Gd-based Contrast Agents Research Articles

Novel manganese carbon quantum dots as a nano-probe: Facile synthesis, characterization and their application in naproxen delivery (Mn/CQD/SiO2@naproxen)

This study for the first time pursues two crucial aims of using Naproxen as a non-steroidal anti-inflammatory drug in a better, non-invasive setting and introducing a simple and biocompatible nano-carrier (Mn/CQD/SiO2) which is a magneto carbon quantum dots modified with mesoporous silica probe which can be served as a drug delivery and tracer system. SiO2modification was doneby mesoporous silica which improves biocompatibility and provideslow cytotoxicity. Naproxen was conjugated to the nano-probe to form Mn/CQD/SiO2@naproxen and biodistribution was investigated. Physicochemical characteristics of the Mn/CQD/SiO2@naproxen were investigated using FT-IR, SEM, TEM, UV–Vis and BET. Antiproliferation assay using MTT assay was performed on HEK-293 cells to determine the cytotoxity of Mn/CQD/SiO2@naproxen. Relaxivity of Mn/CQD/SiO2 was examined thereafter. To investigate the imaging capability of Mn/CQD/SiO2@naproxen and biodistribution of Naproxen, fluorescent imaging was done. To confirm the data, then the levels of COX Gene expression was determined. The specific surface area, pore volume, and pore radius were 44.4 m2/g, 10.23 cm3/g, and 25.9 nm respectively. MTT assay showed no cytotoxicity. Relaxivity of Mn/CQD/SiO2 was higher than conventional Gd-based contrast agent. Fluorescence imaging of Mn/CQD/SiO2@naproxen showed the biodistribution of naproxen. COX Gene expression confirmed the biodistribution data. By increasing the accumulation in liver COX production reduced. All in all, unique features of Mn/CQD/SiO2 including biocompatibility, low toxicity, magnetic and fluorescence properties showed that it can be used in biomedical sciences.

Synthesis of a Thermal-Responsive Dual-Modal Supramolecular Probe for Magnetic Resonance Imaging and Fluorescence Imaging.

Dual-modal imaging can integrate the advantages of different imaging technologies, which could improve the accuracy and efficiency of clinical diagnosis. Herein, a novel amphiphilic thermal-responsive copolymer obtained from three types of monomers, N-isopropyl acrylamide, 2-(acetoacetoxy) ethyl methacrylate, and propargyl methacrylate, by RAFT copolymerization, is reported. It can be grafted with β-cyclodextrin and aggregation-induced emission (AIE) luminogens tetraphenylethylene by click chemistry and Biginelli reaction. The multifunctional supramolecular polymer (P4) can be constructed by host-guest inclusion between the copolymer and the Gd-based contrast agent (CA) modified by adamantane [Ad-(DOTA-Gd)]. And it can form vesicles with a bilayer structure in aqueous which will enhance the AIE and magnetic resonance imaging effects. As fluorescent thermometer, P4 can enter HeLa cells for intracellular fluorescence imaging (FI) and is sensitive to temperature with detection limit value of 1.5°C. As magnetic resonance CA, P4 exhibits higher relaxation compared to Magnevist, which can prolong the circulation time in vivo. In addition, Gd3+ in the polymer can be quickly released from the body by disassembly that reduced the biological toxicity. This work introduces new synthetic ideas for dual-modal probe, which has great potential for clinical diagnostic applications in bioimaging.

Evidence of Anthropogenic Gadolinium in Triangle Area Waters, North Carolina, USA

Gadolinium (Gd), a member of the rare earth elements (REE), is becoming an increasingly observed microcontaminant in waters of developed regions. Anthropogenic Gd anomalies were first noted in 1996 and were determined to be sourced from Gd-based contrast agents used in magnetic resonance imaging (MRI). This study investigates Gd anomalies in North Carolina’s Triangle Area, focusing on surrounding wastewater treatment plants (WWTPs). Samples were obtained from upstream and downstream of selected WWTPs as well as a freshwater reservoir that supplies part of the region’s drinking water. The PAAS-normalized samples indicate Gd anomalies in the influent, effluent, and downstream samples. We quantify the anthropogenic Gd in wastewater samples to constitute between 98.1% to 99.8%. Sample comparisons show an average increase of 45.3% estimated anthropogenic Gd between samples upstream and downstream of WWTPs. This research contributes to the existing database demonstrating the presence of anthropogenic Gd in developed regions. Although current Gd concentrations are not near toxic levels, they should be continuously monitored as a micropollutant and serve as a wastewater tracer.

