Gadolinium-based MRI Contrast Agents Research Articles

The biological fate of gadolinium-based MRI contrast agents: a call to action for bioinorganic chemists.

Gadolinium-based contrast agents (GBCAs) are widely used with clinical magnetic resonance imaging (MRI), and 10 s of millions of doses of GBCAs are administered annually worldwide. GBCAs are hydrophilic, thermodynamically stable and kinetically inert gadolinium chelates. In clinical MRI, 5-10 millimoles of Gd ion is administered intravenously and the GBCA is rapidly eliminated intact primarily through the kidneys into the urine. It is now well-established that the Gd3+ ion, in some form(s), is partially retained in vivo. In patients with advanced kidney disease, there is an association of Gd retention with nephrogenic systemic fibrosis (NSF) disease. However Gd is also retained in the brain, bone, skin, and other tissues in patients with normal renal function, and the presence of Gd can persist months to years after the last administration of a GBCA. Regulatory agencies are restricting the use of specific GBCAs and inviting health care professionals to evaluate the risk/benefit ratio prior to using GBCAs. Despite the growing number of studies investigating this issue both in animals and humans, the biological distribution and the chemical speciation of the residual gadolinium are not fully understood. Is the GBCA retained in its intact form? Is the Gd3+ ion dissociated from its chelator, and if so, what is its chemical form? Here we discuss the current state of knowledge regarding the issue of Gd retention and describe the analytical and spectroscopic methods that can be used to investigate the Gd speciation. Many of the physical methods that could be brought to bear on this problem are in the domain of bioinorganic chemistry and we hope that this review will serve to inspire this community to take up this important problem.

Kinetics and MR-Based Monitoring of AAV9 Vector Delivery into Cerebrospinal Fluid of Nonhuman Primates

Here we evaluated the utility of MRI to monitor intrathecal infusions in nonhuman primates. Adeno-associated virus (AAV) spiked with gadoteridol, a gadolinium-based MRI contrast agent, enabled real-time visualization of infusions delivered either via cerebromedullary cistern, lumbar, cerebromedullary and lumbar, or intracerebroventricular infusion. The kinetics of vector clearance from the cerebrospinal fluid (CSF) were analyzed. Our results highlight the value of MRI in optimizing the delivery of infusate into CSF. In particular, MRI revealed differential patterns of infusate distribution depending on the route of delivery. Gadoteridol coverage analysis showed that cerebellomedullary cistern delivery was a reliable and effective route of injection, achieving broad infusate distribution in the brain and spinal cord, and was even greater when combined with lumbar injection. In contrast, intracerebroventricular injection resulted in strong cortical coverage but little spinal distribution. Lumbar injection alone led to the distribution of MRI contrast agent mainly in the spinal cord with little cortical coverage, but this delivery route was unreliable. Similarly, vector clearance analysis showed differences between different routes of delivery. Overall, our data support the value of monitoring CSF injections to dissect different patterns of gadoteridol distribution based on the route of intrathecal administration.

Noninvasive quantification of fibrosis in skeletal and cardiac muscle in mdx mice using EP3533 enhanced magnetic resonance imaging.

Duchenne muscular dystrophy (DMD) is a genetic condition caused by mutations in the DMD gene leading to muscle degeneration, fatty replacement of muscle cells and fibrosis. A major obstacle to advancing therapeutic research into muscular dystrophies is development of sensitive, noninvasive outcome measures. To date, no validated method to noninvasively quantify fibrosis within skeletal muscle exists. EP3533 is a gadolinium-based MRI contrast agent with an affinity to collagen-1. The purpose of this study was to determine whether EP3533-enhanced MRI could quantify fibrosis in a murine model of DMD (mdx) in muscle. Mdx (n = 8) and control mice (BL10; n = 5) underwent contrast-enhanced MRI acquisitions with EP3533. T1 mapping pre- and postcontrast was performed in skeletal and cardiac muscle. Post-MRI the tibialis anterior (TA) and gastrocnemius (GCN) muscles and the heart were removed for fibrosis quantification by means of Masson's trichrome staining and the hydroxyproline assay. Significant differences in postcontrast R1 were demonstrated between mdx and BL10 mice using EP3533 (cardiac P = 0.02, GCN P = 0.04, TA P = 0.04). Change in R1 from baseline following EP3533 administration correlated strongly to hydroxyproline levels (GCN: r = 0.83, P = 0.001; TA: r = 0.73, P = 0.01). This study provides evidence for the suitability of EP3533 in the quantification of muscular fibrosis in mdx mice and demonstrated that EP3533-derived measurements correlated strongly to ex vivo fibrosis measurement.

