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Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild-type rats who had received an intravenous bolus of either 10, 25 or 40 μmol/kg gadoxetate. T1 was measured at 37 ± 3°C on NMR instruments (1.41 and 3 T), small-animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol -1 s -1 ) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well-known bias in gadoxetate rate constants. This will promote the clinical translation of MR-based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies., (© 2020 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: The measurement of selenium in human plasma is useful to assess deficiency or toxicity. The presence of gadolinium in clinical samples following administration of certain contrast agents used for magnetic resonance imaging can cause a significant positive bias in selenium results when measured using quadrupole inductively coupled plasma mass spectrometry (Q-ICP-MS)., Methods: A mathematical equation to correct for gadolinium interference was assessed using both patient samples and commercial quality control/external quality assurance (QC/EQA) materials spiked with gadolinium. Samples were analysed using an Agilent 7900 ICP-MS operated in 'narrow peak' (half-mass) mode. Accuracy was evaluated by comparing corrected selenium results with target concentrations., Results: Corrected results were found to be accurate at all gadolinium concentrations tested (2, 4, 10 and 20 mg/L). Average recoveries ranged from 97.4 to 106.5%. Results for QC/EQA materials were within specified target ranges. Within-run imprecision was <3%, and between-run imprecision was <4.3%, demonstrating robustness., Conclusions: The correction equation described here is a simple method to correct for gadolinium interference on plasma selenium measurement using ICP-MS. This approach eliminates the need for specimen recollections, and improves patient care by reducing laboratory turnaround times and preventing delays in diagnosis/treatment.

Background: The dentate nuclei of the cerebellum are the areas where gadolinium predominantly accumulates. It is not yet known whether gadolinium deposition affects brain functions., Purpose/hypothesis: To assess whether gadolinium-dependent high signal intensity of the cerebellum on T 1 -weighted images of nonneurological adult patients with Crohn's disease is associated with modifications of resting-state functional connectivity (RSFC) of the cerebellum and dentate nucleus., Study Type: Observational, cross-sectional., Population: Fifteen patients affected by Crohn's disease were compared with 16 healthy age- and gender-matched control subjects. All participants underwent neurological, neurocognitive-psychological assessment, and blood sampling., Field Strength/sequence: 1.5-T magnet blood oxygenation level-dependent (BOLD) functional MRI., Assessment: High signal intensity on T 1 -weighted images, cerebellum functional connectivity, neurocognitive performance, and blood circulating gadolinium levels., Statistical Tests: An unpaired two-sample t-test (age and sex were nuisance variables) was used to investigate between-group differences in cerebellar and dentate nucleus functional connectivity. Z-statistical images were set using clusters determined by Z > 2.3 and a familywise error (FWE)-corrected cluster significance threshold of P = 0.05., Results: Dentate nuclei RSFC was not different (P = n.s.) between patients with gadolinium-dependent high signal intensity on T 1 -weighted images and controls. Pre- and postcentral gyrus bilaterally and the right supplementary motor cortex showed a decrease of RSFC with the cerebellum hemispheres (P < 0.05 FWE-corrected) and was related to disease duration but not to gadodiamide cumulative doses (P = n.s.)., Data Conclusion: Crohn's disease patients with gadolinium-dependent hyperintense dentate nuclei on unenhanced T 1 -weighted images do not show dentate nucleus RSFC changes., Level of Evidence: 2 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:445-455., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: This study investigated the potential to reduce gadolinium levels in rodents after repetitive IV Gadodiamide administration using several chelating agents., Materials and Methods: The following six groups of rats were studied. Group 1: Control; Group 2: Gadodiamide only; Group 3: Meso-2,3-Dimercaptosuccinic acid (DMSA) + Gadodiamide; Group 4: N-Acetyl-L-cysteine (NAC) + Gadodiamide; Group 5: Coriandrum sativum extract + Gadodiamide; and Group 6: Deferoxamine + Gadodiamide. Brain, kidney, and blood samples were evaluated via inductively coupled plasma mass spectrometry. The brain was also evaluated histologically., Results: Kidney gadolinium levels in Groups 4 and 5 were approximately double that of Group 2 (p = 0.033 for each). There was almost no calcification in rat hippocampus for Group 4 rodents when compared with Groups 2, 3, 5 and 6., Conclusion: Our preliminary study shows that excretion to the kidney has a higher propensity in NAC and Coriandrum sativum groups. It may be possible to change the distribution of gadolinium by administrating several agents. NAC may lower Gadodiamide-induced mineralization in rat hippocampus.

A novel method by hyphenating chip-based array ion-imprinted monolithic microextraction with inductively coupled plasma mass spectrometry (ICP-MS) was proposed for the online analysis of trace Gd in biological samples in this work. The poly(γ-methacryloxypropyltrimethoxysilane@Gd3+-surface ion-imprinted polymer) [poly(γ-MAPS@Gd3+-SIIP)] monolithic capillary was prepared via in situ polymerization on the vinyl-modified surface of poly(γ-MAPS) using Eu3+ as the mimic template. The prepared ion-imprinted monolithic capillary possessed higher selectivity and adsorption capacity to Gd3+ than the non-imprinted monolithic capillary. Eight poly(γ-MAPS@Gd3+-SIIP) monolithic capillaries were embedded in the channels of a microfluidic chip to fabricate a chip-based array microextraction device. Factors affecting the selectivity of the prepared ion-imprinted monolithic capillary including imprinted time and the composition of the prepolymerization solution, and extraction conditions for the fabricated chip-based array ion-imprinted monolithic capillary microextraction platform were optimized. A sample throughput of 18 h-1 was achieved along with a low detection limit of 1.27 ng L-1 for Gd3+. The proposed chip-based array poly(γ-MAPS@Gd3+-SIIP) monolithic microextraction-ICP-MS method was used for the analysis of trace Gd in human urine and serum, and the recovery for spiking experiments was in the range of 88.1-96.7%. The developed integrated analysis platform possesses good interference resistance, high automation, high sensitivity and low consumption of the sample/agent, which makes it very suitable for the analysis of trace elements in complicated biological samples.

Purpose: Gadolinium-based contrast agents (GBCAs) for MRI are generally administrated in direct relationship to body weight. Instead, we propose a model for GBCA dosing on the basis of blood volume. The new method was tested by exploring the associations between MRI T1 mapping indices and weight in the MESA (Multi-Ethnic Study of Atherosclerosis., Methods: Empirically derived methods based on sex and body habitus were used to calculate blood volumes. GBCA dose (in mL) in blood (in L) was calculated as the injected volume divided by the blood volume (i.e., DBV). Of the 1219 participants with cardiac MRI T1 mapping, 845 studies had standard dose of 0.15 mmol/kg (cohort 1) and 166 studies had 30 mL of GBCA regardless of weight (cohort 2). We also created a specific cohort with similar DBV (N = 357; cohort 3)., Results: Postcontrast blood relaxation rate R1 blood and DBV were significantly correlated (R = 0.641; P < 0.001). R1 blood was significantly associated with weight in cohort 1 and 2, but the correlation coefficient was positive for cohort 1 and negative for cohort 2, indicating GBCA overdosing in cohort 1 and underdosing in cohort 2 in heavy relative to lean subjects. R1 blood was not associated with weight in cohort 3. Simulated results demonstrated that less contrast should be administrated for heavy subjects compared to the conventional weight-based dose., Conclusion: GBCA dosing on the basis of blood volume could improve the efficacy and safety of contrast-enhanced MRI studies. This method could be implemented to standardize dose and augment precision in study comparisons., (© 2018 International Society for Magnetic Resonance in Medicine.)

Drug biodistribution analyses can be considered a key issue in pharmaceutical discovery and development. Here, mass spectrometric imaging can be employed as a powerful tool to investigate distributions of drug compounds in biologically and medically relevant tissue sections. Both matrix-assisted laser desorption ionization-mass spectrometric imaging as molecular method and laser ablation inductively coupled plasma-mass spectrometric imaging as elemental detection method were applied to determine drug distributions in tissue thin sections. Several mouse organs including the heart, kidney, liver, and brain were analyzed with regard to distribution of Gadovist ™ , a gadolinium-based contrast agent already approved for clinical investigation. This work demonstrated the successful detection and localization of Gadovist ™ in several organs. Furthermore, the results gave evidence that gadolinium-based contrast agents in general can be well analyzed by mass spectrometric imaging methods. In conclusion, the combined application of molecular and elemental mass spectrometry could complement each other and thus confirm analytical results or provide additional information.