Effects of Gadolinium Deposits in the Cerebellum: Reviewing the Literature from In Vitro Laboratory Studies to In Vivo Human Investigations.

Gadolinium (Gd)-based contrast agents (GBCAs) are chemicals injected intravenously during magnetic resonance imaging (MRI) to enhance the diagnostic yield. The repeated use of GBCAs can cause their deposition in the brain, including the cerebellum. Such deposition may affect various cell subsets in the brain and consequently cause behavioral alterations due to neurotoxicity. Caution should thus be exercised in using these agents, particularly in patients who are more likely to have repeated enhanced MRIs during their lifespan. Further studies are required to clarify the toxicity of GBCAs, and potential mechanisms causing neurotoxicity have recently been reported. This review introduces the effects of GBCAs in the cerebellum obtained from in vitro and in vivo studies and considers the possible mechanisms of neurotoxicity involved.

Real-Time Deformability Cytometry Detects Leukocyte Stiffening After Gadolinium-Based Contrast Agent Exposure.

Reports on gadolinium (Gd) retention in soft tissues after administration of Gd-based contrast agents (GBCAs) raise concerns about Gd-induced changes in the biophysical properties of cells and tissues. Here, we investigate if clinical GBCAs of both classes of linear and macrocyclic structure cause changes in the mechanical properties of leukocytes in human blood samples. Real-time deformability cytometry was applied to human blood samples from 6 donors. The samples were treated with 1 mM gadoteric acid (Dotarem), gadopentetic acid (Magnevist), gadobutrol (Gadovist), or Gd trichloride at 37°C for 1 hour to mimic clinical doses of GBCAs and exposure times. Leukocyte subtypes-lymphocytes, monocytes, and neutrophils-were identified based on their size and brightness and analyzed for deformability, which is inversely correlated with cellular stiffness. We observed significant stiffening (3%-13%, P < 0.01) of all investigated leukocyte subtypes, which was most pronounced for lymphocytes, followed by neutrophils and monocytes, and the effects were independent of the charge and steric structure of the GBCA applied. In contrast, no changes in cell size and brightness were observed, suggesting that deformability and cell stiffness measured by real-time deformability cytometry are sensitive to changes in the physical phenotypes of leukocytes after GBCA exposure. Real-time deformability cytometry might provide a quantitative blood marker for critical changes in the physical properties of blood cells in patients undergoing GBCA-enhanced magnetic resonance imaging.

Speciation Analysis of Gadolinium in the Water-Insoluble Rat Brain Fraction After Administration of Gadolinium-Based Contrast Agents.

