the outer-sphere mechanism. The electron spin relaxation was found to be a less important source of modulation of the electron-nuclear dipole-dipole interaction than the mutual translational diffusion.     

Fast and Quantitative NMR Metabolite Analysis Afforded by a Paramagnetic Co‐Solute

NMR spectroscopy is an indispensable technique for the determination of the chemical identity and structure of small molecules. The method is especially recognized for its robustness and intrinsically quantitative nature, and has manifested itself as a key analytical platform for diverse fields of application, ranging from chemical synthesis to metabolomics. Unfortunately, the slow recovery of nuclear spin polarization by spin‐lattice (T₁) relaxation causes most experimental time to be lost on idle waiting. Furthermore, truly quantitative NMR (qNMR) spectroscopy requires waiting times of 5‐times the longest T₁ in the sample, making qNMR spectroscopy slow and inefficient. We demonstrate here that co‐solute paramagnetic relaxation can mitigate these two problems simultaneously. The addition of a small amount of paramagnetic gadolinium chelate, available in the form of commercial contrast‐agent solutions, enables cheap, quantitative, and efficient high‐throughput mixture analysis.     

Lanthanides in magnetic resonance imaging

Magnetic Resonance Imaging is perhaps the most important and prominent technique in diagnostic clinical medicine and biomedical research. Its success and development as an imaging technique has been aided by the characteristics of contrast agents that enhance signal intensities and improve specificity. Gadolinium(iii) remains the dominant starting material for contrast agent design but other lanthanide ions (and other oxidation states i.e. +2) are also being increasingly investigated as alternatives to gadolinium(III) within laboratory conditions. This critical review provides a concise summary of the MRI-active gadolinium(III) complexes to date--their pros and cons, an outline of contrast agents based on other lanthanide ions (e.g. europium, dysprosium), and directs the reader to newer, more speculative areas of lanthanide-containing contrast agent design.     

Spatially Resolved Quantification of Gadolinium(III)‐Based Magnetic Resonance Agents in Tissue by MALDI Imaging Mass Spectrometry after In Vivo MRI

Gadolinium(III)‐based contrast agents improve the sensitivity and specificity of magnetic resonance imaging (MRI), especially when targeted contrast agents are applied. Because of nonlinear correlation between the contrast agent concentration in tissue and the MRI signal obtained in vivo, quantification of certain biological or pathophysiological processes by MRI remains a challenge. Up to now, no technology has been able to provide a spatially resolved quantification of MRI agents directly within the tissue, which would allow a more precise verification of in vivo imaging results. MALDI imaging mass spectrometry for spatially resolved in situ quantification of gadolinium(III) agents, in correlation to in vivo MRI, were evaluated. Enhanced kinetics of Gadofluorine M were determined dynamically over time in a mouse model of myocardial infarction. MALDI imaging was able to corroborate the in vivo imaging MRI signals and enabled in situ quantification of the gadolinium probe with high spatial resolution.     

High-relaxivity MRI contrast agents: where coordination chemistry meets medical imaging

The desire to improve and expand the scope of clinical magnetic resonance imaging (MRI) has prompted the search for contrast agents of higher efficiency. The development of better agents requires consideration of the fundamental coordination chemistry of the gadolinium(III) ion and the parameters that affect its efficacy as a proton relaxation agent. In optimizing each parameter, other practical issues, such as solubility and in vivo toxicity, must also be addressed, making the attainment of safe, high-relaxivity agents a challenging goal. This Minireview presents recent advances in the field, with an emphasis on gadolinium(III) hydroxypyridinone chelate complexes.     

