The gadolinium complexes with polyoxometalates as potential MRI contrast agents

The two gadolinium (Gd) polyoxometalates, K(15)[Gd(BW(11)O(39))(2)] [Gd(BW(11))(2)] and K(17)[Gd(CuW(11)O(39))(2)] [Gd(CuW(11))(2)] have been evaluated by in vivo and in vitro experiments as the candidates of potential tissue-specific magnetic resonance imaging (MRI) contrast agents. T(1) relaxivities of 17.12 mM(-1) x s(-1) for Gd(BW(11))(2) and 19.95 mM(-1) x s(-1) for Gd(CuW(11))(2) (400 MHz, 25 degrees C) were much higher than that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in bovine serum albumin and human serum transferrin solutions were also reported. After administration of Gd(BW(11))(2) and Gd(CuW(11))(2) to Wistar rats, MRI showed longer and remarkable enhancement in rat liver and favorable renal excretion capability. The signal intensity increased by 37.63+/-3.45% for the liver during the whole imaging period (100 min) and by 61.47+/-10.03% for kidney within 5-40 min after injection at 40+/-1-micromol x kg(-1) dose for Gd(CuW(11))(2), and Gd(BW(11))(2) induced 50.44+/-3.51% enhancement in the liver in 5-50-min range and 61.47+/-10.03% enhancement for kidney within 5-40 min after injection at 39+/-4 micromol x kg(-1) dose. In vitro and in vivo study showed that Gd(BW(11))(2) and Gd(CuW(11))(2) are favorable candidates as tissue-specific contrast agents for MRI.     

Binding of MRI contrast agents to albumin: a high-field EPR study

High-field electron paramagnetic resonance (EPR) experiments to monitor binding of lipophilic Gd(III) complexes to human serum albumin (HSA) are described. It was observed that magnetic interactions between the nitroxide moiety ofn-doxyl-stearic acids bound to HSA and Gd(III) complexes resulted in broadening of nitroxide continuous-wave EPR spectra. The broadening effect can be well described by a one-parameter model of additional Lorentzian broadening At 95 GHz, continuous-wave EPR spectra from Gd(III) complexes are fully resolved from the nitroxide signal allowing for simultaneous and independent line shape analysis. Analysis of the line width broadening effects for spectra from a series ofn-doxyl-stearic acids bound to HSA indicated a progressive decrease of spin label-Gd(III) magnetic interactions along the fatty acid (FA) binding channel, consistent with binding of Gd-DOTAP complex in the vicinity of the main FA binding site. The substantial difference in spin label-metal interactions along the FA binding channel for lipophilic Gd(III) complexes with different chelates is indicative of binding to different sites. We also report measurements of dissociation constant for noncovalent binding of Gd(III) complexes to HSA on the basis of analyses of 95 GHz Gd(III) EPR line shapes.     

pH-sensitive paramagnetic liposomes as MRI contrast agents: in vitro feasibility studies.

A novel type of pH-sensitive paramagnetic contrast agent is introduced; a low molecular weight gadolinium (Gd) chelate (GdDTPA-BMA) encapsulated within pH-sensitive liposomes. The in vitro relaxometric properties of the liposomal Gd chelate were shown to be a function of the pH in the liposomal dispersion and the membrane composition. Only a minor pH-dependency of the T1 relaxivity (r1) was observed for liposomal GdDTPA-BMA composed of the unsaturated lipids dioleoyl phosphatidyl ethanolamine (DOPE) and oleic acid (OA). On the other hand, the r1 of GdDTPA-BMA encapsulated within saturated dipalmitoyl phosphatidyl ethanolamine/palmitic acid (DPPE/PA) liposomes demonstrated a strong pH-dependency. At physiological pH and above, the r1 of this system was significantly lowered compared to that of non-liposomal Gd chelate, which was explained by an exchange limited relaxation process. Lowering the pH below physiological value, however, gave a sharp and 6-7 fold increase in r1, due to liposome destabilisation and subsequent leakage of entrapped GdDTPA-BMA. The pH-sensitivity of the DPPE/PA liposome system was confirmed in an in vitro magnetic resonance imaging (MRI) phantom study.     

Dynamic imaging with MRI contrast agents: quantitative considerations

Time-resolved MRI has had enormous impact in cognitive science and may become a significant tool in basic biological research with the application of new molecular imaging agents. In this paper, we examine the temporal characteristics of MRI contrast agents that could be used in dynamic studies. We consider "smart" T1 contrast agents, T2 agents based on reversible aggregation of superparamagnetic nanoparticles and sensors that produce changes in saturation transfer effects (chemical exchange saturation transfer, CEST). We discuss response properties of several agents with reference to available experimental data, and we develop a new theoretical model that predicts the response rates and relaxivity changes of aggregation-based sensors. We also perform calculations to define the extent to which constraints on temporal resolution are imposed by the imaging methods themselves. Our analysis confirms that some small T1 agents may be compatible with MRI temporal resolution on the order of 100 ms. Nanoparticle aggregation T2 sensors are applicable at much lower concentrations, but are likely to respond on a single second or slower timescale. CEST agents work at high concentrations and temporal resolutions of 1-10 s, limited by a requirement for long presaturation periods in the MRI pulse sequence.     

