Gadolinium-based MRI Contrast Agents Research Articles

Gadopiclenol: A q = 2 Gadolinium-Based MRI Contrast Agent Combining High Stability and Efficacy

Objectives Gadopiclenol is a q = 2 pyclen gadolinium-based contrast agent (GBCA) recently approved by the Food and Drug Administration, European Medicines Agency, and other European countries. The aim of this report is to demonstrate its stability in multiple stressed in vitro conditions and in vivo, in rat kidney, while maintaining its higher relaxivity compared with conventional GBCAs on the market. Materials and Methods Both gadopiclenol and its chemical precursor Pi828-Gd were characterized and compared with q = 1 gadolinium (Gd) complexes. The number of water molecules coordinated to the Gd (the hydration number, q) was determined by luminescence. 17O NMR (Nuclear Magnetic Resonance) measurements gave access to the water residence time τM. These parameters were used for the fitting of the nuclear magnetic relaxation dispersion profiles in water. Proton relaxivities of the complexes were determined in different media at 60 MHz (1.4 T), at different pH and temperature. The kinetic inertness was investigated in human serum, acidic media, under zinc competition in the presence of phosphate, and under ligand competition. The in vivo stability was evaluated in rat kidneys 12 months after repeated injections. Results The presence of 2 inner-sphere water molecules per Gd complex was confirmed for both pyclen derivatives. The high relaxivity of the complexes in water is maintained under physiological conditions, even under stressed conditions (ionic media, extreme pH, and temperature), which guarantees their efficiency in a large range of in vivo situations. Gd release from the q = 2 complexes was investigated in different potentially destabilizing conditions. Either no Gd release or a slower one than with “q = 1” stable macrocyclic GBCA (acidic conditions) was observed. Their kinetic inertness was demonstrated in physiological conditions, and the Gd release was below the lower limit of quantification of 0.1 μM after 12 days at 37°C in human serum. It was also demonstrated that gadopiclenol is stable in vivo in rat kidney 12 months after repeated injections. Conclusions Thanks to its optimized structural design, gadopiclenol is a highly stable and effective macrocyclic q = 2 GBCA.

Evaluation of the biodistribution and preliminary safety profile of a novel brain-targeted manganese dioxide-based nanotheranostic system for Alzheimer’s disease

A novel brain-targeted and reactive oxygen species-activatable manganese dioxide containing nanoparticle system functionalized with anti-amyloid-β antibody (named aAβ-BTRA-NC) developed by our group has shown great promise as a highly selective magnetic resonance imaging (MRI) contrast agent for early detection and multitargeted disease-modifying treatment of Alzheimer’s disease (AD). To further evaluate the suitability of the formulation for future clinical application, we investigated the safety, biodistribution, and pharmacokinetic profile of aAβ-BTRA-NC in a transgenic TgCRND8 mouse AD model, wild type (WT) littermate, and CD-1 mice. Dose-ascending studies demonstrated that aAβ-BTRA-NC was well-tolerated by the animals up to 300 μmol Mn/kg body weight [b.w.], 3 times the efficacious dose for early AD detection without apparent adverse effects; Histopathological, hematological, and biochemical analyses indicated that a single dose of aAβ-BTRA-NC did not cause any toxicity in major organs. Immunotoxicity data showed that aAβ-BTRA-NC was safer than commercially available gadolinium-based MRI contrast agents at an equivalent dose of 100 μmol/kg b.w. of metal ions. Intravenously administered aAβ-BTRA-NC was taken up by main organs with the order of liver, kidneys, intestines, spleen, followed by other organs, and cleared after one day to one week post injection. Pharmacokinetic analysis indicated that the plasma concentration profile of aAβ-BTRA-NC followed a 2-compartmental model with faster clearance in the AD mice than in the WT mice. The results suggest that aAβ-BTRA-NC exhibits a strong safety profile as a nanotheranostic agent which warrants more robust preclinical development for future clinical applications.

