Imaging-Based Staging of Hepatic Fibrosis in Patients with Hepatitis B: A Dynamic Radiomics Model Based on Gd-EOB-DTPA-Enhanced MRI.

Accurate grading of liver fibrosis can effectively assess the severity of liver disease and help doctors make an appropriate diagnosis. This study aimed to perform the automatic staging of hepatic fibrosis on patients with hepatitis B, who underwent gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging with dynamic radiomics analysis. The proposed dynamic radiomics model combined imaging features from multi-phase dynamic contrast-enhanced (DCE) images and time-domain information. Imaging features were extracted from the deep learning-based segmented liver volume, and time-domain features were further explored to analyze the variation in features during contrast enhancement. Model construction and evaluation were based on a 132-case data set. The proposed model achieved remarkable performance in significant fibrosis (fibrosis stage S1 vs. S2-S4; accuracy (ACC) = 0.875, area under the curve (AUC) = 0.867), advanced fibrosis (S1-S2 vs. S3-S4; ACC = 0.825, AUC = 0.874), and cirrhosis (S1-S3 vs. S4; ACC = 0.850, AUC = 0.900) classifications in the test set. It was more dominant compared with the conventional single-phase or multi-phase DCE-based radiomics models, normalized liver enhancement, and some serological indicators. Time-domain features were found to play an important role in the classification models. The dynamic radiomics model can be applied for highly accurate automatic hepatic fibrosis staging.

Compound-specific recording of gadolinium pollution in coastal waters by great scallops.

Gadolinium-based contrast agents (GBCAs), routinely used in magnetic resonance imaging (MRI), end up directly in coastal seawaters where gadolinium concentrations are now increasing. Because many aquatic species could be sensitive to this new pollution, we have evaluated the possibility of using shellfish to assess its importance. Gadolinium excesses recorded by scallop shells collected in Bay of Brest (Brittany, France) for more than 30 years do not reflect the overall consumption in GBCAs, but are largely controlled by one of them, the gadopentetate dimeglumine. Although its use has been greatly reduced in Europe over the last ten years, gadolinium excesses are still measured in shells. Thus, some gadolinium derived from other GBCAs is bioavailable and could have an impact on marine wildlife.

Chimeric mouse model for MRI contrast agent evaluation.

PURPOSE: While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use. METHODS: FVB (wild-type) and OATP1B1/1B3 knock-in mice were injected with hepatospecific MRI contrast agents (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific Gd-DTPA. T1 -weighted dynamic contrast-enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured. RESULTS: Following intravenous injection of Gd-BOPTA in chimeric OATP1B1/1B3 knock-in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild-type mice. Gd-BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wild-type mice. Gd-BOPTA elimination in wild-type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd-EOB-DTPA and Gd-DTPA were similar between wild-type and chimeric cohorts. CONCLUSION: Hepatic MRI signal enhancement and elimination of Gd-EOB-DTPA, Gd-BOPTA, and Gd-DTPA in chimeric OATP1B1/1B3 knock-in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock-in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild-type models.

Preparation of gadolinium doped carbon dots for enhanced MR imaging and cell fluorescence labeling.

Gadolinium doped carbon dots (Gd-CDs) were prepared as a dual-modal imaging agent for enhanced MR imaging and cell fluorescence imaging. The Gd-CDs were synthesized via one-step solvent free technique with Gd-DTPA and l-arginine as the Gd and carbon sources with a quantum yield of 57.78%. The Gd-CDs exhibited good crystal structure, excellent aqueous dispersity, high colloidal stability, intense fluorescence and low cytotoxicity. The bio-TEM images revealed that the Gd-CDs could be easily internalized by cancer cells and escape from the endosomes. Furthermore, the Gd-CDs demonstrated wonderful multi-color fluoresence cell labeling ability at various excitation wavelength and much better MR contrast effect compared with commercial Gd-DTPA with a high r1 relaxivity value 6.27 mM-1s-1. In addition, Gd-CDs exhibited brighter MR signal than Gd-DTPA in the animal MR imaging test. Finally, the Gd-CDs also indicated low long-term toxicity by the serum biochemistry analysis. Thus, these results indicated that Gd-CDs would be an excellent dual-modal imaging probe for enhanced MR imaging and fluorescence imaging.