Copper-D-penicillamine complex as potential contrast agent for MRI.

In vitro and in vivo proton T1 data are reported that demonstrate that the paramagnetic copper-D-penicillamine complex can be applied as a potential contrast agent to magnetic resonance imaging.     

Enhanced ferrite nanoparticles as MRI contrast agents

Enhanced ferrite nanoparticles are a new class of contrast agents for magnetic resonance imaging (MRI). The enhanced ferrites are synthesized by reverse micelles technique to form iron core and oxide or ferrite shell preventing further oxidation of the nanoparticles. The nanoparticles are further functionalized using dopamine and PEG-600 to increase the solubility of the high magnetic moment nanoparticles. ¹H relaxation measurements of aqueous solutions of the nanoparticles were conducted at 2.4 T. The relaxivities r₁ and r₂, representing the slopes of these curves, are 7.19 and 9.96 s⁻¹ mM⁻¹, respectively. These values should be compared with relaxivities of 4–5 s⁻¹ mM⁻¹ corresponding to commonly used commercial contrast agents in human MR examinations.     

Investigation of sandwiched gadolinium (III) complexes with tungstosilicates as potential MRI contrast agents

Two gadolinium-sandwiched complexes with tungstosilicates, K(13)[Gd(SiW(11)O(39))(2)] (Gd(SiW(11))(2)) and K(11)H(6)[Gd(3)O(3)(SiW(9)O(34))(2)] (Gd(3)(SiW(9))(2)), have been investigated by in vitro and in vivo experiments as potential contrast agents for magnetic resonance imaging (MRI). T(1)-relaxivity of Gd(SiW(11))(2)was 6.59 mM(-1).s(-1) in aqueous solution and 6.85 mM(-1).s(-1) in 0.725 mmol.L(-1) bovine serum albumin solution at 25 degrees C and 9.39 T, respectively. The corresponding T(1)-relaxivity of Gd(3)(SiW(9))(2) was 12.6 and 19.3 mM(-1).s(-1) per Gd, respectively. MRI for Sprague-Dawley rats showed longer and more remarkable enhancement in rat liver after i.v. injection of these two complexes: 39.4 +/- 3.9% and 57.4 +/- 11.6% within the first 30 min after injection, 31.2 +/- 2.6% and 39.9 +/- 7.6% in the next 60 min for Gd(SiW(11))(2) and Gd(3)(SiW(9))(2) at doses of 0.081 and 0.084 mmol Gd/kg, respectively. Our preliminary in vitro and in vivo study indicates that Gd(SiW(11))(2) and Gd(3)(SiW(9))(2) are favorable candidates for hepatic contrast agents for MRI. However, the two complexes exhibit higher acute toxicity and need to be modified and studied further before clinical use.     

Superparamagnetic FePt nanoparticles as excellent MRI contrast agents

Chemically disordered face-centered cubic (fcc) FePt nanoparticles (NPs) with a mean diameter of 9 nm were synthesized via pyrolysis of iron(III) ethoxide and platinum(II) acetylacetonate. The surface ligands of these NPs were then exchanged from oleic acid to tetramethylammonium hydroxide (TMAOH) to measure the longitudinal (T₁) and transverse (T₂) proton relaxation times of aqueous dispersion of FePt NPs. Magnetic resonance relaxometry reveals that TMAOH-capped FePt NPs have a higher T₂-shortening effect than conventional superparamagnetic iron oxide NPs, indicating that fcc-phase FePt NPs might be superior negative contrast agents for magnetic resonance imaging.     

Aspects of structural order in 209Bi-containing particles for potential MRI contrast agents based on quadrupole enhanced relaxation

ABSTRACT

Quadrupole relaxation enhancement (QRE) has been suggested as the key mechanism for a novel class of field-selective, potentially responsive magnetic resonance imaging contrast agents. In previous publications, QRE has been confirmed for solid compounds containing ²⁰⁹Bi as the quadrupolar nucleus (QN). For QRE to be effective in aqueous dispersions, several conditions must be met, i.e. high transition probability of the QN at the ¹H Larmor frequency, water exchange with the bulk and comparatively slow motion of the Bi-carrying particles. In this paper, the potential influence of structural order within the compounds (‘crystallinity’) on QRE was studied by nuclear quadrupole resonance (NQR) spectroscopy in one crystalline and two amorphous preparations of Triphenylbismuth (BiPh₃). The amorphous preparations comprised (1) a shock-frozen melt and (2) a granulate of polystyrene which contained homogeneously distributed BiPh₃ after common dissolution in THF and subsequent evaporation of the solvent. In contrast to the crystalline powder which exhibits strong, narrow NQR peaks the amorphous preparations did not reveal any NQR signals above the noise floor. From these findings, we conclude that the amorphous state leads to a significant spectral peak broadening and that for efficient QRE in potential contrast agents structures with a high degree of order (near crystalline) are required.     