Impact of gadolinium-based MRI contrast agent and local anesthetics co-administration on chondrogenic gadolinium uptake and cytotoxicity

The gadolinium-based contrast agent DOTA-Gd is clinically used in combination with local anesthetics for direct magnetic resonance arthrography. It remains unclear whether gadolinium uptake into cartilage is influenced by co-administration of bupivacaine or ropivacaine and whether DOTA-Gd alters their chondrotoxicity. Gadolinium quantification of chondrogenic spheroids revealed enhanced gadolinium uptake after simultaneous exposure to local anesthetics. Analyses of the spatial gadolinium distribution using synchrotron X-ray-fluorescence scanning indicates gadolinium exposed chondrocytes. In vitro exposure to DOTA-Gd does not alter viability and proliferation of human chondrocytes and the chondrotoxic potential of the anesthetics. Reduced viability induced by ropivacaine was found to be reversible, while exposure to bupivacaine leads to irreversible cell death. Our data suggest that ropivacaine is more tolerable than bupivacaine and that DOTA-Gd exposure does not alter the cytotoxicity of both anesthetics. Enhanced gadolinium uptake into cartilage due to co-administration of anesthetics should find attention.

Pharmacokinetics, safety, and tolerability of the novel tetrameric gadolinium-based MRI contrast agent gadoquatrane in healthy Chinese and Japanese men: Two randomized dose-escalation studies including concentration–QTc modeling

PurposeTo investigate the pharmacokinetics, safety, and tolerability of the novel tetrameric high-relaxivity gadolinium-based contrast agent gadoquatrane in Japanese (Study 1) and Chinese men (Study 2). Participants and methodsIn two similarly designed single-center, randomized, single-blind, placebo-controlled, consecutive-cohort dose-escalation studies, healthy volunteers were randomly assigned to intravenous administration of gadoquatrane (0.01–0.1 mmol gadolinium/kg body weight) or placebo. Study procedures included blood sampling and collection of urine for pharmacokinetic analyses and safety assessments. ResultsTwenty-five healthy Japanese men (mean age ± standard deviation: 26±5.9 years) and 23 healthy Chinese men (31±7.6 years old) were evaluated. In both studies, the pharmacokinetic profile of gadoquatrane was characterized by rapid distribution of the drug into the extracellular space and fast renal elimination. Postdose gadolinium concentrations rapidly declined with a geometric mean effective half-life of 1.3–1.4 h. The exposure increased approximately dose-proportionally with dose. The body weight-normalized volume of distribution was constant across dose levels (0.21–0.24 L/kg). Total recovery of gadolinium in urine amounted to 82–95 % (Study 1) and 96–99 % (Study 2) of the dose administered.Only a few mild, transient adverse events were reported, none of which gave rise to any safety concerns. Exploratory drug concentration–QTc modeling indicated no risk of a clinically relevant QT/QTc prolongation at the anticipated diagnostic dose. ConclusionGadoquatrane was safe and well tolerated at all doses tested. The pharmacokinetic profile was essentially the same as that of other extracellular macrocyclic gadolinium-based contrast agents and was consequentially also similar for Japanese and Chinese participants.

Effects of Gadolinium Retention in the Brains of Type 2 Diabetic Rats after Repeated Administration of Gadolinium-Based MRI Contrast Agents on Neurobiology and NLRP3 Inflammasome Activation.