Gadolinium Deposition in the Brain: Current Updates.

Gadolinium-based contrast agents (GBCAs) are commonly used for enhancement in MR imaging and have long been considered safe when administered at recommended doses. However, since the report that nephrogenic systemic fibrosis is linked to the use of GBCAs in subjects with severe renal diseases, accumulating evidence has suggested that GBCAs are not cleared entirely from our bodies; some GBCAs are deposited in our tissues, including the brain. GBCA deposition in the brain is mostly linked to the specific chelate structure of the GBCA: linear GBCAs were responsible for brain deposition in almost all reported studies. This review aimed to summarize the current knowledge about GBCA brain deposition and discuss its clinical implications.

An Imaging Biomarker for Assessing Hepatic Function in Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: We aimed to evaluate the potential of hepatobiliary phase magnetic resonance imaging (MRI) as parameter for assessment of hepatocellular function in patients with primary sclerosing cholangitis (PSC). METHODS: We collected data from 111 patients (83 male, 28 female; median, 44 years old), from March 2012 through March 2016, with a confirmed diagnosis of PSC who underwent MRI evaluation before and after injection (hepatobiliary phase) of a hepatocyte-specific contrast agent (gadoxetate disodium). Signal intensities were measured in each liver segment. Mean relative enhancement values were calculated and correlated with findings from liver functions tests, prognostic scoring systems (model for end-stage liver disease [MELD] score; Mayo risk score; Amsterdam-Oxford-PSC score), abnormalities detected by endoscopic retrograde cholangiopancreatography (using the Amsterdam cholangiographic classification system), and clinical endpoints (liver transplantation, cholangiocarcinoma, liver-related death). Our primary aim was to associate relative enhancement values with liver function and patient outcomes. RESULTS: Most patients had moderate-stage disease and had intermediate levels of risk (median MELD score, 8 and median Mayo score, 0.27). Clinical endpoints were reached by 21 patients (6 developed cholangiocarcinoma, 8 underwent liver transplantation, and 7 patients died). The highest levels of correlations were observed for relative enhancement 20 min after contrast injection and level of alkaline phosphatase (r = -0.636), bilirubin (r = -0.646), albumin (r = 0.538); as well as international normalized ratio (r = 0.456); MELD score (r = -0.587); Mayo risk score (r = -0.535), and Amsterdam-Oxford model score (r = -0.595) (P < .0001). Relative enhancement correlated with all clinical endpoints (all P < .05). A cutoff relative enhancement value of 0.65 identified patients with a clinical endpoint with 73.9% sensitivity 92.9% specificity (area under the receiver operating characteristic curve, 0.901; likelihood ratio, 10.34; P < .0001). CONCLUSIONS: In an analysis of 111 patients with PSC, we found MRI-measured relative enhancement, using a hepatocyte-specific contrast agent, to identify patients with clinical outcomes with 73.9% sensitivity 92.9% specificity. Long-term, multicenter studies are needed to further evaluate this marker of PSC progression.

Feasibility of 10-Minute Delayed Hepatocyte Phase Imaging Using a 30° Flip Angle in Gd-EOB-DTPA-Enhanced Liver MRI for the Detection of Hepatocellular Carcinoma in Patients with Chronic Hepatitis or Cirrhosis.