To date, the analysis of gadolinium (Gd) speciation in the brain of animals administered with macrocyclic and linear Gd-based contrast agents (GBCAs) has been limited to Gd soluble in mild buffers. Under such conditions, less than 30% of the brain tissue was solubilized and the extraction recoveries of GBCAs into the aqueous phase were poor, especially in the case of the linear GBCAs. The aim of this study was to find the conditions to solubilize the brain tissue (quasi-)completely while preserving the Gd species present. The subsequent analysis using size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) was intended to shed the light on the speciation of the additionally recovered Gd. Four groups of healthy female Sprague Dawley rats (SPF/OFA rats; Charles River, L'Arbresle, France) received randomly 5 intravenous injections (1 injection per week during 5 consecutive weeks) of either gadoterate meglumine, gadobenate dimeglumine, gadodiamide (cumulated dose of 12 mmol/kg), or no injection (control group). The animals were sacrifice 1 week (W1) after the last injection. Brain tissues were solubilized with urea solution, whereas tissues extracted with water served as controls. Total Gd concentrations were determined in the original brain tissue and its soluble and insoluble fractions by inductively coupled plasma-mass spectrometry (ICP-MS) to calculate the Gd accumulation and extraction efficiency. Size exclusion chromatography coupled to ICP-MS was used to monitor the speciation of Gd in the soluble fractions. The stability of GBCAs in the optimum conditions was monitored by spiking the brain samples from the untreated animals. The column recoveries were precisely determined in the purpose of the discrimination of weakly and strongly bound Gd complexes. The identity of the eluted species was explored by the evaluation of the molecular size and retention time matching with Gd chelates and ferritin standard. The speciation analyses were carried out for 2 different brain structures, cortex and cerebellum. The combination of water and urea extractions (sequential extraction) managed to solubilize efficiently the brain tissue (97% ± 1%) while preserving the stability of the initially injected form of GBCA. For macrocyclic gadoterate, 97% ± 1% and 102% ± 3% of Gd initially present in the cortex and cerebellum were extracted to the soluble fraction. For gadobenate, similar amounts of Gd (49% ± 1% and 46% ± 4%) were recovered from cortex and cerebellum. For gadodiamide, 48% ± 2% of Gd was extracted from cortex and 34% ± 1% from cerebellum. These extraction efficiencies were higher than reported elsewhere. The SEC-ICP-MS and the column recovery determination proved that Gd present at low nmol/g levels in brain tissue was exclusively in the intact GBCA form in all the fractions of brain from the animals treated with gadoterate. For the linear GBCAs (gadobenate and gadodiamide), 3 Gd species of different hydrodynamic volumes were detected in the urea-soluble fraction: (1) larger than 660 kDa, (2) approximately 440 kDa, and (3) intact GBCAs. The species of 440 kDa corresponded, on the basis of the elution volume, to a Gd3+ complex with ferritin. Gd3+ was also demonstrated by SEC-ICP-MS to react with the ferritin standard in 100 mM ammonium acetate (pH 7.4). In contrast to macrocyclic gadoterate, for linear GBCAs, the column recovery was largely incomplete, suggesting the presence of free, hydrolyzed, or weakly bound Gd3+ with endogenous ligands. The sequential extraction of rat brain tissue with water and urea solution resulted in quasi-complete solubilization of the tissue and a considerable increase in the recoveries of Gd species in comparison with previous reports. The macrocyclic gadoterate was demonstrated to remain intact in the brain 1 week after administration to rats. The linear GBCAs gadobenate and gadodiamide underwent ligand exchange reactions resulting in the presence of a series of Gd3+ complexes of different strength with endogenous ligands. Ferritin was identified as one of the macromolecules reacting with Gd3+. For the linear GBCAs, 3% of the insoluble brain tissue was found to contain more than 50% of Gd in unidentified form(s).

Targeting Nanostrategies for Imaging of Atherosclerosis

Despite the progress in cardiovascular research, atherosclerosis still represents the main cause of death worldwide. Clinically, the diagnosis of Atherosclerotic Cardiovascular Disease (ASCVD) relies on imaging methodologies including X-ray angiography and computed tomography (CT), which however still fails in the identification of patients at high risk of plaque rupture, the main cause of severe clinical events as stroke and heart attack. Magnetic resonance imaging, which is characterized by very high spatial resolution, could provide a better characterization of atherosclerotic plaque (AP) anatomy and composition, aiding in the identification of “vulnerable” plaques. In this context, hydrogel matrices, which have been demonstrated able to boost relaxometric properties of Gd-based contrast agents (CAs) by the effect of Hydrodenticity, represent a valuable tool towards the precision imaging of ASCVD improving the performance of this class of CAs while reducing systemic toxicity. In particular, hydrogel nanoparticles encapsulating Gd-DTPA can further contribute to providing CA-specific accumulation in the AP by nanoparticle surface decoration triggering an active targeting of the AP with the overall effect of allowing an earlier and more accurate diagnosis. In this work, we tested crosslinked Hyaluronic Acid Nanoparticles (cHANPs) in the complex environment of human atherosclerotic plaque. In addition, the surface of cHANPs was decorated with the antibody anti-CD36 (Ab36-cHANPs) for the active targeting of AP-associated macrophages. Results demonstrate that the Hydrodenticity of cHANPs and Ab36-cHANPs is preserved in this complex system and, preliminarily, that interaction of these probes with the AP is present.