The neurotoxic potential of gadolinium (Gd)-based contrast agents (GBCAs) retention in the brains of patients with type 2 diabetes mellitus (T2DM) is unclear. To determine the deposition and clearance of GBCAs in T2DM rats and the mechanism by which Gd enhances nucleotide-binding oligomerization domain-3 (NLRP3) inflammasome activation. Cross-sectional, prospective. 104 T2DM male Wistar rats. 9.4-T, T1-weighted fast spin echo sequence. T2DM (male Wistar rats, n = 52) and control group (healthy, male Wistar rats, n = 52) rats received saline, gadodiamide, Gd-diethylenetriaminepentaacetic acid, and gadoterate meglumine for four consecutive days per week for 7 weeks. The distribution and clearance of Gd in the certain brain were assessed by MRI (T1 signal intensity and relaxation rate R1, on the last day of each week), inductively coupled plasma mass-spectroscopy, ultraperformance liquid chromatography mass spectrometry, and transmission electron microscopy. Behavioral tests, histopathological features, and the effects of GBCAs on neuroinflammation were also analyzed. One-way analysis of variance, bonferroni method, and unpaired t-test. A P-value <0.05 was considered statistically significant. The movement distance and appearance time in the open field test of the T2DM rats in the gadodiamide group were significantly shorter than in the other groups. Furthermore, the expression of NLRP3, Pro-Caspase-1, interleukin-1β (IL-1β), and apoptosis-associated speck-like protein containing a CARD protein in neurons was significantly higher in the gadodiamide group than in the saline group, as shown by Western blot. Gadodiamide also induced differentiation of microglia into M1 type, decreased the neuronal mitochondrial membrane potential, and significantly increased neuronal apoptosis from flow cytometry. T2DM may affect both the deposition and clearance of GBCAs in the brain. Informed by the T2DM model, gadodiamide could mediate the neuroinflammatory response by NLRP3 inflammasome activation. 1 TECHNICAL EFFICACY: Stage 1.

Superfluorinated, Highly Water-Soluble Polyphosphazenes as Potential 19F Magnetic Resonance Imaging (MRI) Contrast Agents.

"Hot spot" 19F magnetic resonance imaging (MRI) has garnered significant attention recently for its ability to image various disease markers quantitatively. Unlike conventional gadolinium-based MRI contrast agents, which rely on proton signal modulation, 19F-MRI's direct detection has a unique advantage in vivo, as the human body exhibits a negligible background 19F-signal. However, existing perfluorocarbon (PFC) or PFC-based contrast materials suffer from several limitations, including low longitudinal relaxation rates and relatively low imaging efficiency. Hence, we designed a macromolecular contrast agent featuring a high number of magnetically equivalent 19F-nuclei in a single macromolecule, adequate fluorine nucleus mobility, and excellent water solubility. This design utilizes superfluorinated polyphosphazene (PPz) polymers as the 19F-source; these are modified with sodium mercaptoethanesulfonate (MESNa) to achieve water solubility exceeding 360 mg/mL, which is a similar solubility to that of sodium chloride. We observed substantial signal enhancement in MRI with these novel macromolecular carriers compared to non-enhanced surroundings and aqueous trifluoroacetic acid (TFA) used as a positive control. In conclusion, these novel water-soluble macromolecular carriers represent a promising platform for future MRI contrast agents.

Biomonitoring of rare earth elements in Southern Norway: Distribution, fractionation, and accumulation patterns in the marine bivalves Mytilus spp. and Tapes spp.

Growing extraction and usage of rare earth elements and yttrium (REY) for medical and industrial applications has resulted in increased discharges into the marine environment. Using Mytilus spp. Mussels and Tapes spp. clams as bioindicator organisms, we analyzed 15 REY in soft tissues of specimens collected at two potentially polluted sites in Southern Norway: in the vicinity of an industry producing gadolinium-based MRI contrast agents (GBCAs) (Lindesnes) and in an industrially-affected fjord (Porsgrunn). The spatial distribution of REY and shale-normalized fractionation patterns were determined to assess the potential anthropogenic contribution of REY at the sites. At both sites, the REY fractionation pattern in soft tissue was characterized by enrichment of light rare earth elements (LREE) over heavy rare earth elements (HREE), while also displaying negative cerium and small positive gadolinium (Gd) anomalies. LREEs contributed to over 80% of the total REY concentrations, with increasing relative enrichment following higher total REY. Gd anomalies remained conserved in most sites despite significant differences in total REY; however, a high Gd anomaly (Gd/Gd* = 4.4) was found downstream of the GBCA industry spillwater outlet, indicating biotic uptake of excess anthropogenic Gd at this site. Total REY concentrations in clams in Porsgrunn were one order of magnitude higher than in mussels in Lindesnes. This may be attributable to freshwater influences in Porsgrunn, where clams collected closer to the river mouth had significantly higher total REY concentrations. This study constitutes the first assessment of REY concentrations in marine bivalves in Norway and can provide useful information for future biomonitoring studies on REY contamination.