OBJECTIVES: To compare 10-minute (min) delayed hepatocyte phase imaging (HPI) using a 30° flip angle (FA) (10m-FA30) and 20-min delayed HPI using a 10° FA (20m-FA10) or 30° FA (20m-FA30) in Gd-EOB-DTPA-enhanced MRI in patients with chronic hepatitis or cirrhosis, in terms of lesion-to-liver contrast-to-noise ratio (CNR) for hepatocellular carcinoma (HCC) and detection sensitivity for focal hepatic lesions (FHLs). MATERIALS AND METHODS: One hundred and four patients with 168 HCCs and 55 benign FHLs who underwent Gd-EOB-DTPA-enhanced MRI with 10m-FA30, 20m-FA10, and 20m-FA30 were enrolled. Patients were divided into two groups according to the Child-Pugh classification: group A with chronic hepatitis or Child-Pugh A cirrhosis and group B with Child-Pugh B or C cirrhosis. Lesion-to-liver CNR for HCCs was compared between 10m-FA30 and 20m-FA10 or 20m-FA30 for each group. The presence of FHLs was evaluated using a four-point scale by two independent reviewers, and the detection sensitivity was analyzed. RESULTS: In group A, the CNR for HCCs (n = 86) on 10m-FA30 (165.8 ± 99.7) was significantly higher than that on 20m-FA10 (113.4 ± 71.4) and lower than that of 20m-FA30 (210.2 ± 129.3). However, there was no significant difference in the sensitivity of FHL detection between 10m-FA30 (mean 95.0% for two reviewers) and 20m-FA10 (94.7%) or 20m-FA30 (94.7%). In group B, the CNR (54.0 ± 36.4) for HCCs (n = 57) and the sensitivity (94.2%) of FHL detection for 10m-FA30 were significantly higher than those for 20m-FA10 (41.8 ± 36.4 and 80.8%, respectively) and were not different from those for 20m-FA30 (62.7 ± 44.4 and 93.3%, respectively). CONCLUSION: The diagnostic performance of 10m-FA30 was similar to or higher than 20m-FA10 or 20m-FA30 in both groups A and B. This finding indicates that 10m-FA30 could replace 20-min delayed HPI regardless of patient liver function and reduce the delay time by 10 minutes.

Tracing gadolinium-based contrast agents from surface water to drinking water by means of speciation analysis.

In recent decades, a significant amount of anthropogenic gadolinium has been released into the environment as a result of the broad application of contrast agents for magnetic resonance imaging (MRI). Since this anthropogenic gadolinium anomaly has also been detected in drinking water, it has become necessary to investigate the possible effect of drinking water purification on these highly polar microcontaminats. Therefore, a novel highly sensitive method for speciation analysis of gadolinium is presented. For that purpose, the hyphenation of hydrophilic interaction liquid chromatography (HILIC) and inductively coupled plasma-mass spectrometry (ICP-MS) was employed. In order to enhance the detection power, sample introduction was carried out by ultrasonic nebulization. In combination with a novel HILIC method using a diol-based stationary phase, it was possible to achieve superior limits of detection for frequently applied gadolinium-based contrast agents below 20pmol/L. With this method, the contrast agents Gd-DTPA, Gd-DOTA and Gd-BT-DO3A were determined in concentrations up to 159pmol/L in samples from several waterworks in a densely populated region of Germany alongside the river Ruhr as well as from a waterworks near a catchment lake. Thereby, the direct impact of anthropogenic gadolinium species being present in the surface water on the amount of anthropogenic gadolinium in drinking water was shown. There was no evidence for the degradation of contrast agents, the release of Gd(3+) or the presence of further Gd species.

Distinguishing intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma using precontrast and gadoxetic acid-enhanced MRI.

PURPOSE: We aimed to gain further insight in magnetic resonance imaging characteristics of mass-forming intrahepatic cholangiocarcinoma (mICC), its enhancement pattern with gadoxetic acid contrast agent, and distinction from poorly differentiated hepatocellular carcinoma (pHCC). METHODS: Fourteen mICC and 22 pHCC nodules were included in this study. Two observers recorded the tumor shape, intratumoral hemorrhage, fat on chemical shift imaging, signal intensity at the center of the tumor on T2-weighted image, fibrous capsule, enhancement pattern on arterial phase of dynamic study, late enhancement three minutes after contrast injection (dynamic late phase), contrast uptake on hepatobiliary phase, apparent diffusion coefficient, vascular invasion, and intrahepatic metastasis. RESULTS: Late enhancement was more common in mICC (n=10, 71%) than in pHCC (n=3, 14%) (P < 0.001). A fat component was observed in 11 pHCC cases (50%) versus none of mICC cases (P = 0.002). Fibrous capsule was observed in 13 pHCC cases (59%) versus none of mICC cases (P < 0.001). On T2-weighted images a hypointense area was seen at the center of the tumor in 43% of mICC (6/14) and 9% of pHCC (2/22) cases (P = 0.018). Other parameters were not significantly different between the two types of nodules. CONCLUSION: The absence of fat and fibrous capsule, and presence of enhancement at three minutes appear to be most characteristic for mICC and may help its differentiation from pHCC.