Ischemic Stroke Increased Gadolinium Deposition in the Brain and Aggravated Astrocyte Injury After Gadolinium-Based Contrast Agent Administration: Linear Versus Macrocyclic Agents.

Gadolinium (Gd)-based contrast agents (GBCAs) have been widely used in MRI. However, several studies have reported Gd deposition in the brain, which has raised concerns about safety. To investigate the effects of ischemic stroke on Gd deposition in the brain after repeated administration of linear or macrocyclic GBCAs and to determine whether GBCAs aggravate astrocyte injury after stroke. Animal study. Twenty-seven male Sprague-Dawley rats were randomized to an exposure group (n = 24) and a healthy control group (n = 3). Half of the exposure group (n = 12) underwent transient middle cerebral artery occlusion (tMCAO) and half (n = 12) had a sham procedure. In each subgroup (tMCAO or sham), the rats had repeated gadopentetate (n = 6) or gadobutrol (n = 6) injections. Oxygen-glucose deprivation and reoxygenation (OGD/R) was used as an in vitro model of stroke. On day 3 and day 28 after the last injection (p.i.), the Gd concentration in the cerebrum was quantified by inductively coupled plasma mass spectrometry. Cell viability, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were analyzed in vitro. One-way analysis of variance and two-sample t-tests were performed. The Gd concentration in the ipsilateral hemisphere homogenates of tMCAO group was significantly higher than that in the brain homogenates of the sham group on day 3 p.i. of either gadobutrol (0.065 ± 0.006 vs. 0.042 ± 0.007 μg/g, P < 0.05) or gadopentetate (0.093 ± 0.010 vs. 0.069 ± 0.008 μg/g, P < 0.05). Increased Gd deposition was also found in the ipsilateral hemisphere homogenates of the tMCAO group compared with the brain homogenates of the sham group on day 28 p.i. of gadopentetate (0.075 ± 0.012 vs. 0.044 ± 0.003 μg/g, P < 0.05), but not gadobutrol (0.012 ± 0.007 vs. 0.010 ± 0.001 μg/g, P = 0.80). The Gd concentration in the ipsilateral hemisphere in the tMCAO group was significantly higher for gadopentetate than gadobutrol on both day 3 p.i. (0.085 ± 0.006 vs. 0.049 ± 0.005 μg/g, P < 0.05) and day 28 p.i (0.075 ± 0.012 vs. 0.012 ± 0.007 μg/g, P < 0.05). Additionally, compared with gadobutrol, gadopentetate decreased viability, increased ROS accumulation, and decreased MMP in OGD/R-induced astrocytes (all P < 0.05). Administration of GBCAs after an animal model of ischemic stroke increased Gd deposition in the brain and aggravated astrocyte injury. The effect of gadopentetate appeared to be more pronounced than that of gadobutrol.

Gadolinium Concentrations in Biological Matrices From Patients Exposed to Gadolinium-Based Contrast Agents.

There is increasing evidence that Gd may be retained within the skin, bones, and solid organs in patients with normal renal function after exposure to Gd-based contrast agents (GBCAs). Here we present clinical data from 19 patients who requested referral to our clinical toxicology service for assessment of potential "Gd toxicity." Patients had undergone a median of 2 (interquartile range [IQR], 1-5) exposures to GBCAs and were reviewed at a median of 5 months (IQR, 2-8 months) after the last GBCA exposure. Patients had a clinical assessment by a clinical toxicologist, and biological samples were taken in 17 patients (89.5%). Gd concentrations were measured in these samples using inductively coupled plasma mass spectrometry. All patients had significant comorbidities, and after an extensive clinical review, none of the reported symptoms were considered likely to be related to "Gd toxicity." Whole blood, plasma, and urine samples had detectable Gd concentrations in 69.2%, 78.6%, and 95.2% of samples, respectively. Median (IQR) concentrations of Gd were as follows: whole blood, 0.013 ng/mL (IQR, limit of detection [LOD]-0.884 ng/mL); plasma, 0.012 ng/mL (IQR, LOD-0.046 ng/mL); and spot urine, 0.304 μg/g creatinine (IQR, 0.070-3.702 μg/g creatinine). There were positive correlations between whole blood and plasma (P = 0.0024, r = 0.84), whole blood and urine (P = 0.0018, r = 0.82), and plasma and urine (P = 0.0001, r = 0.89) Gd concentrations. There was a negative correlation between Gd concentrations and the period after exposure for whole blood (P = 0.0028, r = -0.80), plasma (P = 0.0004, r = -0.86), and urine (P < 0.0001, r = -0.91). We identified detectable Gd concentrations in biological matrices from all patients reporting exposure to GBCAs who were reviewed in our clinical toxicology outpatient clinic with concerns regarding potential "Gd toxicity"; however, there were no clinical features of toxicity present in this cohort. Further research is required to explore the pharmacokinetics and pharmacodynamics of GBCAs in patients with normal renal function and to determine the clinical significance of these detectable Gd concentrations.