A quantitative dried blood spot (DBS) method based on direct sampling by means of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) is presented. Gadolinium-based contrast agents were used as model metallodrugs with a significant relevance for pharmaceutical applications. Challenges regarding the ablation of the complex blood-filter matrix were characterized and successfully addressed by a thorough adaption of the laser ablation conditions. Especially the laser fluence was optimized with respect to the particle size distribution of the generated aerosol as monitored by an optical particle counter. Thus, generation of micrometer-sized particles could be minimized in favor of smaller particles increasing the transport efficiency of the DBS ablation aerosol to the plasma and the recorded signal stability. Inhomogeneous blood drying on the porous filter paper could be compensated by the addition of an internal standard prior to blood spotting. To preserve the advantages of DBS sampling, such as small blood volumes and minimal invasiveness, the combined use of DBS and a capillary blood sampling system is demonstrated. By placing the internal standard into the capillary prior to blood sampling, a simple workflow usable for clinical application was implemented. The applicability of the developed method, achieving limits of detection and quantification in the low μg L -1 range and covering a linear range of over four orders of magnitude, was demonstrated for blood samples containing different concentrations of the gadolinium contrast agents gadopentetate and gadoterate., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Purpose: To compare the levels of gadolinium in the blood, cerebrum, cerebellum, liver, femur, kidneys, and skin after multiple exposure of rats to the macrocyclic gadolinium-based contrast agents (GBCAs) gadoterate, gadobutrol, and gadoteridol., Materials and Methods: Fifty male Wistar Han rats were randomized to three exposure groups (n = 15 per group) and one control group (n = 5). Animals in the exposure groups received a total of 20 GBCA administrations (four administrations per week for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After a 28-day recovery period animals were sacrificed and the blood and tissues harvested for determination of gadolinium (Gd) levels. Gd determination was performed by inductively coupled plasma mass spectrometry (ICP-MS)., Results: After 28 days' recovery no Gd was found in the blood, liver, or skin of any animal in any group. Significantly lower levels of Gd were noted with gadoteridol compared to gadoterate and gadobutrol in the cerebellum (0.150 ± 0.022 vs. 0.292 ± 0.057 and 0.287 ± 0.056 nmol/g, respectively; P < 0.001), cerebrum (0.116 ± 0.036 vs. 0.250 ± 0.032 and 0.263 ± 0.045 nmol/g, respectively; P < 0.001), and kidneys (25 ± 13 vs. 139 ± 88 [P < 0.01] and 204 ± 109 [P < 0.001], respectively). Higher levels of Gd were noted in the femur (7.48 ± 1.37 vs. 5.69 ± 1.75 and 8.60 ± 2.04 nmol/g, respectively) with significantly less Gd determined for gadoterate than for gadobutrol (P < 0.001) and gadoteridol (P < 0.05)., Conclusion: Differences exist between macrocyclic agents in terms of their propensity to accumulate in tissues. The observed differences in Gd concentration point to differences in GBCA washout rates in this setting and in this experimental model, with gadoteridol being the GBCA that is most efficiently removed from both cerebral and renal tissues., Level of Evidence: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:746-752., (© 2017 The Authors Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

With their intriguing structures and properties, metallofullerenols have attracted considerable attention in biological and medical applications. Due to the increasing biomedical interest, effective detection methods are important to monitor and control metallofullerenols. However, the detection of metallofullerenols becomes very difficult after polyhydroxylated modification due to the lack of detectable features. Antibody-based immunoassay methods have been important tools for detection and will better meet the needs of analysis of metallofullerenols. Thus, the antigenicity of metallofullerenol has been studied for the first time. In this study, no immune response was detected when metallofullerenol Gd@C 82 (OH) x was used as immunogen. However, the polyclonal antibody against metallofullerenol was produced using metallofullerenol-KLH (keyhole limpet hemocyanin) as immunogen, indicating that metallofullerenol can act as hapten. The specificity of the obtained antibody was investigated. It has been found that the hydroxyl groups on the surface of the carbon cage, the encapsulated metal, and the size and shape of the carbon cage did not affect the recognition specificity of the antibody. Based on the obtained antibody, an indirect competitive enzyme immunoassay was developed for the determination of metallofullerenol with detection limits of 18 ng/mL in PBS. This enzyme immunoassay method was successfully used to detect metallofullerenol in serum. This work can provide an innovative way to determine metallofullerenols. Graphical abstract The polyclonal antibody against metallofullerenol was produced using metallofullerenol-KLH (keyhole limpet hemocyanin) as immunogen. Based on the obtained antibody, a competitive enzyme immunoassay was developed for the determination of metallofullerenol.

Purpose: To reanalyze literature data of gadolinium (Gd)-based contrast agents (GBCAs) in plasma with a kinetic model of dissociation to provide a comprehensive assessment of equilibrium conditions for linear GBCAs., Methods: Data for the release of Gd from GBCAs in human serum was extracted from a previous report in the literature and fit to a kinetic dissociation/association model. The conditional stabilities (logK cond ) and percent intact over time were calculated using the model rate constants. The correlations between clinical outcomes and logK cond or other stability indices were determined., Results: The release curves for Omniscan®, gadodiamide, OptiMARK®, gadoversetamide Magnevist® and Multihance® were extracted and all fit well to the kinetic model. The logK cond s calculated from the rate constants were on the order of ~4-6, and were not significantly altered by excess ligand or phosphate. The stability constant based on the amount intact by the initial elimination half-life of GBCAs in plasma provided good correlation with outcomes observed in patients., Conclusions: Estimation of the kinetic constants for GBCA dissociation/association revealed that their stability in physiological fluid is much lower than previous approaches would suggest, which correlates well with deposition and pharmacokinetic observations of GBCAs in human patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To provide a clinically relevant overview of the analytical interference by contrast agents (CA) in laboratory blood test measurements., Materials and Methods: The effects of five CAs, gadobutrol, gadoterate meglumine, gadoxetate disodium, iodixanol, and iomeprol, were studied on the 29 most frequently performed biochemical assays. One-day-old plasma, serum, and whole blood were spiked with doses of each agent such that the gadolinium agents and the iodine agents reached concentrations of 0.5 mM and 12 mg iodine/mL, respectively. Subsequently, 12 assays were reexamined using 1/2 and 1/4 of these CA concentrations. The results were assessed statistically by a paired Student's t -test., Results: Iodixanol produced a negative interference on the bicarbonate ( p = 0.011), lactate dehydrogenase ( p < 0.0001), and zinc ( p = 0.0034) assays and a positive interference on the albumin ( p = 0.0062), calcium ( p < 0.0001), ionized calcium ( p = 0.0086), iron ( p < 0.0001), and potassium ( p = 0.0003) assays. Iomeprol produced a negative interference on the bicarbonate ( p = 0.0057) and magnesium ( p = 0.0001) assays and a positive interference on the calcium ( p < 0.0001) and potassium ( p = 0.0012) assays. Gadoxetate disodium produced a negative interference on the iron ( p < 0.0001) and zinc ( p < 0.0001) assays and a positive interference on the sodium ( p = 0.032) assay., Conclusion: CAs cause analytical interference. Attention should be given to the above-mentioned analyte-CA combinations when assessing laboratory blood test results obtained after CA administration.