Isointense model for the evaluation of tumor-specific MRI contrast agents

An isointense model has been developed to evaluate the applicability of putative tumor-specific MRI contrast agents. Data for tissue relaxation measurements in the presence of Mn(III)TPPS4 are used to illustrate the model. The concentration of contrast agent in tumor tissue required for a tumor/normal tissue signal difference-to-noise ratio of 5 (delta SNR = 5) is determined for a T1 weighted pulse sequence and several hypothetical tumor/normal tissue pairs. The impact of various contrast agent characteristics including initial tumor/normal tissue relaxation values, differential uptake of contrast agent, and in vivo relaxivity are considered. Isointense tumor/normal tissue with longer initial relaxation times are shown to be more affected by the presence of contrast agent. In addition those with initially longer relaxation times have less rigorous requirements for tumor specificity. Typically, a normal tissue/tumor uptake ratio of 1:2 increases the concentration required for delta SNR = 5 by a factor of two compared to that of exclusive uptake in tumor. For the T1 weighted pulse sequence employed, the concentration required for delta SNR = 5 is shown to be linear with the inverse of in vivo relaxivity for the hypothetical tissues considered. The isointense model is also extended to predict the field dependence of tumor-specific contrast enhancement by Mn(III)TPPS4.     

Magnetic and relaxometric properties of polyethylenimine-coated superparamagnetic MRI contrast agents

Novel systems to be employed as superparamagnetic contrast agents (CA) for magnetic resonance imaging (MRI) have been synthesized. These compounds are composed of an iron oxide magnetic core coated by polyethylenimine (PEI) or carboxylated polyethylenimine (PEI-COOH). The aim of the present work was to prepare and study new nanostructured systems (with better or at least comparable relaxivities, R₁ and R₂, with respect to the commercial ones) with controlled, almost monodisperse average dimensions and shape, as candidates for molecular targeting. By means of atomic force microscopy (AFM) measurements we determined the average diameter, of the order of 200 nm, and the shape of the particles. The superparamagnetic behavior was assessed by SQUID measurements. From X-ray data the estimated average diameters of the magnetic cores were found to be 5.8 nm for PEI-COOH60 and 20 nm for the compound named PEI25. By NMR-dispersion (NMRD), we found that PEI-COOH60 presents R₁ and R₂ relaxivities slightly lower than Endorem^®. The experimental results suggest that these novel compounds can be used as MRI CA.     

超声造影剂研究进展

本文综述超声造影剂的现状及新进展，在简要介绍造影剂物理原理的基础上，对超声造影剂在医学超声领域尤其是低速血流测量与组织灌注成像中的应用进行了总结与讨论，并介绍了用于实验研究和第二期临床试验的国际上最新的超声造影剂的特点，制备技术与评价方法。     

Evaluation of two new gadolinium chelates as contrast agents for MRI

Two new gadolinium chelates were investigated for potential use as tissue-specific contrast agents for magnetic resonance imaging. In vitro measurements of stability constants, octanol/water partition coefficients and relaxation times in solutions of water and human serum albumin (HSA) were performed with each new chelate and compared with gadolinium-diethylenetriamine pentaacetic acid, Gd(DTPA). Biodistribution studies and magnetic resonance imaging in rats were used to evaluate the new chelates in vivo. The stability constants (log K) of gadolinium-N,N″-bis(3-hydroxy-6-methyl-2-pyridylmethyl)diethylenetriamine-N,N′,N″-triacetic acid, Gd(DTTA-HP), and gadolinium-1,7-13-triaza-4,10-16-trioxacyclooctadecane-N,N′,N″-triacetic acid, Gd(TTCT), were determined to be 23.65 and 18.07, respectively. These can be compared to a literature value of 22.46 for Gd(DTPA). Octanol/water partition coefficients for both complexes showed they were more lipophilic than Gd(DTPA). Gd(DTTA-HP) exhibited a smaller relaxivity in water but a larger relaxivity in 4% HSA than Gd(DTPA). Gd(TTCT) exhibited a lower relaxivity than Gd(DTPA) in both water and 4% HSA. Both complexes showed similar biodistributions to Gd(DTPA) no carrier-added concentrations. Gd(DTTA-HP) had a greater percent change in signal intensity than Gd(DTPA) on T₁-weighted spin-echo images in the heart, liver, and kidney. Percent change in signal intensity for Gd(TTCT) was lower than Gd(DTPA) in heart, liver, and kidney.     