Brain deposition of gadobutrol in children—a cross-sectional and longitudinal MRI T1 mapping study

ObjectivesDepositions of linear gadolinium-based MRI contrast agents are readily visible in T1-weighted MRIs of certain brain regions in both adults and children. Macrocyclic contrast agents such as gadobutrol have so far escaped detection by qualitative MRI in children. This study aimed to assess whether there is evidence for deposition of gadobutrol in children using quantitative T1 mapping.MethodsThis retrospective study included patients, naive to other gadolinium-based contrast agents than gadobutrol, who had received gadobutrol as part of a clinically indicated MRI. For each patient, T1 relaxation times at 3 T were measured using single-shot T1 mapping at two time points. In each of six brain regions, age-adjusted T1 relaxation times were correlated with a number of previous gadobutrol administrations. To combine interindividual, cross-sectional effects with intraindividual, longitudinal effects, both linear mixed model and generalized additive mixed model were applied.ResultsOne hundred four examinations of 52 children (age median 11.4, IQR 6.3–15, 26 female) with a median of 7 doses of gadobutrol in the history of their neurological or neurooncological disease were included. After correction for age and indeterminate disease-related effects to T1 time, a negative correlation of T1 time with the number of gadobutrol doses administered was observed in both mixed models in the putamen (beta − 1.65, p = .03) and globus pallidus (beta − 1.98, p = .012)ConclusionsThe results indicate that in children, gadobutrol is deposited in the globus pallidus and putamen.Key Points• Previous gadobutrol administration correlates with reduced T1 relaxation times in the globus pallidus and putamen in children.• This decreased T1 might be caused by gadobutrol retention within these gray-matter nuclei.

7T MRI and molecular studies of Dotarem (gadoterate meglumine) retention in macrophages.

Gadolinium-based MRI contrast agent Dotarem is commonly used in the clinic. Free Gd3+ is very toxic. Because the crystallographic radius of Gd3+ and Ca2+ is very similar, Gd3+ can compete with Ca2+ in the regulations of cellular functions. Gadolinium is retained in organs and tissues, but the effects of gadolinium retention are mostly unknown. There is also no information how gadolinium retention impacts immune cells and signaling pathways regulated by Ca2+ such as RhoA/mTORC1 and mTORC2, which control various, including actin cytoskeleton-dependent, cellular functions. We developed the 7T MRI-based method to analyze gadolinium-based MRI contrast agent retention in isolated immune cells (macrophages) and study the effects of gadolinium retention on the expression of RhoA, mTORC1, mTORC2, and mitochondria, Golgi, and ER markers. We showed that macrophages retain gadolinium for at least seven days after exposure. Gadolinium retention downregulated the expression of RhoA, mTORC1 component Raptor and mTORC2 component Rictor proteins, and dysregulated the expression level of organelle markers. The method described here can be used for monitoring gadolinium levels and effects in isolated cells, such as the immune cells in the blood of patients exposed to contrast-enhanced MRI.