Separation of Gd-humic complexes and Gd-based magnetic resonance imaging contrast agent in river water with QAE-Sephadex A-25 for the fractionation analysis.

Gadolinium complexed with naturally occurring, negatively charged humic substances (humic and fulvic acids) was collected from 500 mL of sample solution onto a column packed with 150 mg of a strongly basic anion-exchanger (QAE-Sephadex A-25). A Gd-based magnetic resonance imaging contrast agent (diethylenetriamine-N,N,N',N″,N″-pentaacetato aquo gadolinium(III), Gd-DTPA(2-)) was simultaneously collected on the same column. The Gd-DTPA complex was desorbed by anion-exchange with 50mM tetramethylammonium sulfate, leaving the Gd-humic complexes on the column. The Gd-humic complexes were subsequently dissociated with 1M nitric acid to desorb the humic fraction of Gd. The two-step desorption with small volumes of the eluting agents allowed the 100-fold preconcentration for the fractionation analysis of Gd at low ng L(-1) levels by inductively coupled plasma-mass spectrometry (ICP-MS). On the other hand, Gd(III) neither complexed with humic substances nor DTPA, i.e., free species, was not sorbed on the column. The free Gd in the effluent was preconcentrated 100-fold by a conventional solid-phase extraction with an iminodiacetic acid-type chelating resin and determined by ICP-MS. The proposed analytical fractionation method was applied to river water samples.

Sensitive quantification of gadolinium-based magnetic resonance imaging contrast agents in surface waters using hydrophilic interaction liquid chromatography and inductively coupled plasma sector field mass spectrometry.

The application of gadolinium(Gd)-based contrast agents to support medical examinations by magnetic resonance imaging (MRI) results in a large input of Gd into the environment. The long-term effects of the anthropogenic Gd anomaly, especially on aqueous ecosystems, are mostly unknown. The identification and quantification of Gd-based contrast agents in the aquatic environment requires the use of powerful methods of speciation analysis. Therefore, a method employing the hyphenation of hydrophilic interaction liquid chromatography (HILIC) and inductively coupled plasma sector field mass spectrometry (ICP-SFMS) with sample introduction as dry aerosol generated by desolvation was developed. The desolvation resulted in improved limits of detection for the predominantly used contrast agents well below 0.10 nmol/L. This method was subsequently used for the analysis of Gd species in surface waters. Samples from a nature reserve in the city of Münster (Germany), into which the effluent from the city's main wastewater treatment plant enters the environment, were examined. The contrast agents Gd-DTPA, Gd-DOTA and Gd-BT-DO3A were identified and quantified in constant ratios in those samples. The concentrations were found in a range from 0.59 nmol/L for Gd-DOTA up to 3.55 nmol/L for Gd-BT-DO3A. As a result of mass balancing, the contrast agent concentration was found to account for 74-89% of total Gd concentrations, possibly indicating the presence of further Gd species. Nevertheless, there was no direct indication of species transformation by transmetallation reactions resulting in such Gd species. The determination of REE patterns by means of ICP-MS confirmed the results of speciation analysis showing significant Gd anomalies.

Quantitative imaging of the tissue contrast agent [Gd(DTPA)]²â» in articular cartilage by laser ablation inductively coupled plasma mass spectrometry.

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is an emerging analytical technique in the generation of quantitative images of MR contrast agent distribution in thin tissue sections of articular cartilage. An analytical protocol is described that includes sample preparation by cryo-cutting of tissue sections, mass spectrometric measurements by LA-ICP-MS and quantification of gadolinium images by one-point calibration, standard addition method (employing matrix-matched laboratory standards) and isotope dilution analysis using highly enriched stable Gd-155 isotope (abundance 92 vs 14.8% in the [Gd(DTPA)]²â» contrast agent). The tissue contrast agent concentrations of [Gd(DTPA)]²â» in cartilage measured in this work are in agreement with findings obtained by magnetic resonance imaging and other analytical methodologies. The LA-ICP-MS imaging data also confirm the observation that the spatial distribution of [Gd(DTPA)]²â» in the near-equilibrium state is highly inhomogeneous across cartilage thickness with the highest concentration measured in superficial cartilage and a strong decrease toward the subchondral bone. In the present work, it is shown for the first time that LA-ICP-MS can be applied to validate the results from quantitative gadolinium-enhanced MRI technique of articular cartilage.