Gadolinium is a toxic rare earth element that is used as a contrast enhancement agent for diagnostic medical imaging. However, because of safety concerns to the developing fetus derived from preclinical studies, gadolinium can only be used during pregnancy if the potential benefits justify the potential risks to a fetus. Because there are no previous well designed safety studies on the developing fetus, we aimed to evaluate the potential adverse effects of in utero gadolinium exposure in high-risk premature infants. We performed a prospective dose (cord blood gadolinium concentration) - response (outcomes) study involving 104, 24-33 weeks gestational age (GA) infants. The mean (range) cord blood gadolinium concentration of infants measured using Inductively Coupled Plasma Mass Spectrometry was 191 (3.4-3729.6) pg/ml. The association between cord blood gadolinium concentration and each neonatal outcome was evaluated using linear or logistic regression analysis. The GA, race, gender, and antenatal steroid exposure were considered priori confounders. Recent adult human studies have shown that gadolinium exposure may be associated with nephrotoxicity. However, we found no adverse effects on renal function or other common outcomes including degree of prematurity, small for GA, respiratory distress syndrome, hyperbilirubinemia, intraventricular hemorrhage, necrotizing enterocolitis, patent ductus arteriosus, chronic lung disease, retinopathy of prematurity, and osteopenia of prematurity during the neonatal period with an increase in cord blood gadolinium concentration. None of the infants had clinically evident congenital malformations. In conclusion, gadolinium use during pregnancy is unlikely to be associated with adverse effects in infants during the neonatal period., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Biodegradable magnesium implants are under investigation because of their promising properties as medical devices. For enhancing the mechanical properties and the degradation resistance, rare earth elements are often used as alloying elements. In this study Mg10Gd pins were implanted into Sprague-Dawley® rats. The pin volume loss and a possible accumulation of magnesium and gadolinium in the rats' organs and blood were investigated in a long-term study over 36weeks. The results showed that Mg10Gd is a fast disintegrating material. Already 12weeks after implantation the alloy is fragmented to smaller particles, which can be found within the intramedullary cavity and the cortical bones. They disturbed the bone remodeling until the end of the study. The results concerning the elements' distribution in the animals' bodies were even more striking, since an accumulation of gadolinium could be observed in the investigated organs over the whole time span. The most affected tissue was the spleen, with up to 3240μgGd/kg wet mass, followed by the lung, liver and kidney (up to 1040, 685 and 207μgGd/kg). In the brain, muscle and heart, the gadolinium concentrations were much smaller (less than 20μg/kg), but an accumulation could still be detected. Interestingly, blood serum samples showed no accumulation of magnesium and gadolinium. This is the first time that an accumulation of gadolinium in animal organs was observed after the application of a gadolinium-containing degradable magnesium implant. These findings demonstrate the importance of future investigations concerning the distribution of the constituents of new biodegradable materials in the body, to ensure the patients' safety., Statement of Significance: In the last years, biodegradable Mg alloys are under investigation due to their promising properties as orthopaedic devices used for bone fracture stabilization. Gadolinium as Rare Earth Element enhances the mechanical properties of Mg-Gd alloys but its toxicity in humans is still questionable. Up to now, there is no study investigating the elements' metabolism of a REE-containing Magnesium alloy in an animal model. In this study, we examined the gadolinium distribution and accumulation in rat organs during the degradation of Mg10Gd. Our findings showed that Gd is accumulating in the animal organs, especially in spleen, liver and kidney. This study is of crucial benefit regarding a safe application of REE-containing Magnesium alloys in humans., (Copyright © 2016. Published by Elsevier Ltd.)

Objectives: Gadolinium-based contrast agents (GBCAs) have been used for years for magnetic resonance imaging examinations. Because of their rapid blood clearance, they were considered as very safe products until some of them were shown to induce nephrogenic systemic fibrosis in patients with renal failure and hypersignals on T1-weighted unenhanced brain scans of patients with normal renal function. To date, these adverse effects have been related almost exclusively to the use of low-stability linear agents, which are more prone to release free gadolinium. The aim of the present meta-analysis was to ascertain the existence of a deep compartment for gadolinium storage in the body and to assess whether all the GBCAs present the same toxicokinetic profile., Materials and Methods: Applying a systematic literature search methodology, all clinical and preclinical studies reporting time-dependent plasma concentrations and renal excretion data of gadolinium were identified and analyzed. Since the individual data were not available, the analysis focused on the average values per groups of subjects or animals, which had received a given GBCA at a given dose. The rate constants of the distribution phase (α), rapid elimination phase (β), and residual excretion phase (γ) of gadolinium were determined in each group from the plasma concentration (Cp) time curves and the relative urinary excretion rate (rER) time curves, taking the 2-hour time point as a reference. Moreover, as bone may represent a reservoir for long-term gadolinium accumulation and slow release into the blood stream, the time curves of the relative concentration in the bone (rCB) of Gd-labeled GBCAs in mice or rats were analyzed taking day 1 concentrations as a reference. The ratio of gadolinium concentrations in the bone marrow (CBM) as compared with the bone (CB) was also calculated., Results: The relative urinary excretion rate (rER) plots revealed a prolonged residual excretion phase of gadolinium in healthy volunteers, consistent with the existence of a deep compartment of distribution for the GBCAs. The rate constant γ of gadoterate meglumine (0.107 hour) is 5 times higher than that of the linear agents (0.020 ± 0.008 hour), indicating a much faster blood clearance for the macrocyclic GBCA. Similar results were obtained in the preclinical studies. A strong correlation was shown between the γ values of the different products and their respective thermodynamic stability constants (Ktherm). Greater clearance rates of Gd from murine bone were also found after gadoterate meglumine or gadoteridol injection (0.131-0.184 day) than after administration of the linear agents (0.004-0.067 day). The concentrations of Gd in the bone marrow (CBM) from animals exposed to either gadoterate meglumine or gadodiamide are higher than those in the bone (CB) for at least 24 hours. Moreover, the ratio of concentrations (CBM/CB) at 4 hours is significantly lower with the former agent than the latter (1.9 vs 6.5, respectively)., Conclusions: Using a nonconventional pharmacokinetic approach, we showed that gadoterate meglumine undergoes a much faster residual excretion from the body than the linear GBCAs, a process that seems related to the thermodynamic stability of the different chelates. Gadolinium dissociation occurs in vivo for some linear chelates, a mechanism that may explain their long-term retention and slow release from bone. Potential consequences in terms of bone toxicity warrant further investigations.

Background: The purpose of this study was to define an optimal injection protocol for 5-10 min duration navigator-based coronary MR angiography using an intravascular gadolinium-based contrast agent (GBCA), which is better suited for steady-state coronary MR angiography than conventional GBCAs., Methods: Using projections from pharmacokinetic models of the intravascular concentration of gadofosveset, a dual-injection protocol was formulated and tested on 14 healthy human subjects. Modified Look-Locker inversion recovery (MOLLI) sequences were used for T1 mapping at 3 Tesla to evaluate the concentration of tracer in the aorta over the scanning interval., Results: Pharmacokinetic models for a bolus plus slow infusion technique at a 5, 10, and 15 min steady state intravascular concentration was compared to single bolus curves. The 70 %/30 % bolus/slow infusion technique resulted in the highest intravascular concentration over a 5 min scan duration. Similarly, the 60 %/40 % bolus/slow infusion technique was projected to be ideal for image acquisition duration of 5-10 min. These models were confirmed with T1 maps on normal volunteers. Arterial-venous mixing of contrast was achieved within 90 s of the beginning of the bolus., Conclusions: Gadofosveset injection is optimized for the lowest intravascular T1 time for 5-10 min duration MR angiography by bolus injection of 60-70 % of the total dose followed by slow infusion of the remainder of the total dose. This protocol achieves rapid and prolonged steady state intravascular concentrations of the GBCA that may be useful for prolonged image acquisition, such as required for navigator-based coronary MR angiography at 3 Tesla., Trial Registration: ClinicalTrials.gov identifier: NCT01130545 NCT01130545 , registered as of May 25, 2010.