Gadolinium-Based MRI Contrast Agent for Targeted Imaging of Vascular Endothelial Growth Factor Receptor-2-Expressing Tumors

Development of imaging methods that can detect target molecules will be of great significance for non-invasive molecular diagnosis. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a broadly expressed target, and VEGFR-2-specific agents have been used in biological therapy. In this study, amine-reactive coupling was used to label the polypeptide VEGF125–136 with a Gd(DOTA) complex to create a magnetic resonance contrast agent, VEGF125–136-Gd, which binds to VEGFR-2. Using T1-weighted magnetic resonance imaging, we explored the tumor cell-targeting ability of VEGF125–136-Gd and its enhancement of T1-weighted image intensity using human hepatoma (HepG2) cells and found that the signal-to-noise ratio (SNR) increased commensurately with the concentration of VEGF125–136-Gd. At a concentration of 2 mM, the SNR produced by VEGF125–136-Gd was 5.4-fold higher than that produced by a Gd-labelled non-targeting polypeptide (NTPP-Gd) control. We also evaluated the tumor-targeting efficiency of VEGF125–136-Gd in nude mice injected with human hepatoma (HepG2) cells. Preliminary in vivo imaging of VEGFR-2 in tumor tissue revealed a targeting peak 60 min post administration of VEGF125–136-Gd, the intensity of which was 23% higher than the SNR of NTPP-Gd at the same time point. Our findings may help lay the foundation for clinical applications of VEGF125–136-Gd in targeted imaging.

Naturally grown duckweeds as quasi-hyperaccumulators of rare earth elements and yttrium in aquatic systems and the biounavailability of gadolinium-based MRI contrast agents

The use of rare earths and yttrium (REY) in high-technology products is accompanied by their increasing release into the environment. Concerns regarding the (eco-)toxicity and bioaccumulation of these emerging contaminants highlight the need for research on REY uptake by (aquatic) plants.Duckweeds are widespread macrophytes in lentic waters and receive increasing attention as a potential protein-rich food additive. We here provide a baseline dataset for the complete set of REY in naturally grown duckweed assemblages and ambient freshwater and coastal brackish seawater. Our results show that duckweeds strongly bioaccumulate REY and incorporate them at the μg/kg level (dry matter basis). Their shale-normalised (SN) REY patterns are mildly fractionated relative to upper continental crust, regardless of sampling location and season. In contrast, the patterns of ambient waters increase from light to heavy REY (LREY and HREY, resp.) and may show prominent positive anthropogenic GdSN anomalies due to the presence of Gd-based contrast agents (Gd-CAs) applied for magnetic resonance imaging (MRI). The lack of GdSN anomalies in the duckweed assemblages reveals discrimination against the uptake of Gd-CAs by the macrophytes, providing further evidence for the conservative behaviour of these xenobiotics in the environment. High REY concentrations and apparent bulk distribution coefficients between duckweeds and ambient waters of up to 105 show that duckweeds are quasi-hyperaccumulators of REY. Uptake of LREY is up to two orders of magnitude higher than of HREY, possibly due to stronger complexation of HREY with dissolved ligands. The REY closely correlate with Mn but not with Ca, suggesting that uptake of REY and Mn occurs via the same pathway and revealing the negligible role of calcium oxalates. Our study demonstrates that while duckweeds are quasi-hyperaccumulators of REY, there is currently no risk that anthropogenic Gd from MRI contrast agents may enter the food chain via consumption of duckweeds.

Safety of Off-Label Use of Ferumoxtyol as a Contrast Agent for MRI: A Systematic Review and Meta-Analysis of Adverse Events.