Gadolinium distribution in kidney tissue determined and quantified by micro synchrotron X-ray fluorescence.

Aims of this study were to investigate gadolinium (Gd) in kidney tissue from a female patient with severe renal failure, who had a magnetic resonance imaging (MRI) with Gd-based contrast agent (GBCA) three times prior to kidney transplantation. Secondly to assess (semi-)quantitatively the Gd concentration in renal tissue and the spatial distribution of Gd in association to suspected co-elements such as calcium (Ca) and zinc (Zn). Archival paraffin embedded kidney tissue was investigated by micro Synchrotron X-ray fluorescence (µSRXRF) at the DORIS III storage ring at beamline L, HASYLAB/DESY(Hamburg, Germany). Elementary gadolinium (Gd) could be demonstrated in a near histological resolution in areas of about 2 × 1.5 mm2 of size. Mean Gd resulted in 200ppm with a huge width of distribution (Gd-max: 2000ppm). In kidney cortex Gd was in-homogeneously, but not randomly, distributed. Gd was verified throughout the investigated tissue. Low Gd was predominately concentrated either in areas with focally atrophic tubules or in areas with totally preserved uriniferous tubes. Moreover, strong correlations existed between Gd and calcium (Ca) or Gd and zinc (Zn) or Gd and strontium (Sr) distribution. Throughout our analysed areas copper (Cu) was nearly homogeneously distributed and Cu association to Gd could not be established, and also not for Gd to Fe. Gd in glomeruli was relatively reduced compared with mean Gd-values, while iron (Fe) distribution clearly demarks glomeruli mostly due to red blood cell iron in these capillary convolutes. Quantitative µSRXRF analysis provided an insight in element spatial distribution of Gd in the renal cortex. The strong correlation of the spatial distribution and associations between elements like Ca, Zn and Sr let us suspect that these elements are involved in the cell metabolism of GBCA. Low Gd in areas with extreme fibrosis and tubule atrophy or in areas with histologically intact tubes, let us suspect that on the one side Gd cannot be transported and deposited into these tissue areas and on the other side we assume that intact renal tubes do not reabsorb and store excreted Gd.

Neurotoxicity of subarachnoid Gd-based contrast agent accumulation: a potential complication of intraoperative MRI?

Intraoperative MRI with Gd-based contrast agent (GBCA) improves the extent of resection of contrast-enhancing brain tumors. Signal changes of CSF due to perioperative GBCA leakage in the subarachnoid space have been reported. However, although GBCA potentially exhibits neurotoxic effects, so far no associated complications have been described. In this case series, the authors report a single-center cohort of patients with subarachnoid GBCA extravasation after intraoperative MRI and discuss potential neurotoxic complications and potential ways of avoiding them. All patients with CSF signal increase on unenhanced T1-weighted and FLAIR images on postoperative MRI, who had previously undergone tumor resection with use of intraoperative MRI, were retrospectively included and compared with a control cohort. The control group was matched in age, tumor characteristics, and extent of resection; comparisons were made regarding postoperative seizures and ICU stay. A subgroup with initially diagnosed malignant glioma was additionally analyzed for potential delay of initiation of adjuvant treatment and overall survival. Seven patients with postoperative GBCA accumulation in the subarachnoid space were identified; 5 presented with focal seizures and altered mental status postoperatively. Poor patient condition led to extended ICU stay and prolonged delay of the initiation of adjuvant treatment in patients with newly diagnosed malignant glioma. Overall survival was reduced compared to the matched control group. The results suggest that there might be a risk of neurotoxic complications if GBCA that is intravenously applied during neurosurgery leaks into the subarachnoid space. Patients with highly vascularized tumors with intraoperative bleeding seem to be especially at risk for GBCA accumulation and neurotoxic complications. Therefore, awareness of the potential risk of complicating GBCA leakage is mandatory in the application of intraoperative GBCA.