While not acutely toxic, chronic hepatic effect of certain gadolinium chelates (GC), used as contrast agent for magnetic resonance imaging, might represent a risk in renally-impaired patients due to free gadolinium accumulation in the liver. To answer this question, this study investigated the consequences of the presence of small amounts of either a soluble gadolinium salt ("free" Gd) or low-stability chelating impurity in the pharmaceutical solution of gadoteric acid, a macrocyclic GC with high thermodynamic and kinetic stabilities, were investigated in renally-impaired rats. Renal failure was induced by adding 0.75% adenine in the diet for three weeks. The pharmaceutical and commercial solution of gadoteric acid was administered (5 daily intravenous injections of 2.5 mmol Gd/kg) either alone or after being spiked with either "free" gadolinium (i.e., 0.04% w/v) or low-stability impurity (i.e., 0.06 w/v). Another GC, gadodiamide (low thermodynamic and kinetic stabilities) was given as its commercial solution at a similar dose. Non-chelated gadolinium was tested at two doses (0.005 and 0.01 mmol Gd/kg) as acetate salt. Gadodiamide induced systemic toxicity (mortality, severe epidermal and dermal lesions) and substantial tissue Gd retention. The addition of very low amounts of "free", non-chelated gadolinium or low thermodynamic stability impurity to the pharmaceutical solution of the thermodynamically stable GC gadoteric acid resulted in substantial capture of metal by the liver, similar to what was observed in "free" gadolinium salt-treated rats. Relaxometry studies strongly suggested the presence of free and soluble gadolinium in the liver. Electron microscopy examinations revealed the presence of free and insoluble gadolinium deposits in hepatocytes and Kupffer cells of rats treated with gadoteric acid solution spiked with low-stability impurity, free gadolinium and gadodiamide, but not in rats treated with the pharmaceutical solution of gadoteric acid. The presence of impurities in the GC pharmaceutical solution may have long-term biological consequences., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A series composed of a tetra-, a tris- and a bisphosphonated ligand based on a pyridine scaffold (L(4) , L(3) and L(2) , respectively) was studied within the frame of lanthanide (Ln) coordination. The stability constants of the complexes formed with lanthanide cations (Ln=La, Nd, Eu, Gd, Tb, Er and Lu) were determined by potentiometry in aqueous solutions (25.0 °C, 0.1 M NaClO4 ), showing that the tetraphosphonated complexes are among the most stable Ln(III) complexes reported in the literature. The complexation of L(4) was further studied by different titration experiments using mass spectrometry and various spectroscopic techniques including UV/Vis absorption, and steady state and time-resolved luminescence (Ln=Eu and Tb). Titration experiments confirmed the formation of highly stable [LnL(4) ] complexes. (31) P NMR experiments of the LuL(4) complex revealed an intramolecular interconversion process which was studied at different temperatures and was rationalized by DFT modelling. The relaxivity properties of the Gd(III) complexes were studied by recording their (1) H NMRD profiles at various temperatures, by temperature dependent (17) O NMR experiments (GdL(4) ) and by pH dependent relaxivity measurements at 0.47 T (GdL(3) and GdL(2) ). In addition to the high relaxivity values observed for all complexes, the results showed an important second-sphere contribution to relaxivity and pH dependent variations associated with the formation of aggregates for GdL(2) and GdL(3) . Finally, intravenous injection of GdL(4) to a mouse was followed by dynamic MRI imaging at 1.5 T, which showed that the complex can be immediately found in the blood stream and rapidly eliminated through the liver and in large part through the kidneys., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Low gas flow ICP-OES with a total argon consumption below 0.7 L/min is introduced for the analysis of trace elements in blood samples to investigate the influence of samples containing an organic solvent in a demanding matrix on the performance of this plasma for the first time. Therefore, gadolinium was determined in human plasma samples and mercury in red blood cells, human plasma, and precipitated plasma protein fraction. Limits of detection (LOD) were determined to be in the low microgram per liter range for the analytes and the accuracy of the method was assessed by comparison with a conventional Fassel-type torch-based ICP-OES. It was proven that the low gas flow ICP-OES leads to comparable results with the instrument based on the Fassel-type torch.

Background: Trace elements are commonly measured by inductively coupled mass spectrometry (ICP-MS). A 30-year-old man had a plasma selenium (Se) concentration on ICP-MS of 66 µmol/L (reference interval 0.45-1.40), a potentially lethal level, despite no history of Se exposure or toxicity symptoms. He had earlier undergone magnetic resonance imaging with a gadolinium (Gd) contrast agent, which is known to interfere with Se on ICP-MS. We aimed to adjust our method by monitoring a second Se isotope that is unaffected by Gd to detect this preanalytical interference., Methods: Plasma samples referred for trace metal testing had Se measured on ICP-MS (monitoring (78)Se), which we modified to also monitor a second isotope ((82)Se). The modified method was then applied to a specimen with known Gd contamination., Results: Plasma Se results (n = 41) derived from monitoring the two different Se isotopes were similar with a good correlation (R (2 )= 0.991) over a range of 0.23-2.21 µmol/L. On repeat analysis, our patient had a Se concentration of 65 µmol/L using the (78)Se isotope but only 1.43 µmol/L using (82)Se., Conclusion: To avoid reporting a falsely elevated plasma Se result, we suggest that Se analysis by ICP-MS should include a second Se isotope for monitoring, that is not subject to Gd interference., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: Measurement of selenium in serum is an important clinical biomarker of nutritional status. The presence of gadolinium (Gd) in samples following administration of the contrast agents used for magnetic resonance imaging (MRI) results in a significant positive bias when using quadrupole inductively coupled plasma mass spectrometry (Q-ICP-MS)., Methods: Three instrumental set-ups were assessed: standard mode with no collision gas and collision cell mode with either a hydrogen:helium mixture or hydrogen. The effect of Gd on the selenium (Se) signal was assessed using external quality assurance (EQA) specimens and internal quality control (IQC) materials, both unspiked and spiked with Gd. Serum previously shown to contain high concentrations of Gd-containing contrast agents were also analysed., Results: Recoveries of Se in the spiked compared to the unspiked samples were: between 500% and 1300% using standard mode; 100% and 29,000% using collision cell mode with hydrogen:helium mixture; and between 99% and 103% using hydrogen. The use of H2 in the collision cell provided accurate results, indicating that the charge exchange reaction (CER) of Gd(2+) with H2 removes this interference. Analysis of patient serum known to contain the Gd contrast agent using the method gave results within the selenium reference range (adults 0.89-1.65 µmol/L). The presence of Gd, as low as 0.2 mg/L, in serum samples causes a positive interference on the measurement of Se by ICP-MS., Conclusions: Using a CER mode with pure H2 in the collision cell it was possible to fully remove the interference due to Gd(2+) from the signal for Se.

To enhance tumor magnetic resonance imaging (MRI) signals via the selective accumulation of contrast agents, we prepared folate-modified gadolinium-lipid-based nanoparticles as MRI contrast agents. Folate-modified nanoparticles were comprised of polyethylene glycol (PEG)-lipid, gadolinium diethylenetriamine pentaacetic acid lipid, cationic cholesterol derivatives, folate-conjugated PEG-lipid, and Cy7-PEG-lipid. Folate receptor-mediated cellular nanoparticle association was examined in KB cells, which overexpress the folate receptor. The biodistribution of nanoparticles after their intravenous injection into KB tumor-bearing mice was measured. Mice were imaged through in vivo fluorescence imaging and MRI 24 h after nanoparticle injection, and the intensity enhancement of the tumor MRI signal was evaluated. Increased cellular association of folate-modified nanoparticles was inhibited by excess free folic acid, indicating that nanoparticle association was folate receptor-mediated. Irrespective of folate modification, the amount of nanoparticles in blood 24 h after injection was ca. 10% of the injected dose. Compared with non-modified nanoparticles, folate-modified nanoparticles exhibited significant accumulation in tumor tissues without altering other biodistribution, as well as enhanced tumor fluorescence and MRI signal intensity. The results support the feasibility of MRI- and in vivo fluorescence imaging-based tumor visualization using folate-modified nanoparticles and provide opportunities to develop folate targeting-based imaging applications.

We have previously reported enhancing the imaging of atherosclerotic plaques in mice using reconstituted high density lipoproteins (HDL) as nanocarriers for the MRI contrast agent gadolinium (Gd). This study focuses on the underlying mechanisms of Gd delivery to atherosclerotic plaques. HDL, LDL, and VLDL particles containing Gd chelated to phosphatidyl ethanolamine (DTPA-DMPE) and a lipidic fluorophore were used to demonstrate the transfer of Gd-phospholipids among plasma lipoproteins in vitro and in vivo. To determine the basis of this transfer, the roles of phospholipid transfer protein (PLTP) and lipoprotein lipase (LpL) in mediating the migration of Gd-DTPA-DMPE among lipoproteins were investigated. The results indicated that neither was an important factor, suggesting that spontaneous transfer of Gd-DTPA-DMPE was the most probable mechanism. Finally, two independent mouse models were used to quantify the relative contributions of HDL and LDL reconstituted with Gd-DTPA-DMPE to plaque imaging enhancement by MR. Both sets of results suggested that Gd-DTPA-DMPE originally associated with LDL was about twice as effective as that injected in the form of Gd-HDL, and that some of Gd-HDL's effectiveness in vivo is indirect through transfer of the imaging agent to LDL. In conclusion, the fate of Gd-DTPA-DMPE associated with a particular type of lipoprotein is complex, and includes its transfer to other lipoprotein species that are then cleared from the plasma into tissues.

The speciation of Al3+, Gd3+ and Y3+ ions in human plasma has been studied by computer simulation using the program HySS2009. A literature computer model of blood plasma was updated and comprised 9 metals, 43 ligands and over 6100 complexes. To this model critically evaluated data of Al3+, Gd3+ and Y3+ constants with blood plasma ligands have been added. Low molecular mass (LMM) speciation of Al3+ ion strongly depends upon the chosen equilibrium model of the metal - phosphate and metal - citrate systems. The obtained computer simulation of LMM speciation data of Al3+ ion were: AlPO4Cit (40.7%), AlPO4CitOH (22.9%), AlCitOH (19.2%) and AlPO4(OH) (12.7%) (% of total LMM Al species pool); for Gd3+ ion: GdAspCit (30%) and GdCit(OH)2 (20%) (% of total [Gd]) and for Y3+ ion: YCit (48%), Y(CO3)2 (32%) and Y(CO3) (11%) (% of total [Y]). Citrate appears as the important binding and mobilizing ligand for all examined ions, while the dominating species are the ternary ones.