Low concentration of a Gd-chelate increases the signal-to-noise ratio in fast pulsing BEST experiments.

Despite numerous developments in the past few years that aim to increase the sensitivity of NMR multidimensional experiments, NMR spectroscopy still suffers from intrinsic low sensitivity. In this report, we show that the combination of two developments in the field, the Band-selective Excitation Short-Transient (BEST) experiment [Schanda et al., J. Am. Chem. Soc., 128 (2006) 9042] and the addition of the nonionic paramagnetic gadolinium chelate gadodiamide into NMR samples, enhances the signal-to-noise ratio. This effect is shown here for four different proteins, three globular and one unfolded, of molecular weights ranging from 6.5 kDa to 40 kDa, using 2D BEST HSQC and 3D BEST triple resonance sequences. Moreover, we show that the increase in signal-to-noise ratio provided by the gadodiamide is higher for peak resonances with lower than average intensity in BEST experiments. It is interesting to note that these residues are on average the weakest ones in those experiments. In this case, the gadodiamide-mediated increase can reach a value of 60% for low and 30% for high molecular weight proteins respectively. An investigation into the origin of this "paramagnetic gain" in BEST experiments is presented.

The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound.

Focused ultrasound (FUS) combined with a circulating microbubble agent is a promising strategy to non-invasively disrupt the blood-brain barrier (BBB) and could enable targeted delivery of therapeutics that normally do not leave the brain vasculature. This study investigated the kinetics of the BBB permeability using dynamic contrast-enhanced MRI (DCE-MRI) and the resulting payload of the chemotherapy agent, doxorubicin (DOX). We also investigated how the disruption and drug delivery were affected by a double sonication (DS) with two different time intervals (10 or 120 min). Two locations were sonicated transcranially in one hemisphere of the brain in 20 rats using a 690 kHz FUS transducer; the other hemisphere served as a control. For BBB disruption, 10 ms bursts were applied at 1 Hz for 60s and combined with IV injection of a microbubble ultrasound contrast agent (Definity; 10 µl/kg). DOX was injected immediately after the second location was sonicated. The transfer coefficient (K(trans)) for an MRI contrast agent (Gd-DTPA) was estimated serially at 4-5 time points ranging from 30 min to 7.5 hrs after sonication using DCE-MRI. After a single sonication (SS), the mean K(trans) was 0.0142 ± 0.006 min(-1) at 30 min and was two or more orders of magnitude higher than the non-sonicated targets. It decreased exponentially as a function of time with an estimated half-life of 2.22 hrs (95% confidence intervals (CI): 1.06-3.39 hrs). Adding a second sonication increased K(trans), and with a 120 min interval between sonications, prolonged the duration of the BBB disruption. Mean K(trans) estimates of 0.0205 (CI: 0.016-0.025) and 0.0216 (CI: 0.013-0.030) min(-1) were achieved after DS with 10 and 120 min delays, respectively. The half-life of the K(trans) decay that occurred as the barrier was restored was 1.8 hrs (CI: 1.20-2.41 hrs) for a 10 min interval between sonications and increased to 3.34 hrs (CI: 0.84-5.84 hrs) for a 120 min interval. DOX concentrations were significantly greater than in the non-sonicated brain for all experimental groups (p<0.0001), and 1.5-fold higher for DS with a 10 min interval between sonications. A linear correlation was found between the DOX concentration achieved and the K(trans) measured at 30 min after sonication (R: 0.7). These data suggest that one may be able to use Gd-DTPA as a surrogate tracer to estimate DOX delivery to the brain after FUS-induced BBB disruption. The results of this study provide information needed to take into account the dynamics BBB disruption over time after FUS.