Defining the conditions for the development of the emerging class of FeIII-based MRI contrast agents.

Fe(iii) complexes are attracting growing interest in chemists developing diagnostic probes for Magnetic Resonance Imaging because they leverage on an endogenous metal and show superior stability. However, in this case a detailed understanding of the relationship between the chemical structure of the complexes, their magnetic, thermodynamic, kinetic and redox properties and the molecular parameters governing the efficacy (relaxivity) is still far from being available. We have carried out an integrated 1H and 17O NMR relaxometric study as a function of temperature and magnetic field, on the aqua ion and three complexes chosen as reference models, together with theoretical calculations, to obtain accurate values of the parameters that control their relaxivity. Moreover, thermodynamic stability and dissociation kinetics of the Fe(iii) chelates, measured in association with the ascorbate reduction behaviour, highlight their role and mutual influence in achieving the stability required for use in vivo.

Iron(iii) chelated paramagnetic polymeric nanoparticle formulation as a next-generation T 1-weighted MRI contrast agent.

Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics. To enhance the quality of MR images, contrast agents (CAs) are used, which account for nearly 40% of MRI exams in the clinic globally. The most used CAs are gadolinium-based CAs (GBCAs) but the use of GBCAs has been linked with metal-deposition in vital organs. Gadolinium deposition has been shown to be correlated with nephrogenic systemic fibrosis, a fibrosis of the skin and internal organs. Therefore, there is an unmet need for a new CA alternative to GBCAs for T1-weighted Ce-MRI. Herein, we designed paramagnetic ferric iron(iii) ion-chelated poly(lactic-co-glycolic)acid nanoparticle formulation and routinely examined their application in Ce-MRI using clinical and ultra-high-field MRI scanners. Nanoparticles were monodispersed and highly stable at physiological pH over time with the hydrodynamic size of 130 ± 12 nm and polydispersity index of 0.231 ± 0.026. The T1-contrast efficacy of the nanoparticles was compared with commercial agent gadopentetate dimeglumine, called Magnevist®, in aqueous phantoms in vitro and then validated in vivo by visualizing an angiographic map in a clinical MRI scanner. Relaxivities of the nanoparticles in an aqueous environment were r1 = 10.59 ± 0.32 mmol−1 s−1 and r1 = 3.02 ± 0.14 mmol−1 s−1 at 3.0 T and 14.1 T measured at room temperature and pH 7.4, respectively. The clinically relevant magnetic field relaxivity is three times higher compared to the Magnevist®, a clinical GBCA, signifying its potential applicability in clinical settings. Moreover, iron is an endogenous metal with known metabolic safety, and the polymer and phospholipids used in the nanoconstruct are biodegradable and biocompatible components. These properties further put the proposed T1 agent in a promising position in contrast-enhanced MRI of patients with any disease conditions.

Determination of gadolinium MRI contrast agents in fresh and oceanic waters of Australia employing micro-solid phase extraction, HILIC-ICP-MS and bandpass mass filtering

Speciation analysis of Gd-based MRI contrast agents in fresh and oceanic waters employing an automatised micro-solid phase extraction method and HILIC-ICP-MS detection operating an increased mass bandpass.

Comparison of DCE-MRI of murine model cancers with a low dose and high dose of contrast agent.