Safety considerations for nanoparticles in tumor treatment.

Safety considerations for nanoparticles in tumor treatment.

Gadolinium contrast medium administration does not adversely affect T2*-weighted gradient recalled echo magnetic resonance imaging of the canine brain at 1.5 Tesla.

As gadolinium-based contrast agents are paramagnetic and have T2 shortening effects, they have the potential to adversely affect gradient recalled echo sequences. The aim of this prospective, cross-sectional study was to evaluate the effects of gadolinium administration on T2*-weighted sequence diagnostic quality and signal intensity when imaging the canine brain. A total of 100 dogs underwent brain magnetic resonance imaging (MRI) including pre- and postcontrast T2*-weighted sequences acquired with a delay (Group A) or immediately (Group B) following gadolinium administration. Pre- and postcontrast images were subjectively compared. In dogs with intracranial enhancing masses, regions of interest were drawn on corresponding images and signal intensity ratios were calculated. The effect of degree and pattern of contrast enhancement, susceptibility artifacts, and time between contrast injection and T2*-weighted sequence acquisition on signal intensity ratio was evaluated. Overall 31 dogs had contrast enhancing intracranial masses. Subjectively, there was no difference in image quality of T2*-weighted sequences obtained before and after contrast medium administration. No significant signal intensity differences of intracranial contrast enhancing masses were found (Group A P=0.9999; Group B P=0.9992). Susceptibility artifacts did not differ in appearance, and there was no effect on calculated signal intensity ratio (P=0.8142). Similarly, there was no effect of degree of enhancement or contrast heterogeneity on signal intensity ratio (P=0.4413). No correlation was found between signal intensity ratio and the time to acquisition (P=0.199). Administration of gadolinium-based MRI contrast agents does not adversely affect T2*-weighted imaging of the brain in dogs at 1.5T even in the presence of contrast enhancing lesions.

Effects of gadolinium-based MRI contrast agents on liver tissue.

MRI with contrast is often used clinically. However, recent studies have reported a high accumulation of gadolinium-based contrast agents (GBCAs) in kidney, liver, and spleen tissues in several mouse models. To compare the effects on liver tissue of gadolinium-based MRI contrast agents in the light of biochemical and histopathological evaluation. Institutional Review Board (IRB)-approved controlled longitudinal study. In all, 32 male Sprague-Dawley rats were divided into a healthy control group subjected to no procedure (Group 1), a sham group (Group 2), a gadodiamide group (Group 3), and a gadoteric acid group (Group 4). Not applicable. Liver tissues removed at the end of the fifth week and evaluated pathologically (scored Knodell's histological activity index [HAI] method by two histopathologists) immunohistochemical (caspase-3 and biochemical tests (AST, ALT, TAS, TOS, and OSI method by Erel et al) were obtained. Differences between groups were analyzed using the nonparametric Kruskal-Wallis test followed by the Tamhane test, and one-way analysis of variance (ANOVA) followed by Turkey's HSD test. An increase was observed in histological activity scores in sections from rats administered gadodiamide and gadoteric acid, and in caspase-3, AST and ALT values (P < 0.05). In contrast, we determined no change in TOS (P = 0.568 and P = 0.094, respectively), TAS (P = 0.151 and P = 0.055, respectively), or OSI (P = 0.949 and P = 0.494, respectively) values. These data suggest that gadodiamide and gadoteric acid trigger hepatocellular necrosis and apoptosis by causing damage in hepatocytes, although no change occurs in total antioxidant and antioxidant capacity. 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1367-1374.