Frequency-shift based detection of BMS contrast agents using SSFP: potential for MRA

A novel mechanism of MRI contrast enhancement, based on the detection by a balanced steady-state free precession (SSFP) sequence of the proton resonance frequency shift induced by bulk magnetic susceptibility (BMS) contrast agents, was investigated. The potential for this contrast mechanism to image blood vessels was explored. The relaxation time and the frequency shift effects of gadolinium- and dysprosium-DOTA on SSFP signal was first simulated and evaluated on a water phantom at 1.5 T. In vitro, a 5-mM concentration in contrast agent induced a 20-Hz frequency shift, leading to a signal increase of 92% for Dy-DOTA, and a 10-Hz frequency shift, leading to a signal increase of 58% for Gd-DOTA at the reference frequency, taking into account the nonlinear SSFP signal response on frequency offset. The concept was then evaluated in vivo on anesthetized rabbits. Low doses of dysprosium-DOTA were injected in their vascular system, and imaging was performed at the level of neck vessels. Following a bolus injection, mean signal changes of 31%, 20% and 14% were observed in the carotid arteries, the vertebral veins and the jugular veins, respectively. The bolus peak times in arteries and veins were consistent with the rabbit vascular circulation. This frequency-shift based contrast mechanism presents interesting potential for contrast-enhanced MR angiography (CE-MRA) compared to usual relaxation-based contrast, but further investigations on reproducibility will be necessary.     

Carboxylated magnetic nanoparticles as MRI contrast agents: Relaxation measurements at different field strengths

At the moment the biomedical applications of magnetic fluids are the subject of intensive scientific interest. In the present work, magnetite nanoparticles (MNPs) were synthesized and stabilized in aqueous medium with different carboxylic compounds (citric acid (CA), polyacrylic acid (PAA), and sodium oleate (NaOA)), in order to prepare well stabilized magnetic fluids (MFs). The magnetic nanoparticles can be used in the magnetic resonance imaging (MRI) as contrast agents. Magnetic resonance relaxation measurements of the above MFs were performed at different field strengths (i.e., 0.47, 1.5 and 9.4 T) to reveal the field strength dependence of their magnetic responses, and to compare them with that of ferucarbotran, a well-known superparamagnetic contrast agent. The measurements showed characteristic differences between the tested magnetic fluids stabilized by carboxylic compounds and ferucarbotran. It is worthy of note that our magnetic fluids have the highest r2 relaxivities at the field strength of 1.5 T, where the most of the MRI works in worldwide.     

MRI based on iron oxide nanoparticles contrast agents: effect of oxidation state and architecture

Iron oxide nanoparticles (IONPs) extensively employed beyond regenerative medicines to imaging disciplines because of their great constituents for magneto-responsive nano-systems. The unique superparamagnetic behavior makes IONPs very suitable for hyperthermia and imaging applications. From the last decade, versatile functionalization with surface capabilities, efficient contrast properties and biocompatibilities make IONPs an essential imaging contrast agent for magnetic resonance imaging (MRI). IONPs have shown signals for both longitudinal relaxation and transverse relaxation; therefore, negative contrast as well as dual contrast can be used for imaging in MRI. In the current review, we have focused on different oxidation state of iron oxides, i.e., magnetite, maghemite and hematite for their T₁ and T₂ contrast enhancement properties. We have also discussed different factors (synthesis protocols, biocompatibility, toxicity, architecture, etc.) that can affect the contrast properties of the IONPs.

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Magnetic properties of novel superparamagnetic MRI contrast agents based on colloidal nanocrystals

Novel systems based on colloidal magnetic nanocrystals (NCs), potentially useful as superparamagnetic (SP) contrast agents for magnetic resonance imaging (MRI) have been investigated. The NCs we have studied comprise organic-capped single-crystalline maghemite (γ-Fe₂O₃) cores possessing controlled sizes and shapes. We have comparatively examined spherical and tetrapod-like NCs, the latter being branched particles possessing four arms which depart out at tetrahedral angles from a central point. The as-synthesized NCs are passivated by hydrophobic surfactant molecules and thus are fully dispersible in nonpolar media only. The NCs have been made soluble in aqueous solution by applying a procedure based on the surface intercalation and coating with an amphiphilic polymer shell. NMR relaxivities R₁ and R₂ were compared with ENDOREM^®, one of the standard commercial SP-MRI contrast agent. We found that the spherical NCs exhibit R₁ and R₂ relaxivities slightly lower than those of ENDOREM^®, over the whole frequency range; on the contrary, tetrapods show relaxivities about one order of magnitude lower. The physical origin of such difference in relaxivities between tetrapod- and spheres-based nanostructures is under investigation and it is possibly related to different sources of the magnetic anisotropy.