Ferumoxytol has been studied as an alternative to gadolinium-based MRI contrast agents, but regulatory body warnings currently limit its use. Estimate the adverse event rate in patients undergoing MRI with ferumoxytol as a contrast agent. Systematic review. Thirty-nine studies including 5411 ferumoxytol administrations in 4336 patients. Multiple databases were searched for studies using ferumoxytol as an off-label MRI contrast agent in any patient population as of April 2020. Studies were eligible for inclusion if they reported the number and severity of adverse events (classified by American College of Radiology [ACR] severity of acute reactions). Risk of bias was assessed using the ROBINS-I tool. The proportion of administrations with adverse events was calculated using random effects meta-analysis of proportions. No deaths related to ferumoxytol administration were reported. Sixteen studies reported immediate adverse events in 3849 patients undergoing 4901 ferumoxytol administrations. Ninety-seven immediate adverse events were reported and the pooled adverse event proportion for immediate adverse events was 0.02 (95% confidence interval [CI] 0.02-0.02). Twenty-three studies reported time-unspecified adverse events in 487 patients undergoing 510 ferumoxytol administrations. Five time-unspecified adverse events were reported; the pooled adverse event proportion for time-unspecified adverse events was 0.01 (95% CI 0.00-0.04). 88% of adverse events were mild (90/102), 11% (11/102) were moderate, and 1% (1/102) was severe. Sixteen studies were at low risk of bias, 23 studies were at serious risk of bias. Subgroup analysis by patient population revealed no significant variability (adult vs. pediatric). No studies evaluated the use of ferumoxytol as an alternative to patients who had a prior hypersensitivity reaction to gadolinium-based contrast agents (GBCAs). The overall adverse event rate for off-label ferumoxytol use as an MRI contrast agent is 2%, with rare severe reactions and no deaths. To date, there are no studies evaluating the safety of ferumoxytol as an alternative to GBCAs in patients with a prior hypersensitivity reaction. 2 TECHNICAL EFFICACY STAGE: 5.

Investigating the Impact of Gadolinium-Based Contrast Agents on the Corrected QT Interval.

IntroductionThe manufacturing labels for all currently marketed gadolinium-based MRI contrast agents describe adverse cardiac events reported during post-market use. The goal of this study was to determine prolongation of the rate-corrected QT interval occurs in the immediate setting after gadolinium-based MRI contrast agent injection.MethodsThis study enrolled adults scheduled to have a gadolinium-based MRI contrast agent injection as part of a diagnostic MRI. A single-lead electrocardiogram was recorded using the AliveCor Kardia® ECG (Mountain View, CA) device before and after injection. The rate-corrected QT interval was subsequently measured by two independent investigators. The QT interval was corrected for rate using the two most common formulas, originally cited by Bazett and Fridericia. These rate-corrected QT intervals from before and after gadolinium-based MRI contrast agent injection were compared using the Wilcoxon signed-rank test paired analysis.ResultsA total of 24 consenting adults had electrocardiogram that were free of motion artifact. The mean age of the final patient cohort was 59.4 years. There was an equal split of 12 men and 12 women. The mean pre-injection, rate-corrected QT interval, corrected using Bazett’s formula, was 395 msec. The mean post-injection, rate-corrected QT interval, corrected using Bazett’s formula, was 396 msec. The corrections using Fridericia's formula were 384 and 381 msec, respectively. There was no statistically significant change in Bazett-corrected QT interval (QTc-B) when pre-injection and post-injection values were directly compared.DiscussionThe results of the present investigation support the conclusion that gadolinium-based MRI contrast agents do not commonly affect rate-corrected QT interval in routine clinical use. While the frequency of rate-corrected QT interval prolongation might be overstated, the severity of adverse events is definitively not. A role for concomitant rate-corrected QT interval-prolonging drugs or unidentified rare factors such as genetic predisposition cannot be ruled out. The limitations of this study include its relatively small size and the implementation of a single-lead electrocardiogram to measure rate-corrected QT interval.ConclusionThe present investigation revealed that significant rate-corrected QT interval prolongation, while previously reported in as many as 55% of patients after gadolinium-based MRI contrast agent injection, is not a common occurrence in the routine clinical setting.

Gadolinium-Based Neuroprognostic Magnetic Resonance Imaging Agents Suppress COX-2 for Prevention of Reperfusion Injury after Stroke.