Four gadolinium (Gd)-based macromolecular contrast agents, G3-(Gd-DOTA)(24), G5-(Gd-DOTA)(96), G3-(Gd-DTPA)(24), and G5-(Gd-DTPA)(96), were prepared that varied in the size of dendrimer (generation three and five), the type of chelate group (DTPA or DOTA), and the theoretical number of metalated chelates (24 and 96). Synthesis relied on a dichlorotriazine derivatized with a DOTA or DTPA ligand that was incorporated into the dendrimer and ultimately metalated with Gd ions. Paramagnetic characteristics and in vivo pharmacokinetics of all four contrast agents were investigated. The DOTA-containing agents, G3-(Gd-DOTA)(24) and G5-(Gd-DOTA)(96), demonstrated exceptionally high r1 relaxivity values at off-peak magnetic fields. Additionally, G5-(Gd-DOTA)(96) showed increased r1 relaxivity in serum compared to that in PBS, which was consistent with in vivo images. While G3-(Gd-DOTA)(24) and G3-(Gd-DTPA)(24) were rapidly excreted into the urine, G5-(Gd-DOTA)(96) and G5-(Gd-DTPA)(96) did not clear as quickly through the kidneys. Molecular simulation of the DOTA-containing dendrimers suggests that a majority of the metalated ligands are accessible to water. These triazine dendrimer-based MRI contrast agents exhibit several promising features such as high in vivo r1 relaxivity, desirable pharmacokinetics, and well-defined structure.

The use of gadolinium-based contrast agents (GBCA) is integral to the field of diagnostic magnetic resonance imaging (MRI). Pharmacokinetic evaluation of the plasma clearance of GBCA is required for all new agents or improved formulations, to address concerns over toxicity or unforeseen side effects. Current methods to measure GBCA in plasma lack either a rapid readout or the sensitivity to measure small samples or require extensive processing of plasma, all obstacles in the development and characterization of new GBCA. Here, we quantify the plasma concentration of a labeled analogue of a common clinical GBCA by ligand triplet harvesting and energy transfer. The nonemittive GBCA becomes a "dark donor" to a fluorescent detector molecule, with a lower limit of detection of 10(-7) M in unprocessed plasma. On a time scale of minutes, we determine the plasma clearance rate in the wild-type mouse, using time-resolved fluorescence on a standard laboratory plate reader.

Macromolecular contrast agents have the potential to assist magnetic resonance imaging (MRI) due to their high relaxivity, but are not clinically useful because of toxicity due to poor clearance. We have prepared a biodegradable ketal-based polymer contrast agent which is designed to degrade rapidly at physiological pH by hydrolysis, facilitating renal clearance. In vitro, the agent degraded more rapidly at lower pH, with complete fragmentation after 24 h at pH 7.4. In vitro relaxivity measurements showed a direct correlation between molecular weight and relaxivity. We compared our polymer contrast agent with commercially available Magnevist in vivo by MRI imaging, as well as measuring the Gd concentration in blood. Our results show that our polymer contrast agent gives a higher contrast and intensity in the same organs and areas as Magnevist and is cleared from the blood at a similar rate. We aim to improve our polymer contrast agent design to develop it for use as a MRI contrast agent, and explore its use as a platform for other imaging modalities.

Background and Purpose: Hyperphosphataemia is common in patients with nephrogenic systemic fibrosis (NSF). NSF has been linked to administration of gadolinium (Gd) chelates (GCs) and elevated serum phosphate levels accelerate the release of Gd from linear, non-ionic GCs but not macrocyclic GCs. Hence, we determined whether hyperphosphataemia is a cofactor or risk factor for NSF by investigating the role of hyperphosphataemia in renally impaired rats., Experimental Approach: Firstly, the clinical, pathological and bioanalytical consequences of hyperphosphataemia were investigated in subtotal nephrectomized (SNx) Wistar rats following i.v. administration of the non-ionic, linear GC gadodiamide (5 × 2.5 mmol·kg(-1) ·day(-1) ). Secondly, the effects of several GCs were compared in these high-phosphate diet fed rats. Total Gd concentration in skin, femur and plasma was measured by inductively coupled plasma mass spectrometry (ICP-MS) and free Gd(3+) in plasma by liquid chromatography coupled to ICP-MS. Relaxometry was used to measure dissociated Gd in skin and bone., Key Results: Four out of seven SNx rats fed a high-phosphate diet administered gadodiamide developed macroscopic and microscopic (fibrotic and inflammatory) skin lesions, whereas no skin lesions were observed in SNx rats treated with saline, the other GCs and free ligands or in the normal diet, gadodiamide-treated group. Unlike the other molecules, gadodiamide gradually increased the r(1) relaxivity value, consistent with its in vivo dissociation and release of soluble Gd., Conclusions and Implications: Hyperphosphataemia sensitizes renally impaired rats to the profibrotic effects of gadodiamide. Unlike the other GCs investigated, gadodiamide gradually dissociates in vivo. Our data confirm that hyperphosphataemia is a risk factor for NSF., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

A simple and rapid method to determine gadolinium (Gd) concentrations in urine and blood plasma samples by means of total reflection X-ray fluorescence (TXRF) was developed. With a limit of detection (LOD) of 100 μg L(-1) in urine and 80 μg L(-1) in blood plasma and a limit of quantification (LOQ) of 330 μg L(-1) in urine and 270 μg L(-1) in blood plasma, it allows analyzing urine samples taken from magnetic resonance imaging (MRI) patients during a period of up to 20 hours after the administration of Gd-based MRI contrast agents by means of TXRF. By parallel determination of the urinary creatinine concentration, it was possible to monitor the excretion kinetics of Gd from the patient's body. The Gd concentration in blood plasma samples, taken immediately after an MRI examination, could be determined after rapid and easy sample preparation by centrifugation. All measurements were validated with inductively coupled plasma mass spectrometry (ICP-MS). TXRF is considered to be an attractive alternative for fast and simple Gd analysis in human body fluids during daily routine in clinical laboratories., (This journal is © The Royal Society of Chemistry 2011)

MEKC with DAD was applied to detect six Gd-based contrasting agents (CAs) (Gd-DTPA-BMA (Omniscan), Gd-HPDO3A (ProHance), Gd-DOTA (Dotarem), Gd-AAZTA, Gd-BOPTA (Multihance) and Gd-DTPA (Magnevist)) commonly used in MRI diagnostics. The achieved LODs ranged between 0.40 and 20 μM and the optimized method gave excellent precision, especially when two internal standards were applied (less than 0.34 RSD% for migration time). The MEKC technique made it possible to determine the CAs in urine and serum samples of patients having a therapeutic dose. Due to the SDS content of the running buffer, the serum samples can be directly injected to analyze Gd-based CAs without interference of high protein content., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Selenium is an important clinical biomarker of nutritional status; however, the occurrence of gadolinium in a patient's serum as a result of the contrast agents used during magnetic resonance imaging investigations, results in a significant positive bias in its measurement by inductively coupled plasma-quadrupole mass spectrometry.

Rationale and Objectives: The observed relaxivity of gadolinium-based contrast agents has contributions from the water molecule(s) that bind directly to the gadolinium ion (inner-sphere water), long-lived water molecules and exchangeable protons that make up the second-sphere of coordination, and water molecules that diffuse near the contrast agent (outer-sphere). Inner- and second-sphere relaxivity can both be increased by optimization of the lifetimes of the water molecules and protons in these coordination spheres, the rotational motion of the complex, and the electronic relaxation of the gadolinium ion. We sought to identify new high-relaxivity contrast agents by systematically varying the donor atoms that bind directly to gadolinium to increase inner-sphere relaxivity and concurrently including substituents that influence the second-sphere relaxivity., Methods: Twenty gadolinium-1,4,7,10-tetraazacyclo-dodecane-N,N',N″,N'″-tetraacetato derivatives were prepared and their relaxivity determined in presence and absence of human serum albumin as a function of temperature and magnetic field. Data was analyzed to extract the underlying molecular parameters influencing relaxivity. Each compound had a common albumin-binding group and an inner-sphere donor set comprising the 4 tertiary amine N atoms from cyclen, an α-substituted acetate oxygen atom, 2 amide oxygen atoms, an inner-sphere water oxygen atom, and a variable donor group. Each amide nitrogen was substituted with different groups to promote hydrogen bonding with second-sphere water molecules., Results: Relativities at 0.47 and 1.4 T, 37°C, in serum albumin ranged from 16.0 to 58.1 mM(-1)s(-1) and from 12.3 to 34.8 mM(-1)s(-1), respectively. The reduction of inner-sphere water exchange typical of amide donor groups could be offset by incorporating a phosphonate or phenolate oxygen atom donor in the first coordination sphere, resulting in higher relaxivity. Amide nitrogen substitution with pendant phosphonate or carboxylate groups increased relaxivity by as much as 88% compared with the N-methyl amide analog. Second-sphere relaxivity contributed as much as 24 and 14 mM(-1)s(-1) at 0.47 and 1.4 T, respectively., Conclusions: Water/proton exchange dynamics in the inner- and second-coordination sphere can be predictably tuned by choice of donor atoms and second-sphere substituents, resulting in high-relaxivity agents.