Synthesis, characterization, and pharmacokinetic evaluation of a potential MRI contrast agent containing two paramagnetic centers with albumin binding affinity

A dinuclear gadolinium(III) complex of an amphiphilic chelating ligand, containing two diethylenetriamine-N,N,N',N',N'-pentaacetate (DTPA) moieties bridged by a bisindole derivative with three methoxy groups, has been synthesized and evaluated as a potential magnetic resonance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37 degrees C the dinuclear gadolinium(III) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s(-1) mmol(-1)). The higher relaxivity of the dinuclear gadolinium(III) complex can be related to its reduced motion and larger rotational correlation time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the noncovalently bound dinuclear complex increases to 15.2 s(-1) per mmol of Gd3+, due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (Ka) was found to be 10(4) M(-1). Because of its interaction with HSA, the dinuclear complex exhibits a longer elimination half-life from the plasma, and a better confinement to the vascular space compared to the commercially available [Gd(DTPA)] contrast agent. Transmetalation of the dinuclear gadolinium(III) complex by zinc(II) has been investigated. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepatobiliary route. In vivo studies indicated that half of the normal dose of the gadolinium(III) complex enhanced the contrast in hepatic tissues around 40 % more effectively than [Gd(DTPA)]. The dinuclear gadolinium(III) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis-targeting properties.     

Comparison of different methods for calculating the paramagnetic relaxation enhancement of nuclear spins as a function of the magnetic field

The enhancement of the spin-lattice relaxation rate for nuclear spins in a ligand bound to a paramagnetic metal ion [known as the paramagnetic relaxation enhancement (PRE)] arises primarily through the dipole-dipole (DD) interaction between the nuclear spins and the electron spins. In solution, the DD interaction is modulated mostly by reorientation of the nuclear spin-electron spin axis and by electron spin relaxation. Calculations of the PRE are in general complicated, mainly because the electron spin interacts so strongly with the other degrees of freedom that its relaxation cannot be described by second-order perturbation theory or the Redfield theory. Three approaches to resolve this problem exist in the literature: The so-called slow-motion theory, originating from Swedish groups [Benetis et al., Mol. Phys. 48, 329 (1983); Kowalewski et al., Adv. Inorg. Chem. 57, (2005); Larsson et al., J. Chem. Phys. 101, 1116 (1994); T. Nilsson et al., J. Magn. Reson. 154, 269 (2002)] and two different methods based on simulations of the dynamics of electron spin in time domain, developed in Grenoble [Fries and Belorizky, J. Chem. Phys. 126, 204503 (2007); Rast et al., ibid. 115, 7554 (2001)] and Ann Arbor [Abernathy and Sharp, J. Chem. Phys. 106, 9032 (1997); Schaefle and Sharp, ibid. 121, 5387 (2004); Schaefle and Sharp, J. Magn. Reson. 176, 160 (2005)], respectively. In this paper, we report a numerical comparison of the three methods for a large variety of parameter sets, meant to correspond to large and small complexes of gadolinium(III) and of nickel(II). It is found that the agreement between the Swedish and the Grenoble approaches is very good for practically all parameter sets, while the predictions of the Ann Arbor model are similar in a number of the calculations but deviate significantly in others, reflecting in part differences in the treatment of electron spin relaxation. The origins of the discrepancies are discussed briefly.     

二乙三胺四乙酸双核钆磁共振成像造影剂的合成及其弛豫性能

合成了以对苯二甲酰基(TP)为连接体的双核Gd-DTTA(DTTA:二乙三胺四乙酸)线型磁共振造影剂Gd2(TP(DTTA)2)。 在20 MHz、37 ℃和pH=7的条件下,此造影剂对水质子的纵向弛豫效率为21.7 L/(mmol·s),比已有的双核Gd-DTTA型磁共振造影剂提高了70%。 荧光寿命测试显示,Tb2(TP(DTTA)2)的内配层水分子数q=1.4。 结果显示,刚性连接链有利于提高多核造影剂的弛豫效率。     

Yttrium‐86 Is a Positron Emitting Surrogate of Gadolinium for Noninvasive Quantification of Whole‐Body Distribution of Gadolinium‐Based Contrast Agents