Advancements in recanalization therapies have rendered reperfusion injury an important challenge for stroke management. It is essential to work toward effective therapeutics that protect the ischemic brain from reperfusion injury. Here, we report a new concept of neuroprognostic agents, which combine molecular diagnostic imaging and targeted neuroprotection for treatment of reperfusion injury after stroke. These neuroprognostic agents are inflammation-targeted gadolinium compounds conjugated with nonsteroidal anti-inflammatory drugs (NSAIDs). Our results demonstrated that gadolinium-based MRI contrast agents conjugated with NSAIDs suppressed the increase in cyclooxygenase-2 (COX-2) levels, ameliorated glial activation, and neuron damage that are phenotypic for stroke by mitigating neuroinflammation, which prevented reperfusion injury. In addition, this study showed that the neuroprognostic agents are promising T1 molecular MRI contrast agents for detecting precise reperfusion injury locations at the molecular level. Our results build on this new concept of neuroprognostics as a novel management strategy for ischemia-reperfusion injury, combining neuroprotection and molecular diagnostics.

Gadolinium-based MRI contrast agent for the detection of tyrosinase.

Tyrosinase is a key enzyme that has long been considered as a biomarker for melanoma as it catalyzes the oxidation of tyrosine and l-DOPA in melanogenesis. Recent studies also suggest a link between tyrosinase activity and Parkinson's disease; however, the mechanism of tyrosinase-mediated melanin formation in the brain is poorly understood. To better understand this connection, more advanced tools for the detection of tyrosinase in the brain are required. Herein, we successfully designed and synthesized a tyrosinase-targeting Gd(iii)-based MR contrast agent Tyr-GBCA 1. Tyr-GBCA 1 was synthesized by linking m-hydroxyphenyl to Gd-DOTA via a self-immolative linker. Tyr-GBCA 1 shows a 21% increase in the T1 relaxation rate (R1) in the presence of tyrosinase in artificial cerebral spinal fluid. Furthermore, Tyr-GBCA 1 is unreactive to hydrogen peroxide, which is a potential interferent in oxidation-based tyrosinase sensing systems. The reaction mechanism of the probe was studied by electrospray ionization (ESI) mass spectrometry and supports the cleavage of a reaction site.

Empirical and Theoretical Characterization of the Diffusion Process of Different Gadolinium-Based Nanoparticles within the Brain Tissue after Ultrasound-Induced Permeabilization of the Blood-Brain Barrier.

Low-intensity focused ultrasound (FUS), combined with microbubbles, is able to locally, and noninvasively, open the blood-brain barrier (BBB), allowing nanoparticles to enter the brain. We present here a study on the diffusion process of gadolinium-based MRI contrast agents within the brain extracellular space after ultrasound-induced BBB permeabilization. Three compounds were tested (MultiHance, Gadovist, and Dotarem). We characterized their diffusion through in vivo experimental tests supported by theoretical models. Specifically, by estimation of the free diffusion coefficients from in vitro studies and of apparent diffusion coefficients from in vivo experiments, we have assessed tortuosity in the right striatum of 9 Sprague Dawley rats through a model correctly describing both vascular permeability as a function of time and diffusion processes occurring in the brain tissue. This model takes into account acoustic pressure, particle size, blood pharmacokinetics, and diffusion rates. Our model is able to fully predict the result of a FUS-induced BBB opening experiment at long space and time scales. Recovered values of tortuosity are in agreement with the literature and demonstrate that our improved model allows us to assess that the chosen permeabilization protocol preserves the integrity of the brain tissue.