Rationale and Objectives: The donor atoms that bind to gadolinium in contrast agents influence inner-sphere water exchange and electronic relaxation, both of which determine observed relaxivity. The effect of these molecular parameters on relaxivity is greatest when the contrast agent is protein bound. We sought to determine an optimal donor atom set to yield high relaxivity compounds., Methods: A total of 38 gadolinium-1,4,7,10-tetraazacyclo-dodecane-N,N',N'',N'''-tetraacetato derivatives were prepared and relaxivity was determined in the presence and absence of human serum albumin as a function of temperature and magnetic field. Each compound had a common albumin-binding group and differed only by substitution of different donor groups at one of the macrocycle nitrogens. Oxygen-17 isotope relaxometry at 7.05 T was performed to estimate water exchange rates., Results: Changing a single donor atom resulted in changes in water exchange rates ranging across 3 orders of magnitude. Donor groups increased water exchange rate in the order: phosphonate ∼ phenolate > α-substituted acetate > acetate > hydroxamate ∼ sulfonamide > amide ∼ pyridyl ∼ imidazole. Relaxivites at 0.47 and 1.4 T, 37°C, ranged from 12.3 to 55.6 mM(-1)s(-1) and from 8.3 to 32.6 mM(-1)s(-1) respectively. Optimal relaxivities were observed when the donor group was an α-substituted acetate. Electronic relaxation was slowest for the acetate derivatives as well., Conclusions: Water exchange dynamics and relaxivity can be predictably tuned by choice of donor atoms.

Purpose: Accelerated blood clearance (ABC) is induced by repeated injections of PEGylated liposomes. In this study, the ABC was investigated for a gadolinium-containing PEG-poly(L-lysine)-based polymeric micelle (Gd-micelle) and PEGylated liposome (Gd-liposome) in mice., Materials and Methods: Effects of the first injection of Gd-micelle on the tissue distribution of the second dose of Gd-micelle were studied. Additionally, effects of the first injection of Gd-micelle, Gd-liposome, empty liposome, polyethyleneglycol (PEG(500,000)), and PEG-lipid on the distribution of the second dose of the Gd-liposome were evaluated., Results: Results indicated that the tissue distribution of the second injection of the Gd-micelle at a dose of 33, 5, or 2 micromol Gd/kg was not affected by the first injection of the Gd-micelle at different doses and time intervals or of the empty PEGylated liposome 7 days before. ABC of Gd-liposome at a dose of 2.3 micromol Gd/kg (corresponding to 10 micromol lipids/kg) was observed when the empty PEGylated liposome or Gd-liposome, but not the Gd-micelle, PEG(500,000) or PEG-lipid, was pre-administered., Conclusions: The hydrophobic core of the micelle or lipid bilayer of PEGylated liposome has a major effect on this phenomenon. These studies have significant implications for the evaluation of PEG-poly(L-lysine)-based micellar formulation of Gd-based contrast agents.

Current clinical applications of dynamic contrast-enhanced MRI (DCE-MRI) are based on the extravasation of relatively small contrast agents (SCAs). SCAs are considered disadvantageous, as they require high image sampling rates. Medium-sized contrast agents (MCAs) leak more slowly into tissue and allow longer dynamic acquisition times, enabling improved image quality. The influence of molecular size on the reliability of pharmacokinetic parameters, including the transfer constant K(trans), was investigated. Computer simulations were performed, with in vivo measured arterial input functions (AIFs), to determine the bias and variance of pharmacokinetic parameters as a function of contrast agent size, sampling frequency, noise level, and acquisition time. Better reliability of all parameters was obtained for the MCA compared to the SCA. To obtain similar variance (10%) in K(trans), the sampling frequency for the SCA (28 min(-1)) had to be 20 times faster than for the MCA (1.3 min(-1)). Optimal reliability in parameter estimation required longer acquisition times for MCAs (13 min for the fraction of the extravascular extracellular space into which the contrast agent distributes (v(e)) and 5 min for K(trans)) than for SCAs (1.7 min for K(trans) and v(e)). Reliable estimation of the fractional blood plasma volume (v(p)) was only achieved with MCAs. In conclusion, MCAs provided superior reliability for pharmacokinetic parameter estimation compared to SCAs.

A polymeric micelle drug carrier system was applied to the targeting of an MRI (magnetic resonance imaging) contrast agent. A block copolymer, PEG-b-poly(L-lysine), was used for conjugation of gadolinium ions through chelating moieties, DOTA. The DOTA moieties were successfully conjugated to all primary amine groups of the lysine residues. The obtained block copolymer, PEG-b-poly(L-lysine-DOTA), formed a polymeric micelle. The polymeric micelle structure was maintained even after partial gadolinium chelation ( approximately 40%) to the DOTA moieties. The prepared polymeric micelle MRI contrast agent was injected into a mouse tail vein at a dose of 0.05 mmol Gd/kg. The polymeric micelle-based MRI contrast agent exhibited stable blood circulation. A considerable amount (6.1+/-0.3% of ID/g of the polymeric micelle) was found to accumulate at solid tumors 24 h after intravenous injection by means of the EPR effect. An MRI analysis revealed that the signal intensity of the tumor was enhanced 2.0-fold by the use of this contrast agent.

A functional form for the vascular concentration of MRI contrast agent after intravenous bolus injection was developed that can be used to model the concentration at any vascular site at which contrast concentration can be measured. The form is based on previous models of blood circulation, and is consistent with previously measured data at long post-injection times, when the contrast agent is fully and evenly dispersed in the blood. It allows the first-pass and recirculation peaks of contrast agent to be modelled, and measurement of the absolute concentration of contrast agent at a single time point allows the whole time course to be rescaled to give absolute contrast agent concentration values. This measure of absolute concentration could be performed at a long post-injection time using either MRI or blood-sampling methods. In order to provide a model that is consistent with measured data, it was necessary to include both rapid and slow extravasation, together with excretion via the kidneys. The model was tested on T(1)-weighted data from the descending aorta and hepatic portal vein, and on T*(2)-weighted data from the cerebral arteries. Fitting of the model was successful for all datasets, but there was a considerable variation in fit parameters between subjects, which suggests that the formation of a meaningful population-averaged vascular concentration function is precluded.

The first analytical method for simultaneous speciation analysis of five of the most important gadolinium-based magnetic resonance imaging (MRI) contrast agents in blood plasma samples was developed. Gd-DTPA (Magnevist), Gd-BT-DO3A (Gadovist), Gd-DOTA (Dotarem), Gd-DTPA-BMA (Omniscan), and Gd-BOPTA (Multihance) were separated by hydrophilic interaction liquid chromatography (HILIC) and detected with electrospray mass spectrometry (ESI-MS). Spiking experiments of blank plasma with Magnevist and Gadovist were performed to determine the analytical figures of merit and the recovery rates. The limits of detection ranged from 1 x 10 (-7) to 1 x 10 (-6) mol/L depending on the ionization properties of the individual compounds, and limits of quantification ranged from 5 x 10 (-7) to 5 x 10 (-6) mol/L. The linear concentration range comprised 2 orders of magnitude. With application of this method, blood plasma samples of 10 healthy volunteers, with Magnevist or Gadovist medication, were analyzed for Gd-DTPA and Gd-BT-DO3A, respectively. The obtained results were successfully validated with inductively coupled plasma-optical emission spectroscopy (ICP-OES).