Gadolinium‐based contrast agents (GBCAs) are used to provide diagnostic information in clinical magnetic resonance (MR) examinations. Gadolinium (Gd) has been detected in the brain, bone and skin of patients, months and years following GBCA administration, raising concerns about long term toxicity. Despite increased scrutiny, the concentration, chemical form and fate of the retained gadolinium species remain unknown. Importantly, the whole body biodistribution and organ clearance of GBCAs is poorly understood in humans. Gadolinium lacks suitable isotopes for nuclear imaging. We demonstrate that the yttrium‐86 isotope can be used as a gadolinium surrogate. We show that Gd and their analogous Y complexes have similar properties both in solution and in vivo, and that yttrium‐86 PET can be used to track the biodistribution of GBCAs over a two‐day period.     

Solvent Extraction Studies of Gadolinium in Tri-Butyl Phosphate

Fast reactor spent fuel reprocessing plants should be designed for inherent criticality safety due to high plutonium content. Addition of soluble neutron poison is one way to do that. Gadolinium is the best choice based on neutron absorption cross section and chemical compatibility. In this work, using classical thermodynamic approach, the distribution coefficient of gadolinium in tributyl phosphate has been calculated and compared with the experimental data. The influence of acidity and uranium at equilibrium on gadolinium distribution in tributyl phosphate has been investigated. The result establishes the feasibility of employing gadolinium as soluble neutron poison in fast fuel reprocessing.     

Microstructural Characteristics and Magnetic Properties of Gadolinium-Substituted Cobalt Ferrite Nanocrystals Synthesized by Hydrothermal Processing

Gadolinium substituted cobalt ferrite nanocrystals with composition of CoFe_2?xGd_xO₄ (x = 0–0.04 in a step of 0.01) were prepared by a hydrothermal process and without subsequent annealing. X-ray diffraction, field-emission scanning electron microscopy, and vibrating sample magnetometer were used to investigate the effect of Gd³⁺ cation substitution on structural Characteristics and magnetic properties of cobalt ferrite nanocrystals. The X-ray diffraction analysis demonstrated that single phase spinel ferrites were obtained. The FE-SEM micrographs of the synthesized samples indicated the presence of two distinct groups of grains exhibiting different sizes and, more important, different shapes. The results of magnetic hysteresis at a room temperature showed that with an increase in gadolinium content, the coercive field decreased from 1250 Oe for x = 0 to 450 Oe for x = 0.03. In addition, it was observed that with substitutions of gadolinium cations, the values of saturation magnetization decreased.     

Is metabolomics reachable? Different purification strategies of human colon cancer cells provide different CE-MS metabolite profiles

In this work, four different metabolite purification approaches are investigated prior to metabolomics of human HT29 colon cancer cells. Namely, methanol deproteinization, ultrafiltration and two SPE methods using C18 and polymer-based cartridges were studied. The extracts were characterized via a metabolomic approach based on the application of CE TOF MS (CE-MS). CE-MS analysis time was less than 20 min per sample and allowed the simultaneous and reproducible analysis of more than 80 metabolites in a single run with a minimum consumption of sample and reagents. Metabolome analysis revealed in some cases important differences among the studied metabolite purification procedures. No significant differences were observed in the metabolite profile using C18 and polymer-based cartridges, or between ultrafiltration and methanol deproteinization. However, important differences were observed in the metabolomic profiles obtained from SPE and methanol deproteinization samples. These results demonstrate the crucial role of the metabolite purification strategy in metabolomics since it can bias (and in some cases mislead) the conclusions achieved by the metabolomic study.     

Synthesis of novel texaphyrins containing lanthanides and boron

Texaphyrin macrocycles that contain gadolinium or lutetium, such as motexafin gadolinium and motexafin lutetium, are versatile anticancer therapeutics and diagnostics. Gadolinium texaphyrins substituted with carborane clusters could also find application in combined gadolinium and boron neutron capture therapy (GdB-NCT). The synthesis and characterization of novel texaphyrins containing gadolinium or lutetium in the pentaaza core and two carborane clusters bound to opposite pyrrol units of the macrocycle are described.     