Distribution and Diffusion of Macromolecule Delivery to the Brain via Focused Ultrasound using Magnetic Resonance and Multispectral Fluorescence Imaging

Focused ultrasound (FUS), in combination with microbubble contrast agents, can be used to transiently open the blood–brain barrier (BBB) to allow intravascular agents to cross into the brain. Often, FUS is carried out in conjunction with magnetic resonance imaging (MRI) to evaluate BBB opening to gadolinium-based MRI contrast agents. Although MRI allows direct visualization of the distribution of gadolinium-based contrast agents in the brain parenchyma, it does not allow measurements of the distribution of other molecules crossing the BBB. Therapeutic molecules (e.g., monoclonal antibodies) are much different in size than MRI contrast agents and have been found to have different distributions in the brain after FUS-mediated BBB opening. In the work described here, we combined in vivo MRI and ex vivo multispectral fluorescence imaging to compare the distributions of MRI contrast and dextran molecules of different molecular weights (3, 70 and 500 kDa) after FUS-mediated BBB opening through a range of ultrasound pressures (0.18–0.46 MPa) in laboratory mice. The volume of brain exposed was calculated from the MRI and fluorescence images and was significantly dependent on both molecular weight and ultrasound pressure. Diffusion coefficients of the different-molecular-weight dextran molecules in the brain parenchyma were also calculated from the fluorescence images and were negatively correlated with the molecular weight of the dextran molecules. The results of this work build on a body of knowledge that is critically important for the FUS technique to be used in clinical delivery of therapeutics to the brain.

Intravenous gadolinium-based hepatocyte-specific contrast agents (HSCAs) for contrast-enhanced liver magnetic resonance imaging in pediatric patients: what the radiologist should know.

Hepatocyte-specific contrast agents (HSCAs) are a group of intravenous gadolinium-based MRI contrast agents that can be used to characterize hepatobiliary pathology. The mechanism by which these agents are taken up by hepatocytes and partially excreted into the biliary tree improves characterization of hepatic lesions and biliary abnormalities relative to conventional extracellular gadolinium-based contrast agents (GBCAs). This manuscript presents an overview of HSCA use in pediatric patients with the intent to provide radiologists a guide for clinical use. We review available HSCAs and discuss dosing and age specifications for use in children. We also review various hepatic and biliary indications for HSCA use in children, with emphasis on the imaging characteristics distinct to HSCAs, as well as discussion of pitfalls one can encounter when imaging with HSCAs. Given the growing concern regarding gadolinium deposition in soft tissues and brain, we also discuss safety of HSCA use in children.

Using Dynamic Contrast-enhanced MRI as an Imaging Biomarker for Migraine: Proceed with Caution

Using Dynamic Contrast-enhanced MRI as an Imaging Biomarker for Migraine: Proceed with Caution

Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent

This preclinical study was devised to investigate potential cellular toxicity in human neurons induced by gadolinium-based contrast agents (GBCAs) used for contrast-enhanced magnetic resonance imaging (MRI). Neurons modeling a subset of those in the basal ganglia were tested, because the basal ganglia region is 1 of 2 brain regions that displays the greatest T1-dependent signal hyperintensity changes. Eight GBCAs were tested. Dopaminergic neurons modeling a subset of those in the basal ganglia were differentiated from an established human neuroblastoma cell line and exposed to increasing concentrations of each agent for 7 days. The tested dosages ranged from clinically relevant concentrations measured in some autopsy patients who had received repeated injections of contrast for MRI, to higher concentrations to reveal dose-dependent toxicity trends. Cell death, mitochondrial membrane potential, mitochondrial oxidative capacity, and mitochondrial function measured by oxygen consumption were quantified in cells treated with each GBCA or the osmolality control mannitol and compared to untreated cells which served as a negative control. Mannitol caused no change from negative controls in any of the tests, at any concentration tested. For all GBCAs, cell death increased with exposure dose, with toxicity at clinically relevant doses for agents with lower kinetic stability. Reduction of mitochondrial membrane potential and oxidative respiratory function also generally mirrored the agents' structural kinetic stabilities, with greater impairment at lower concentration for the less stable agents. In human neurons modeling a subset of those in the basal ganglia, these results demonstrate a toxic effect of gadolinium-containing MRI contrast agents on mitochondrial respiratory function and cell viability. Toxicity increases as agent concentration increases and as the kinetic stability of the agent decreases.