Simple method for quantification of gadolinium magnetic resonance imaging contrast agents using ESR spectroscopy.

To develop an estimation method of gadolinium magnetic resonance imaging (MRI) contrast agents, the effect of concentration of Gd compounds on the ESR spectrum of nitroxyl radical was examined. A solution of either 4-oxo-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPONE) or 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) was mixed with a solution of Gd compound and the ESR spectrum was recorded. Increased concentration of gadolinium-diethylenetriamine pentaacetic acid chelate (Gd-DTPA), an MRI contrast agent, increased the peak-to-peak line widths of ESR spectra of the nitroxyl radicals, in accordance with a decrease of their signal heights. A linear relationship was observed between concentration of Gd-DTPA and line width of ESR signal, up to approximately 50 mmol/L Gd-DTPA, with a high correlation coefficient. Response of TEMPONE was 1.4-times higher than that of TEMPOL as evaluated from the slopes of the lines. The response was slightly different among Gd compounds; the slopes of calibration curves for acua[N,N-bis[2-[(carboxymethyl)[(methylcarbamoyl)methyl]amino]ethyl]glycinato(3-)]gadolinium hydrate (Gd-DTPA-BMA) (6.22 µT·L/mmol) and gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid chelate (Gd-DOTA) (6.62 µT·L/mmol) were steeper than the slope for Gd-DTPA (5.45 µT·L/mmol), whereas the slope for gadolinium chloride (4.94 µT·L/mmol) was less steep than that for Gd-DTPA. This method is simple to apply. The results indicate that this method is useful for rough estimation of the concentration of Gd contrast agents if calibration is carried out with each standard compound. It was also found that the plot of the reciprocal square root of signal height against concentrations of contrast agents could be useful for the estimation if a constant volume of sample solution is taken and measured at the same position in the ESR cavity every time.

A synthetic cartilage extracellular matrix model: hyaluronan and collagen hydrogel relaxivity, impact of macromolecular concentration on dGEMRIC.

OBJECTIVE: To develop and characterize the MR properties of a synthetic model for cartilage extra-cellular matrix using hydrogels and to determine the concentration dependence of spin-lattice (T1) and spin-spin (T2) relaxation times of hydrogels and their glycosaminoglycan and collagen components in the presence and absence of gadopentetate dimeglumine (Gd-DTPA) for use in dGEMRIC. MATERIALS AND METHODS: T1 and T2 measurements were made at 3 Tesla on a range of gelatin (i.e., collagen) and hyaluronan (i.e., glycosaminoglycan) solutions (6.25-100 g/l), alone, together in a composite, and as dityramine-bridged hydrogels. Relaxivity was calculated as a function of macromolecular concentration. RESULTS: Even at the highest concentrations, gelatin and hyaluronan solutions had T1 and T2 values significantly larger than those reported for cartilage. Only composite hydrogels with gelatin and hyaluronan concentrations naturally found in cartilage resulted in T1 values, but not T2 values, representative of cartilage. Relaxivities were slightly dependent on both hyaluronan concentration (R1 = 0.0027 l g(-1) s(-1); R2 = 0.025 l g(-1) s(-1)) and gelatin concentration (R1 = 0.0032 l g(-1) s(-1); R2 = 0.020 l g(-1) s(-1)) alone and as a composite (R1 = 0.0068 l g(-1) s(-1); R2 = 0.101 l g(-1) s(-1)). Gd-DTPA relaxivities were dependent upon macromolecular concentration and varied by 14-32% (R1 = 4.24 to 5.55 mM(-1) s(-1); R2 = 4.60 to 6.27 mM(-1) s(-1)) over the range of cartilage biochemistry. CONCLUSIONS: Without the contrast agent, hyaluronan and gelatin, alone or in a composite, have a very small impact on the relaxivities of the model system. The impact on R1 was approximately tenfold less than on R2. In contrast, macromolecular concentrations above 50 g/l significantly impacted Gd-DTPA relaxivity and should be accounted for when measuring the glycosaminoglycan content of cartilage in vivo using dGEMRIC.