Magnetic Resonance Imaging and Histopathological Visualization of Human Dural Lymphatic Vessels.

In this protocol, we describe a method to visualize and map dural lymphatic vessels in-vivo using magnetic resonance imaging (MRI) and ex-vivo using histopathological techniques. While MRI protocols for routine imaging of meningeal lymphatics include contrast-enhanced T2-FLAIR and T1-weighted black-blood imaging, a more specific 3D mapping of the lymphatic system can be obtained by administering two distinct gadolinium-based MRI contrast agents on different days (gadofosveset and gadobutrol) and subsequently processing images acquired before and after administration of each type of contrast. In addition, we introduce methods for optimal immunostaining of lymphatic and blood vessel markers in human dura mater ex-vivo.

Neuroimaging in Pregnant Women.

Choosing the most appropriate diagnostic neuroimaging study for a pregnant woman involves assessing the pretest likelihood of serious treatable neurologic disease, the diagnostic utility of various available computed tomography (CT) and magnetic resonance (MR) modalities, and the risks of each. Of these three elements-pretest differential diagnosis, utility of MRI and CT, and risks of MR and CT-the risk component is perhaps the least well understood by most physicians. We provide a basic review of the intrinsic risks of MRI and CT, particularly radiation biology and radiation safety, as well as the risks pertaining to the use of contrast agents, to reduce provider confusion and anxiety and improve quality, safety, and efficiency of neuroimaging diagnosis in pregnant patients. We believe that a better understanding of the associated very low risks with mother and fetus will reassure the reader that CT remains the most appropriate tool for initial rapid diagnosis of acute neurological conditions in pregnancy and that in urgent situations CT should not be withheld or delayed due to exaggerated concern about radiation. Noncontrast MRI, while not without risk, is generally considered safe in pregnancy, as no evidence of fetal adverse effects has been demonstrated to date. Iodinated CT contrast agents are likely safer than gadolinium-based MRI contrast agents because of gadolinium accumulation in the amniotic fluid and fetal tissue, although no harmful effects of tissue gadolinium accumulation are known. In most but not all pregnant patients presenting with a new or worsening neurological abnormality, the risks intrinsic to the disease will outweigh the risks of imaging. In an individual patient, the pretest probability of serious treatable disease and acuity of presentation will usually suggest an optimal imaging strategy and choice of test. This optimal strategy will also depend on the immediate availability and level of sophistication of the scanners, software, technologists, and radiologists. As such, the standard of care for imaging in pregnancy requires direct consultation between the referring clinician and radiologist to determine the most appropriate strategy and brief documentation of the resulting consensus risk-benefit assessment.

Proton Neutron Gamma-X Detection (PNGXD): An introduction to contrast agent detection during proton therapy via prompt gamma neutron activation

Proton therapy is an alternative external beam cancer treatment modality to the conventional linear accelerator-based X-ray radiotherapy. An inherent by-product of proton-nuclear interactions is the production of secondary neutrons. These neutrons have long been thought of as a secondary contaminant, nuisance, and source of secondary cancer risk. In this paper, a method is proposed to use these neutrons to identify and localize the presence of the tumor through neutron capture reactions with the gadolinium-based MRI contrast agent. This could provide better confidence in tumor targeting by acting as an additional quality assurance tool of tumor position during treatment. This effectively results in a neutron induced nuclear medicine scan. Gadolinium (Gd), is an ideal candidate for this novel nuclear contrast imaging procedure due to its unique nuclear properties and its widespread use as a contrast agent in MRI. Gd has one of the largest thermal neutron capture cross sections of all the stable nuclides, and the gadolinium-based contrast agents localize in leaky tissues and tumors. Initial characteristics of this novel concept were explored using the Monte Carlo code MCNP6. The number of neutron capture reactions per Gy of proton dose was found to be approximately 50,000 neutron captures/Gy, for a 8cm3 tumor containing 300ppm Gd at 8cm depth with a simple simulation designed to represent the active delivery method. Using the passive method it is estimated that this number can be up to an order of magnitude higher. The thermal neutron distribution was found to not be localized within the spread out Bragg peak (SOBP) for this geometrical configuration and therefore would not allow for the identification of a geometric miss of the tumor by the proton SOBP. However, this potential method combined with nuclear medicine imaging and fused with online CBCT and prior MRI or CT imaging could help to identify tumor position during treatment. More computational and experimental work are required to determine the feasibility of this new technique termed Proton Neutron Gamma-X Detection (PNGXD). The initial concept of this procedure is presented in this paper as well as future research directions.