There are increasing concerns regarding intracellular accumulation of gadolinium (Gd) after multiple dynamic contrast enhanced (DCE) MRI scans. We investigated whether a low dose (LD) of Gd-based contrast agent is as effective as a high dose (HD) for quantitative analysis of DCE-MRI data, and evaluated the use of a split dose protocol to obtain new diagnostic parameters. Female C3H mice (n=6) were injected with mammary carcinoma cells in the hind leg. MRI experiments were performed on 9.4T scanner. DCE-MRI data were acquired with 1.5s temporal resolution before and after a LD (0.04mmol/kg), then again after 30min followed by a HD (0.2mmol/kg) bolus injection of Omniscan. The standard Tofts model was used to extract physiological parameters (Ktrans and ve) with the arterial input function derived from muscle reference tissue. In addition, an empirical mathematical model was used to characterize maximum contrast agent uptake (A), contrast agent uptake rate (α) and washout rate (β and γ). There were moderate to strong correlations (r=0.69-0.97, p<0001) for parameters Ktrans, ve, A, α and β from LD versus HD data. On average, tumor parameters obtained from LD data were significantly larger (p<0.05) than those from HD data. The parameter ratios, Ktrans, ve, A and α calculated from the LD data divided by the HD data, were all significantly larger than 1.0 (p<0.003) for tumor. T2* changes following contrast agent injection affected parameters calculated from HD data, but this was not the case for LD data. The results suggest that quantitative analysis of LD data may be at least as effective for cancer characterization as quantitative analysis of HD data. In addition, the combination of parameters from two different doses may provide useful diagnostic information.

1H NMR Relaxometric Study of Chitosan-Based Nanogels Containing Mono- and Bis-Hydrated Gd(III) Chelates: Clues for MRI Probes of Improved Sensitivity

Hydrogel nanoparticles composed of chitosan and hyaluronate and incorporating Gd-based MRI contrast agents with different hydration number (e.g., [Gd(DOTA)(H2O)]- and [Gd(AAZTA)(H2O)2]-) were prepared and fully characterized. In particular, 1H NMR relaxometric data, acquired as a function of temperature and applied magnetic field strength, were for the first time thoroughly analyzed using a theoretical model that includes the effects of a static zero-field splitting and an anisotropic molecular tumbling. The paramagnetic nanoparticles show excellent stability in aqueous solution for over 150 h and do not release the load of Gd(III) chelates. These nanoparticles exhibit enhanced efficacy (relaxivity) as relaxation agents, over 6 times that of the free complexes, thanks to the combination of a restricted molecular dynamics in the presence of a fast exchange of metal-bound water molecule(s) and between the water inside the nanogel and the bulk water. The knowledge of the molecular parameters that control the effectiveness of these MRI nanoprobes and those that limit their further increase will be crucial for the development of optimized systems with high sensitivity and stability.

Maltodextrin-Conjugated Gd-Based MRI Contrast Agents for Specific Diagnosis of Bacterial Infections.

Bacterial infections are one of the most serious health risks worldwide, and their rapid diagnosis remains a major challenge in clinic. To enhance the relaxivity and bacterial specificity of magnetic resonance imaging (MRI) contrast agents, here, a kind of gadolinium-based nanoparticles (NPs) of impressive biocompatibility is constructed as a contrast agent for maltodextrin-mediated bacteria-targeted diagnosis. To realize this, positively charged ultrasmall gadolinium oxide (Gd2O3, 2-3 nm) NPs are embedded in mesoporous silica NPs (MSN) with pore size around 6.38 nm. The resulting Gd2O3@MSN exhibits enhanced r1 value and T1-weighted MRI performance. Interestingly, upon conjugation of Gd2O3@MSN with maltodextrin to produce Gd2O3@MSN-Malt NPs, a remarkable decrease in internalization by osteosarcoma cells, alongside an increased adsorption toward E. coli and S. aureus, is achieved. It is therefore conceivable that the bacteria-targeted Gd2O3@MSN-Malt might be a promising MRI contrast agent for effective discrimination of bacterial infections from tumor.