Synthesis, in vitro and in vivo studies of Gd-DTPA-XDA-D1-Glc(OH) complex as a new potential MRI contrast agent.

A new type of dendritic molecules Gd-DTPA-XDA-D1-Glc(OH), which work as a functionalized ligand coordinating gadolinium(III) ion at the center of their frameworks with two glucose moieties on the molecular surfaces, were readily synthesized with high yield. The structures were established by IR, (1)H, (13)C NMR, and mass spectral studies. Its bio-distribution patterns were evaluated on rats.

Incorporation of excess gadolinium into human bone from medical contrast agents.

We find anomalously high gadolinium (Gd) concentrations in the femoral head bones of patients exposed to chelated Gd, commonly used as a contrast agent for medical imaging. Gd is introduced in chelated form to protect patients from exposure to toxic free Gd(3+), a calcium antagonist which disrupts cellular processes. Recent studies suggest Gd chelates break down in vivo, and Gd accumulation in tissue is linked to medical conditions such as nephrogenic systemic fibrosis (NSF), acute kidney failure, and in some cases death. We measure Gd and other rare earth element (REE) concentrations in 35 femoral heads by solution based ICP-MS. Gd concentrations in patients with documented exposure to Gd-based contrast agents (n = 13: Gd DTPA-BMA (Omniscan) n = 6; Gd HP-DO3A (Prohance) n = 5; unknown type n = 4) are significantly higher (p < 0.001) than the control group (n = 17). We use our control group to establish the 'natural' background level of Gd in human bone (cortical 95% CI: 0.023, 0.041 nmol/g; trabecular 95% CI: 0.054, 0.107 nmol/g). A control group outlier reveals the occurrence of individuals with high concentrations of all REEs, including Gd. Because of this, we calculate Gd anomalies from the concentrations of adjacent REEs and normalize to the control group mean to isolate Gd input from contrast agents. Normalized Gd anomalies, (Gd/Gd*)(N), for exposed patients range up to >800 times the 'natural' level (95% CI: 124, 460). Our data confirm that Gd, introduced in chelated form, incorporates into bone and is retained for more than 8 years. No difference was observed in bone Gd concentrations and anomalies between patients dosed with Gd DTPA-BMA (Omniscan; n = 6) and Gd HP-DO3A (Prohance; n = 5). Osteoporotic fracture patients exposed to Gd have significantly lower Gd concentrations than osteoarthritis patients (p < 0.001). This indicates different mechanisms of metal incorporation and/or retention in osteoporotic bone tissues, and may signal an increased risk of endogenous Gd release for patients with increased rates of bone resorption (e.g. osteoporosis patients and menopausal, pregnant, and lactating women) who are exposed to Gd-based contrast agents.

Imaging of cationic multifunctional liposome-mediated delivery of COX-2 siRNA.

Liposomes are a useful means of delivering molecular targeting agents such as small interfering RNA (siRNA) to downregulate specific pathways important in cancer growth and progression. The ability to non-invasively image these carriers is important to ascertain their delivery within the tumor. As cyclooxygenase-2 (COX-2) is an important therapeutic target in cancer, we investigated loading COX-2-specific siRNA into cationic liposomes containing MR contrast agents for imaging delivery in cancer cells and tumors. COX-2 and GAPDH siRNA, as well as Magnevist or Feridex, were loaded directly into the liposomes. These lipoplexes were used for cell transfection of the poorly differentiated and highly metastatic breast cancer cell line MDA-MB-231. PEGylated liposomes loaded with Feridex and fluorescently labeled COX-2 siRNA were used for in vivo delivery of lipoplexes in MDA-MB-231 breast cancer xenografts in female SCID mice. Transient transfection assays demonstrated potent and specific downregulation of the COX-2 protein in cells in culture. Tail vein injections of PEGylated COX-2 lipoplexes resulted in intratumoral delivery of siRNA. Biodistribution studies showed significant localization in the lung, liver and kidney at 24 h. These data demonstrate the feasibility of liposomal-mediated delivery of COX-2-specific siRNA to downregulate COX-2 in cancer cells, and multi-modality imaging of the delivery of specific siRNA in tumors.