Thrombus (blood clot) is implicated in a number of life threatening diseases, e.g., heart attack, stroke, pulmonary embolism. EP-2104R is an MRI contrast agent designed to detect thrombus by binding to the protein fibrin, present in all thrombi. EP-2104R comprises an 11 amino acid peptide derivatized with 2 GdDOTA-like moieties at both the C- and N-terminus of the peptide (4 Gd in total). EP-2104R was synthesized by a mixture of solid phase and solution techniques. The La(III) analogue was characterized by and 1D and 2D NMR spectroscopy and was found to have the expected structure. EP-2104R was found to be significantly more inert to Gd(III) loss than commercial contrast agents. At the most extreme conditions tested (pH 3, 60 degrees C, 96 hrs), less than 10% of Gd was removed from EP-2104R by a challenge with a DTPA based ligand, while the commercial contrast agents equilibrated within minutes to hours. EP-2104R binds equally to two sites on human fibrin (Kd = 1.7 +/- 0.5 microM) and has a similar affinity to mouse, rat, rabbit, pig, and dog fibrin. EP-2104R has excellent specificity for fibrin over fibrinogen (over 100-fold) and for fibrin over serum albumin (over 1000-fold). The relaxivity of EP-2104R bound to fibrin at 37 degrees C and 1.4 T was 71.4 mM(-1) s(-1) per molecule of EP-2104R (17.4 per Gd), about 25 times higher than that of GdDOTA measured under the same conditions. Strong fibrin binding, fibrin selectivity, and high molecular relaxivity enable EP-2104R to detect blood clots in vivo.

Luminescent hybrid nanoparticles with a paramagnetic Gd2O3 core were applied as contrast agents for both in vivo fluorescence and magnetic resonance imaging. These hybrid particles were obtained by encapsulating Gd2O3 cores within a polysiloxane shell which carries organic fluorophores and carboxylated PEG covalently tethered to the inorganic network. Longitudinal proton relaxivities of these particles are higher than the positive contrast agents like Gd-DOTA which are commonly used for clinical magnetic resonance imaging. Moreover these particles can be followed up by fluorescence imaging. This study revealed that these particles suited for dual modality imaging freely circulate in the blood vessels without undesirable accumulation in lungs and liver.

A high-molecular weight tetrametallic supramolecular complex [(Ln-DTPA-phen)3Fe]- (Ln = Gd, Eu, La) has been obtained upon self-assembly around one iron(II) ion of three 1,10-phenantroline-based molecules substituted in 5'-position with the polyaminocarboxylate diethylenetriamine-N,N,N',N',N'-pentaacetate, DTPA-phen(4-). The ICP-MS measurements indicated that the lanthanide:iron ratio is 3:1. Photoluminescence spectra of [Eu-DTPA-phen](-) and of [(Eu-DTPA-phen)3Fe]- are nearly identical, implying that the first coordination sphere of the lanthanide(III) ion has not been changed upon coordination of phenantroline unit to iron(II) ion. NMRD measurements revealed that at 20 MHz and 310 K the relaxivity of the [(Gd-DTPA-phen)3Fe]- is equal to 9.5 +/- 0.3 s(-1) mM(-1) of Gd (28.5 s(-1) per millimole per liter of complex) which is significantly higher than that for Gd-DTPA (3.9 s(-1) mM(-1)). The pharmacokinetic parameters of [(Gd-DTPA-phen)3Fe]- in rats indicate that the elimination of [(Gd-DTPA-phen)3Fe]- is significantly slower than that of Gd-DTPA and is correlated with a reduced volume of distribution. The low volume of distribution and the longer elimination time (T(e1/2)) suggest that the agent is confined to the blood compartment, so it could have an important potential as a blood pool contrast agent. The biodistribution profile of [(Gd-DTPA-phen)3Fe]- 2 h after injection indicates significantly higher concentrations of [(Gd-DTPA-phen)3Fe]- as compared with Gd-DTPA in kidney, liver, lungs, heart and spleen. The images obtained on rats by MR angiography show the enhancement of the abdominal blood vessels. The signal intensity reaches a maximum of 55% at 7 min post-contrast and remains around 25% after 90 min. MRI-histomorphological correlation studies of [Gd-DTPA-phen]- and [(Gd-DTPA-phen)3Fe]- showed that both agents displayed potent contrast enhancement in organs including the liver. The necrosis avidity tests indicated that, in contrast to the [Gd-DTPA-phen](-) precursor complex, the supramolecular complex [(Gd-DTPA-phen)3Fe]- exhibits necrosis avidity., (Copyright 2006 John Wiley & Sons, Ltd.)

Rationale and Objectives: To characterize and compare commercially available contrast media (CM) for magnetic resonance imaging (MRI) in terms of their relaxivity at magnetic field strengths ranging from 0.47 T to 4.7 T at physiological temperatures in water and in plasma. Relaxivities also were quantified in whole blood at 1.5 T., Methods: Relaxivities of MRI-CM were determined by nuclear magnetic resonance (NMR) spectroscopy at 0.47 T and MRI phantom measurements at 1.5 T, 3 T, and 4.7 T, respectively. Both longitudinal (T1) and transverse relaxation times (T2) were measured by appropriate spin-echo sequences. Nuclear magnetic resonance dispersion (NMRD) profiles were also determined for all agents in water and in plasma., Results: Significant dependencies of relaxivities on the field strength and solvents were quantified. Protein binding leads to both increased field strength and solvent dependencies and hence to significantly altered T1 relaxivity values at higher magnetic field strengths., Conclusions: Awareness of the field strength and solvent associated with relaxivity data is crucial for the comparison and evaluation of relaxivity values. Data observed at 0.47 T can thus be misleading and should be replaced by relaxivities measured at 1.5 T and at 3 T in plasma at physiological temperature.

Purpose: To investigate the pharmacokinetics, long-term tissue retention of Gd(III) ions, and magnetic resonance imaging (MRI) contrast enhancement of extracellular biodegradable macromolecular Gd(III) complexes, (Gd-DTPA)-cystamine copolymers (GDCC), of different molecular weights., Methods: The pharmacokinetics of blood clearance and long-term Gd(III) retention of GDCC were investigated in Sprague-Dawley rats. Pharmacokinetic parameters were calculated by using a two-compartment model. The blood pool contrast enhancement of GDCC was evaluated in Sprague-Dawley rats on a Siemens Trio 3T MR scanner. Gd-(DTPA-BMA) was used as a control., Results: The alpha phase half-life of Gd-(DTPA-BMA) and GDCC with molecular weights of 18,000 (GDCC-18) and 60,000 Da (GDCC-60) was 0.48 +/- 0.16 min, 1.08 +/- 0.24 min, and 1.74 +/- 0.57 min, and the beta phase half-life was 21.2 +/- 5.5 min, 26.5 +/- 5.9 min, and 53.7 +/- 15.9 min, respectively. GDCC had minimal long-term Gd tissue retention comparable to that of Gd-(DTPA-BMA). GDCC resulted in more significant contrast enhancement in the blood pool than Gd-(DTPA-BMA)., Conclusions: GDCC provides a prolonged blood pool retention time for effective MRI contrast enhancement and then clears rapidly with minimal accumulation of Gd (III) ions. It is promising for further development as a blood pool MRI contrast agent.

Rationale and Objectives: To investigate in a unilaterally nephrectomized porcine model whether gadolinium contrast media (Gd-CM) are less nephrotoxic than iodine media (I-CM) in x-ray arteriography of a kidney made temporarily ischemic by arterial balloon occlusion., Materials and Methods: In a noncrossover design, 3 mL of each test solution were injected in eight pigs (mean weight 19 kg) at a rate of 20 mL/min into the right renal artery at the start of a 10-minute period of ischemia. In group 1 (40 pigs) we injected 0.5 M gadopentetate, 0.5 M gadodiamide, 0.5 M iohexol (190 mg I/mL), 0.18 M iohexol (70 mg I/mL; with an x-ray attenuation equal to that of 0.5 M Gd-CM at 80 kV), and saline. In group 2 (24 pigs), we tested 0.18 M iohexol with ischemia and saline with and without ischemia. Gd- and iodine contrast media functioned as markers of glomerular filtration rate (GFR). When saline was tested, a low dose of iohexol (3 mL per pig; 300 mg I/mL) was injected as GFR marker intravenously in group 1 and into the renal artery in group 2. The plasma half-life elimination times of the CM 1-3 hours after injection were used to compare the effects of the different test solutions on GFR. Longer half-life means lower GFR., Results: Group 1: median plasma half-life elimination time of the GFR marker was 3 340 minutes after injection of 0.5 M gadopentetate, 256 after 0.5 M gadodiamide, 179 after 0.5 M iohexol, 143 after 0.18 M iohexol, and 133 minutes after saline. All differences except that between 0.18 M iohexol and saline were statistically significant (P < .01). Group 2: median plasma half-life was 174 minutes after 0.18 M iohexol with ischemia, 196 minutes after saline with ischemia, and 195 minutes after saline without ischemia. There were no significant differences between the test solutions in group 2 (P > .05)., Conclusion: In pigs, 0.5 M Gd-CM were more nephrotoxic than both equal-attenuating (70 mg I/mL) and equimolar (190 mg I/mL) concentrations of the I-CM iohexol. These results do not support the "off-label" use of Gd-CM for renal x-ray arteriography in man instead of commercially available concentrations of iodine contrast media at 140, 150 and 180 mg I/mL or diluted to 70 mg I/mL.