Speciation analysis of Gadolinium-based contrast agents using aqueous eluent-hydrophilic interaction liquid chromatography hyphenated with inductively coupled plasma-mass spectrometry

Gadolinium chelates are widely used as contrast agents for magnetic resonance imaging (MRI). In recent decades, the amount of Gd in river water has been increasing owing to the input of Gd-based contrast agents. To identify and quantify the Gd-based contrast agents in river water, the novel technique of hydrophilic interaction liquid chromatography (HILIC) hyphenated with inductively coupled plasma-mass spectrometry (ICP-MS) was developed. To avoid deposition of carbon on the ICP-MS interface, a mobile phase consisting of an ammonium acetate buffer diluted with pure water was applied to separate Gd-based contrast agents. Despite the absence of an organic solvent in the mobile phase, six Gd-based contrast agents, Gd-DTPA, Gd-EOB-DTPA, Gd-DOTA, Gd-DTPA-BMA, Gd-BT-DO3A, and Gd-HP-DO3A, were successfully separated. This technique was applied for river water samples. As a result, Gd-DOTA, Gd-BT-DO3A, and Gd-HP-DO3A were observed from the sample near the outfall of a wastewater treatment plant (WWTP), indicating that at least some of the Gd-based contrast agents are passed through treatment in a WWTP. In addition to Gd-based contrast agents, unidentified Gd compounds were found to be present in river water. These results infer that transformation and/or dissociation of Gd chelates may be caused during the treatment procedure in a WWTP.

Current and Future MR Contrast Agents: Seeking a Better Chemical Stability and Relaxivity for Optimal Safety and Efficacy.

This review summarizes 30 years of experience in the development and clinical use of magnetic resonance (MR) contrast agents. Despite their undisputable usefulness for disease diagnosis, gadolinium (Gd)-based contrast agents (GBCAs) have gone through 2 major safety crises. Approximately 10 years ago, the regulatory agencies decided to restrict the use of GBCAs to minimize the risk of nephrogenic systemic fibrosis in patients with severe renal insufficiency. Yet, following the recent discovery of Gd retention in brain, the same agencies adopted different positions ranging from suspension of marketing authorizations, changes in GBCA safety labeling, and performing preclinical and clinical studies to assess the potential long-term consequences of Gd accumulation on motor and cognitive functions. Besides, magnetic resonance imaging (MRI) has benefited from MR technological advances, which provide alternative solutions to increase the MR signal, generate new contrasts on MRI scans, and accelerate their acquisition and analysis. Altogether, GBCAs in combination with new MR techniques have found their place in the diagnostic pathway of various diseases. Despite the large research efforts to identify and develop alternative Gd-free MR agents, manganese- and iron-based contrast agents have failed to reach market approval. In this context, the development of next-generation MR contrast agents should focus on high-stability and high-relaxivity GBCAs, such as gadopiclenol, which offer the possibility to adapt the administered Gd dose to each indication while ensuring an optimal patient safety.

The contribution of enhancing lesions in monitoring multiple sclerosis treatment: is gadolinium always necessary?

MRI is highly sensitive for monitoring of disease activity and treatment efficacy in MS. Patients treated with disease modifying therapy (DMT), who experience MRI activity, including contrast-enhancing lesions (CEL) or new/enlarged T2 lesions, should be evaluated for a switch to more effective treatment. Due to recent evidence of gadolinium (Gd) accumulation in the brain after repeated administration of Gd-based contrast agents, FDA recommended to limit its use. To investigate the proportion of cases in which MRI activity would be detectable only using contrast-enhanced T1-weighted sequences.Secondary aims were to assess the presence of clinical or demographic variables associated with reactivation of pre-existing lesions and to analyse therapeutic consequences of different types of MRI lesions. We retrospectively evaluated brain MRI scans, performed between 2014 and 2018, in patients treated with DMT for at least 6months. We analysed 906 scans in 255 patients. New/enlarged T2 lesions were detected in 13.7% of cases, CEL in 3.5%, CEL without new T2 lesions (old lesions reactivated) in 1.1%. No variables were associated with old lesions reactivated. CEL with T2 equivalent were at higher risk of DMT switch, compared with new/enlarged T2 lesions without corresponding CEL (OR 4.0, 95% CI 1.5-10.4, p = 0.005). Reactivation of pre-existing lesions is limited to a tiny fraction of MRI studies. Gd + T1-weighted images could be omitted, in patients treated with DMT for at least 6months, without relevant loss of information.