Comparative study of the effects of gadolinium chloride and gadolinium – based magnetic resonance imaging contrast agent on freshwater mussel, Dreissena polymorpha

Gadolinium (Gd), a metal of the lanthanide series used in various industrial and medical purposes is released into the aquatic environment. However, there are few aquatic toxicological studies addressing environmental effects of Gd which remains unknown in aquatic animals. Therefore, this study aimed to compare the effects of GdCl3 and a gadolinium-based MRI contrast agent (Omniscan), in zebra mussels after 28 days through a multibiomarker approach. Data revealed that after GdCl3 exposure, the mRNA level of metallothionein (MT) was modulated, those of cytochrome c oxidase (CO1) and superoxide dismutase (SOD) were increased, while gene expressions of catalase (CAT) and glutathione-S-transferase (GST) were downregulated. Furthermore, neither lipoperoxidation (LPO) nor genotoxicity were detected but only a decrease in the cyclooxygenase (COX) activity was observed. In addition, a significant correlation was found between biomarkers and bioaccumulated Gd, suggesting that mitochondrial and anti-inflammatory pathways were triggered with GdCl3. By opposition, the contrasting agent formulation induced downregulation of SOD, CAT, GST and CO1, a decrease in the level of LPO and an increase in the GST and COX activities. This suggests that the chelated form of Gd did not promote reactive oxygen species (ROS) production and exhibits antioxidant and proinflammatory effects in mussels. Therefore, this study revealed that ionic and the chelated form of Gd influence different cellular pathways to initiate cellular changes.

Gd3+ Tethered Gold Nanorods for Combined Magnetic Resonance Imaging and Photo-Thermal Therapy

Near infrared (NIR) mediated photothermal therapy and magnetic resonance imaging (MRI) are promising treatment and imaging modalities in the field of cancer theranostics. Gold nanorods are the first choice of materials for NIR-mediated photothermal therapy due to their strong localized surface plasmon resonance (LSPR) at NIR region. Similarly, gadolinium based MRI contrast agents have an ability to increase the ionic and molecular relaxivity, thereby enhancing the solvent proton relaxation rate resulting in contrast enhancement. Herein, the effort has been made to engineer a dual front theranostic agent with combined photothermal and magnetic resonance imaging capacity using gadolinium tethered gold nanorods (Gd3+-AuNR). NIR-responsive gold nanorods were surface fabricated by means of Au-thiol interaction using a thiolated macrocyclic chelator that chelates Gd3+ ions, and further stabilized by thiolated polyethylene glycol (PEG-SH). The magnetic properties of the Gd3+-AuNR displayed an enhanced r 1 relaxivity of 12.1 mM–1s–1, with higher biological stability, and contrast enhancement in both solution state and in cell pellets. In-vitro (cell-free) and ex-vivo (on pig skin) analysis of the Gd3+-AuNR shows enhanced photothermal properties as equivalent to that of the raw AuNR. Furthermore, Gd3+-AuNR showed competent cellular entry and intracellular distribution as revealed by hyperspectral microscopy. In addition, Gd3+-AuNR also exhibits significant thermal ablation of B16–F10 cells in the presence of NIR. Thus, Gd3+-AuNR features a significant theranostic potential with combined photothermal and imaging modality, suggesting a great potential in anticancer therapy.