Long-circulating gadolinium-loaded liposomes: potential use for magnetic resonance imaging of the blood pool

In our previous paper, we reported a method of liposome loading with Gadolinium (Gd) via so called polychelating amphiphilic polymer (PAP). A novel Gd-containing polymeric probe, suitable for the incorporation into the liposomal membrane, was prepared from a low-molecular-weight DTPA-polylysine by linking its N-terminus to a lipid anchor, NGPE-PE. When compared with known membranotropic MR probes, such as Gd-DTPA-SA and Gd-DTPA-PE, liposomes containing new membrane-bound polychelator possess enhanced relaxivity for water protons resulting in an increase of tissue signal intensity on MR images. In this study, we developed the optimized protocol to prepare a liposomal MR contrast agent with high relaxivity and narrow size distribution. Gd-containing liposomes were additionally modified with PEG to provide longevity in vivo. We also demonstrated that upon intravenous administration in rabbit and dog, the new preparation causes a prolonged decrease in the blood T₁ value (reflecting the proton relaxation rate in the blood) and may be considered as a potential contrast agent for MRI of the blood pool.     

Synthesis and characterization of a new lanthanide based MRI contrast agent,potential and versatile tracer for multimodal imaging

In the present work a modular pathway towards the synthesis of a new versatile MRI contrast agent is reported and its physico-chemical properties are described. Two different functional groups were attached on two arms of the gadolinium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA) in order to get a platform able to bind one probe designed to target specific biological marker and a fluorescent molecule likely to be used for optical imaging. The nuclear magnetic relaxation dispersion (NMRD) profile, the oxygen-17 relaxometric NMR study and stability assessment versus transmetalation of the Gd-complex show that this new contrast agent has a relaxivity and transmetalation stability similar to Gd–DOTA.     

Relaxivity of Gd-Based MRI Contrast Agents in Crosslinked Hyaluronic Acid as a Model for Tissues

The efficiency of MRI contrast agents depends on the relaxation rate enhancement that they can induce at imaging fields. It is well known that, at these fields, large relaxation rates are obtained by binding of gadolinium(III) ions to large molecules. By the same token, the interaction of the gadolinium(III) complexes with macromolecules that are found in biological tissues can be responsible for an increase of the relaxation rate with respect to the value observed in liquids. We investigate here the relaxation enhancement of gadoteridol (Gd-HP-DO3A) in crosslinked hyaluronic acid, taken as model tissue, using fast field-cycling relaxometry. The analysis of the relaxation profiles as a function of the magnetic fields indicates that a sizable increase in the relaxation rates is due to a modest interaction of the contrast agent with the hydrogel and to the slower mobility of the water molecules outside the first-coordination sphere of the gadolinium(III) ion.     

Physical signal modulation of time-of-flight mass analyzers increases precision and decreases noise

Recently, an increased emphasis has been placed on the ability to make mass measurements with high accuracy and precision. The motivation for this is that high-precision mass measurements, together with isotope intensity matching, permit confirmation of molecular formulas and de novo molecular formula prediction, both of which enhance the value of proteomics and metabolomics data. The confidence of mass-based conclusions also depends on reliable estimates of uncertainty. However, determining the precision of a particular measurement remains a complicated process. For signals which are well-resolved and of sufficient intensity, an often-overlooked factor for high precision is the mass sampling frequency (abscissa, Δx). We have analyzed the impact of Δx on the centroid calculation of peak position, and find that existing quality standards, such as 4 or 5 samples per peak, may not be sufficient to achieve high precision. Time-domain and m/z-domain sampling frequency on time-of-flight (TOF) mass analyzers can be improved using a new method that we call Physical Signal Modulation (PSM). PSM allows very substantial improvements by decreasing Δx without requiring specialized hardware or digitizers. In addition to providing accuracy improvements, PSM also dramatically improves signal-to-noise ratios by removing coherent noise. Software to perform PSM data processing is available as part of the PySpecTools package.     