Background: Gadolinium formulations, which are administered as contrast agents in magnetic resonance imaging examinations, interfere with colorimetric serum calcium determinations., Methods: We performed an in vitro study to determine the extent to which three gadolinium formulations-gadodiamide (Omniscan), gadopentetate dimeglumine (Magnevist), and gadoversetamide (OptiMARK)-affect measurements by two methods that use o-cresolphthalein (Dade Behring, Inc. and Roche Diagnostics) and one that uses arsenazo dye (Equal Diagnostics). We also compared values from the o-cresolphthalein methods for 116 samples from patients administered gadodiamide., Results: Magnevist did not affect any of the methods evaluated, whereas Omniscan and OptiMARK were identical in their effects. For the Dade method, the differences from the control sample were < or =4.0 and 7.0 mg/L at 0.25 and 0.5 mmol/L gadolinium, respectively. For the Roche method, the differences were 19, 9.0, and 5.0 mg/L at 0.5, 0.25, and 0.125 mmol/L gadolinium, respectively. Falsely increased calcium values were seen when samples were measured by the arsenazo-based method: differences were 6.0 and 3.0 mg/L at 1.0 and 0.5 mmol/L gadolinium. Using patient data collected at our institution, we were able to generate a model for predicting, from a patient's glomerular filtration rate and the time elapsed since administration, the impact of Omniscan on calcium measurements by the o-cresolphthalein method from Roche Diagnostics., Conclusions: The predictive model can be used to calculate, in patients who have received gadodiamide, the minimum length of time to wait before blood collection to avoid pseudohypocalcemia when the Roche o-cresolphthalein method is used.

Rationale and Objectives: To characterize the pharmacokinetics of gadolinium and to evaluate the safety of gadobenate dimeglumine (Gd-BOPTA) compared with placebo, in subjects with impaired liver function., Methods: Volunteer adult subjects with hepatic impairment (Child-Pugh classification B or C) received, randomly and in double-blind fashion, either 0.1 mmol/kg gadobenate dimeglumine (n = 11) or placebo (n = 5) by intravenous injection. Blood and urine gadolinium concentrations were determined by ICP-AES and data were analyzed by compartmental and noncompartmental modeling. A full safety evaluation was performed. No magnetic resonance imaging was performed., Results: A bi-exponential model fit the gadolinium blood concentration-time data for 10 of 11 subjects administered Gd-BOPTA. The mean (CV%) distribution and elimination half-lives for these subjects were 0.18 (71.9) and 2.18 (44.2) hours, respectively. Non-parametric analysis of all 11 subjects revealed a mean (CV%) area under the curve [0-inf] of 138 (41.9) microg(Gd).h/mL. Mean (CV%) values for blood clearance, steady-state volume of distribution, and renal clearance were 172 (36.0) mL/minute, 22.9 (16.7) L, and 142 (49.0) mL/minute, respectively. A mean (CV%) of approximately 80% (24.5) of the administered dose was excreted in urine during 60 to 72 hours. No safety concerns were apparent., Conclusion: Hepatic impairment did not modify the pharmacokinetics of gadobenate dimeglumine compared with values reported elsewhere for healthy subjects. The contrast agent was well tolerated and safe with an overall incidence of adverse events comparable to that of placebo.

Two DTPA derivatives (PIP-DTPA and AZEP-DTPA) as potential contrast enhancement agents in MRI are synthesized. The T1 and T2 relaxivities of their corresponding Gd(III) complexes are reported. At clinically relevant field strengths, the relaxivities of the complexes are comparable to that of the contrast agent, Gd(DTPA) which is in clinical use. The serum stability of the (153)Gd-labeled complexes is assessed by measuring the release of (153)Gd from the ligands. The radiolabeled Gd chelates are found to be kinetically stable in human serum for up to at least 14 days without any measurable loss of radioactivity.

Rationale and Objectives: Gadomer-17 is a new magnetic resonance (MR) contrast medium presently in clinical development. It is a dendritic gadolinium (Gd) chelate carrying 24 Gd ions. This study investigated the pharmacokinetic behavior of this contrast medium., Methods: The pharmacokinetics of Gadomer-17 were investigated in different species (rat, rabbit, dog, monkey) for up to 7 days after intravenous (i.v.) injection of 25-100 micromol/kg body weight. In addition, elimination and biodistribution were evaluated after single i.v. injection of Gadomer-17 in rats., Results: After i.v. injection Gadomer-17 distributes almost exclusively within the intravascular space without significant diffusion into the interstitial space. The volume of distribution (Vc) in the initial or alpha-phase ranged from 0.04 l/kg (rats, rabbits) to 0.06 l/kg (monkeys) and 0.07 l/kg (dogs), which reflects mainly the plasma volume. The blood/plasma concentration profile was found to be biphasic. The volume of distribution at a steady state is clearly smaller than that of other contrast media, which distribute to the extracellular space. After single i.v. injection in rats, the dendritic contrast medium was rapidly and completely eliminated from the body, mainly via glomerular filtration. No long-term accumulation or retention of the nonmetabolized agent was detectable in organs or tissues., Conclusions: Gadomer-17 is a promising new MR contrast medium that has an intravascular distribution and a rapid renal elimination.

The aim of this study was to validate an experimental model designed to distinguish four categories of contrast agents, non specific agents (NDA, Gd-DOTA) characterized by rapid and total extravasation; low diffusion agents (LDA, P760) characterized by delayed extravasation; and rapid (P792) and slow clearance (P717) blood pool agents (BPA) characterized by limited extravasation. Plasma and peritoneal gadolinium concentrations were simultaneously measured after intravenous injection of various contrast agents in mice. Products of each category were compared in this model.The plasma pharmacokinetic profiles were similar for Gd-DOTA and P760 (t1/2=13.3 and 13.8 min, respectively), whereas the half-lives were 22 and 1212 min for P792 and P717, respectively. The plasma clearance was inversely related to the size of the contrast agent. The intraperitoneal diffusion patterns of the various products were related to the molecular volume: C(max) per dose decreased progressively (78.7, 51.2, 44.2, 33.5 1/l) and t(max) increased (7, 15, 40, and 120 min) for Gd-DOTA, P760, P792 and P717, respectively. Nevertheless, the same quantities of Gd-DOTA and P760 (AUC ratio of 78.4 and 76.8, respectively) diffused into the peritoneum, whereas only 44.5% of P792 and 21.5% of P717 extravasated.The data obtained in this peritoneal permeability model with the various categories of contrast agents provide an estimation of the quantities of contrast agents diffusing into a permeable interstitium and may be used to predict the corresponding signal intensity, which can be measured locally.

Boron neutron capture therapy (BNCT) is a form of targeted radiotherapy that relies on the uptake of the capture element boron by the volume to be treated. The treatment procedure requires the measurement of boron in the patient's blood. The investigation of a simple and inexpensive method for determining the concentration of the capture element 10B in blood is described here. This method, neutron flux depression measurement, involves the determination of the flux depression of thermal neutrons as they pass through a boron-containing sample. It is shown via Monte Carlo calculations and experimental verification that, for a maximum count rate of 1 x 10(4) counts/s measured by the detector, a 10 ppm 10B sample of volume 20 ml can be measured with a statistical precision of 10% in 32 +/- 2 min. For a source activity of less than 1.11 x 10(11) Bq and a maximum count rate of less than 1 x 10(4) counts/s, a 10 ppm 10B sample of volume 20 ml can be measured with a statistical precision of 10% in 58 +/- 3 min. It has also been shown that this technique can be applied to the measurement of the concentration of any element with a high thermal neutron cross section such as 157Gd.