Gadolinium-based nanoscale MRI contrast agents for tumor imaging.

Gadolinium-based nanoscale magnetic resonance imaging (MRI) contrast agents (CAs) have gained significant momentum as a promising nanoplatform for detecting tumor tissue in medical diagnosis, due to their favorable capability of enhancing the longitudinal relaxivity (r1) of individual gadolinium ions, delivering to the region of interest a large number of gadolinium ions, and incorporating different functionalities. This mini-review highlights the latest developments and applications, and simultaneously gives some perspectives for their future development.

Combining hyperpolarized 13 C MRI with a liver-specific gadolinium contrast agent for selective assessment of hepatocyte metabolism.

Hyperpolarized 13 C MRI is a powerful tool for studying metabolism, but can lack tissue specificity. Gadoxetate is a gadolinium-based MRI contrast agent that is selectively taken into hepatocytes. The goal of this project was to investigate whether gadoxetate can be used to selectively suppress the hyperpolarized signal arising from hepatocytes, which could in future studies be applied to generate specificity for signal from abnormal cell types. Baseline gadoxetate uptake kinetics were measured using T1 -weighted contrast enhanced imaging. Relaxivity of gadoxetate was measured for [1-13 C]pyruvate, [1-13 C]lactate, and [1-13 C]alanine. Four healthy rats were imaged with hyperpolarized [1-13 C]pyruvate using a three-dimensional (3D) MRSI sequence prior to and 15 min following administration of gadoxetate. The lactate:pyruvate ratio and alanine:pyruvate ratios were measured in liver and kidney. Overall, the hyperpolarized signal decreased approximately 60% as a result of pre-injection of gadoxetate. In liver, the lactate:pyruvate and alanine:pyruvate ratios decreased 42% and 78%, respectively (P < 0.05) following gadoxetate administration. In kidneys, these ratios did not change significantly. Relaxivity of gadoxetate for [1-13 C]alanine was 12.6 times higher than relaxivity of gadoxetate for [1-13 C]pyruvate, explaining the greater selective relaxation effect on alanine. The liver-specific gadolinium contrast-agent gadoxetate can selectively suppress normal hepatocyte contributions to hyperpolarized 13 C MRI signals. Magn Reson Med 77:2356-2363, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Magnetic resonance imaging of primary pediatric liver tumors.

Although primary hepatic neoplasms are less common than other intra-abdominal tumors in children, these neoplasms are a significant source of morbidity and mortality in the pediatric population. MRI is increasingly relied upon in the diagnostic evaluation of these lesions, both before and after treatment, and familiarity with the MRI findings associated with these neoplasms is a must for pediatric radiologists. Advances in MRI technology, particularly the advent of hepatocyte-specific gadolinium-based MRI contrast agents, have allowed for accurate characterization of several types of hepatic neoplasms on the basis of imaging appearance. In this review, we provide an overview of the approach to imaging hepatic neoplasms in children using MRI, including a sample imaging protocol. We also discuss the relevant clinical features and MRI findings of the most clinically relevant entities, including their appearance on post-contrast imaging using hepatocyte-specific gadolinium-based MRI contrast agents.

WITHDRAWN: Dose enhancement in radiotherapy by novel application of gadolinium based MRI contrast agent nanomagnetic particles in gel dosimetry

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Parallel Comparative Studies on Mouse Toxicity of Oxide Nanoparticle- and Gadolinium-Based T1 MRI Contrast Agents.

Magnetic resonance imaging (MRI) contrast agents with high relaxivity are highly desirable because they can significantly increase the accuracy of diagnosis. However, they can be potentially toxic to the patients. In this study, using a mouse model, we investigate the toxic effects and subsequent tissue damage induced by three T1 MRI contrast agents: gadopentetate dimeglumine injection (GDI), a clinically used gadolinium (Gd)-based contrast agent (GBCAs), and oxide nanoparticle (NP)-based contrast agents, extremely small-sized iron oxide NPs (ESIONs) and manganese oxide (MnO) NPs. Biodistribution, hematological and histopathological changes, inflammation, and the endoplasmic reticulum (ER) stress responses are evaluated for 24 h after intravenous injection. These thorough assessments of the toxic and stress responses of these agents provide a panoramic description of safety concerns and underlying mechanisms of the toxicity of contrast agents in the body. We demonstrate that ESIONs exhibit fewer adverse effects than the MnO NPs and the clinically used GDI GBCAs, providing useful information on future applications of ESIONs as potentially safe MRI contrast agents.