A novel kernel Fisher discriminant analysis: constructing informative kernel by decision tree ensemble for metabolomics data analysis

Large amounts of data from high-throughput metabolomics experiments become commonly more and more complex, which brings an enormous amount of challenges to existing statistical modeling. Thus there is a need to develop statistically efficient approach for mining the underlying metabolite information contained by metabolomics data under investigation. In the work, we developed a novel kernel Fisher discriminant analysis (KFDA) algorithm by constructing an informative kernel based on decision tree ensemble. The constructed kernel can effectively encode the similarities of metabolomics samples between informative metabolites/biomarkers in specific parts of the measurement space. Simultaneously, informative metabolites or potential biomarkers can be successfully discovered by variable importance ranking in the process of building kernel. Moreover, KFDA can also deal with nonlinear relationship in the metabolomics data by such a kernel to some extent. Finally, two real metabolomics datasets together with a simulated data were used to demonstrate the performance of the proposed approach through the comparison of different approaches.     

DNP by thermal mixing under optimized conditions yields >60,000-fold enhancement of 89Y NMR signal

Hyperpolarized (89)Y complexes are attractive NMR spectroscopy and MR imaging probes due to the exceptionally long spin-lattice relaxation time (T(1) ≈ 10 min) of the (89)Y nucleus. However, in vivo imaging of (89)Y has not yet been realized because of the low NMR signal enhancement levels previously achieved for this ultra low-γ(n) nucleus. Here, we report liquid-state (89)Y NMR signal enhancements over 60,000 times the thermal signal at 298 K in a 9.4 T magnet, achieved after the dynamic nuclear polarization (DNP) of Y(III) complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) samples at 3.35 T and 1.4 K. The (89)Y DNP was shown to proceed by thermal mixing and the liquid state (89)Y NMR signal enhancement was maximized by (i) establishing the optimal microwave irradiation frequency, (ii) optimizing the glassing matrix, (iii) choosing a radical with negligible inhomogeneous line broadening contribution to the ESR linewidth, and (iv) addition of an electron T(1e) relaxation agent. The highest enhancements were achieved using a trityl OX063 radical combined with a gadolinium relaxation agent in water-glycerol matrix. Co-polarization of (89)YDOTA and sodium [1-(13)C]pyruvate showed that both (89)Y and (13)C nuclear species acquired the same spin temperature, consistent with thermal mixing theory of DNP. This methodology may be applicable for the optimization of DNP of other low-γ(n) nuclei.     

Rheological investigations on the creaming of depletion-flocculated emulsions

Preventing creaming or sedimentation by the addition of thickeners is an important industrial challenge. We study the effect of the addition of a "free" nonadsorbing polymer (xanthan gum) on the stability against creaming of sterically stabilized O/W emulsions. Therefore, we analyze our samples using microscopy and rheological measurements. At low xanthan concentrations, the emulsions cream. However, above a certain concentration a three-dimensional network of droplets is formed, which can prevent creaming. We attribute the formation of this structure to depletion attraction. The rheological behavior of an emulsion that is macroscopically stable should be elastic, while it should be viscous for a creaming emulsion. In order to distinguish between stable and unstable samples, we measure their relaxation time by mechanical rheology and find a good correlation to the visual observation. However, the measured relaxation times are much shorter than the time-scales, on which we observe creaming. We hypothesize that the measured relaxation time is related to the droplet-droplet interaction. This determines the frequency at which microscopic rearrangements occur, which weaken the network structure prior to creaming. Based on this interpretation, the relaxation time gives direct access to the microstructural processes involved in creaming. We therefore suggest using it as a predictive parameter of creaming stability.