Peptide Materials Obtained by Aggregation of Polyphenylalanine Conjugates as Gadolinium‐Based Magnetic Resonance Imaging Contrast Agents

Peptide materials based on the aggregation of polyphenylalanine conjugates containing gadolinium complexes and acting as potential contrast agents (CAs) in magnetic resonance imaging (MRI) are described. Monomers contain two (F2) or four (F4) phenylalanine residues for self‐assembly, a chelating agent, 1,4,7,10‐tetraazacyclododecane‐N,N,N,N‐tetraacetic acid (DOTA) or diethylenetriaminepentaacetic acid (DTPA), for achieving gadolinium coordination, and ethoxylic linkers at two (L2) or six (L6) poly(ethylene glycol) (PEG) units between the chelating group and the peptide region. Both DOTA and DTPA tetraphenylalanine derivatives, and their gadolinium complexes DOTA(Gd)‐L6‐F4 and DTPA(Gd)‐L6‐F4, are able to self‐aggregate at very low concentration. Structural characterization, obtained by circular dichroism and infrared measurements, confirms the amyloid type fibril formation in which an antiparallel peptide alignment is preferred. Amyloid type fibril formation is also observed, in solid state, by transmission electron microscopy images and X‐ray diffraction patterns. The relaxivity values of DOTA(Gd)‐L6‐F4 and DTPA(Gd)‐L6‐F4 and their ability to enhance the MRI cellular response on the J774A.1 mouse macrophages cell line indicate that these peptide materials are promising candidate as a new class of supramolecular gadolinium based MRI contrast agents.

Application of Extracellular Gadolinium-based MRI Contrast Agents and the Risk of Nephrogenic Systemic Fibrosis

Application of Extracellular Gadolinium-based MRI Contrast Agents and the Risk of Nephrogenic Systemic Fibrosis

Vibrational dynamics of zero-field-splitting hamiltonian in gadolinium-based MRI contrast agents from ab initio molecular dynamics

The electronic relaxation of gadolinium complexes used as MRI contrast agents was studied theoretically by following the short time evolution of zero-field-splitting parameters. The statistical analysis of ab initio molecular dynamics trajectories provided a clear separation between static and transient contributions to the zero-field-splitting. For the latter, the correlation time was estimated at approximately 0.1 ps. The influence of the ligand was also probed by replacing one pendant arm of our reference macrocyclic complex by a bulkier phosphonate arm. In contrast to the transient contribution, the static zero-field-splitting was significantly influenced by this substitution.

Application of Extracellular Gadolinium-based MRI Contrast Agents and the Risk of Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is a serious, sometimes fatal disease. Findings in recent years have shown that a causal association between gadolinium containing contrast media and NSF is most likely. Therefore, the regulatory authorities have issued guidelines on the use of gadolinium-containing contrast media which have reduced the number of new cases of NSF to almost zero. However, it is for precisely this reason that the greatest care must still be taken to ensure that these guidelines are complied with. The most important factors are renal function, the quantity of gadolinium administered and coexisting diseases such as inflammation. All of these factors crucially influence the quantity of gadolinium released from the chelat in the body. This free gadolinium is thought to be the trigger for NSF. Other important factors are the stability of the gadolinium complex and furthermore the route of its elimination from the body. Partial elimination via the liver might be an additional protective mechanism. In conclusion, despite the NSF risk, contrast-enhanced MRI is a safe diagnostic procedure which can be used reliably and safely even in patients with severe renal failure, and does not necessarily have to be replaced by other methods.