Gd Toxicity Research Articles

Gadolinium induced effects on mammalian cell motility, adherence and chromatin structure.

The toxicity of gadolinium is reduced by chelating agents that render this heavy metal into contrast complexes used for medical magnetic resonance imaging. However, the dissociation of gadolinium chelates is known to generate Gd3+ ions, the cellular toxicity of which has not been tested in details. The cytotoxic effects of Gd(III) ions were evaluated by monitoring the proliferation, measuring the cellular motility and following chromatin changes in various cell lines upon Gd3+ treatment. Measurements applied long-term scanning microscopy and a perfusion platform that replaced the medium with test solutions, bypassed physical contact with the cell culture during experiments, and provided uninterrupted high time-resolution time-lapse photomicrography for an extended period of time. Genotoxicity specific chromatin changes characteristic to Gd(III) were distinguished in human skin keratinocytes (HaCaT), human limbal stem cells (HuLi), colorectal adenocarcinoma (CaCO2), murine squamous carcinoma (SCC) and Indian muntjac (IM) cell lines. Characteristic features of Gd(III) toxicity were: loss of cellular motility, irreversible attachment of cells to the growth surface and cell death. Injury-specific chromatin changes manifested at micromolar Gd3+ concentrations as premature chromatin condensation and highly condensed sticky chromatin patches. Gd(III) concentration- and cell type-dependent reduction of normal adherence, as well as premature chromatin condensation confirmed apoptosis. The risk related to the release of toxic Gd3+ ions from gadolinium complexes and their effects on mono- and multi-layer cellular barriers have to be reconsidered when these chelated complexes are used as contrasting agents especially in relation to possible blood-brain barrier damages.

TH-AB-209-02: Gadolinium Measurements in Human Bone Using in Vivo K X-Ray Fluorescence (KXRF) Technique

Purpose: Improvement in an in vivo K x-ray fluorescence system, based on 109Cd source, for the detection of gadolinium (Gd) in bone has been investigated. Series of improvements to the method is described. Gd is of interest because of the extensive use of Gd-based contrast agents in MR imaging and the potential toxicity of Gd exposure. Methods: A set of seven bone equivalent phantoms with different amount of Gd concentrations (from 0–100 ppm) has been developed. Soft tissue equivalent plastic plates were used to simulate the soft tissue overlaying the tibia bone in an in vivo measurement. A new 5 GBq 109Cd source was used to improve the source activity in comparison to the previous study (0.17 GBq). An improved spectral fitting program was utilized for data analysis. Results: The previous published minimum detection limit (MDL) for Gd doped phantom measurements using KXRF system was 3.3 ppm. In this study the MDL for bare bone phantoms was found to be 0.8 ppm. Our previous study used only three layers of plastic (0.32, 0.64 and 0.96 mm) as soft tissue equivalent materials and obtained the MDL of 4–4.8 ppm. In this study the plastic plates with more realistic thicknesses to simulate the soft tissue covering tibia bone (nine thicknesses ranging from 0.61–6.13 mm) were used. The MDLs for phantoms were determined to be 1.8–3.5 ppm. Conclusion: With the improvements made to the technology (stronger source, improved data analysis algorithm, realistic soft tissue thicknesses), the MDL of the KXRF system to measure Gd in bare bone was improved by a factor of 4.1. The MDL is at the level of the bone Gd concentration reported in literature. Hence, the system is ready to be tested on human subjects to investigate the use of bone Gd as a biomarker for Gd toxicity.

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd(3+) toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd(3+) and a 10(11)-fold greater selectivity for Gd(3+) over Zn(2+) compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r1/r2: 66.8 mmol(-1)⋅s(-1)/89.2 mmol(-1)⋅s(-1) per particle). Using T1- and T2-weighted, as well as T2/T1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10-20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.

Gadolinium detection via in vivo prompt gamma neutron activation analysis following gadolinium-based contrast agent injection: a pilot study in 10 human participants

Gadolinium (Gd) based contrast agents are routinely used as part of many magnetic resonance imaging (MRI) procedures. The widespread use of these agents and concerns about Gd toxicity, motivated us to develop a monitoring procedure that could non-invasively measure quantitatively potential retention of toxic free Gd in tissues after use of the agent. We have been developing a method to measure Gd painlessly and non-invasively by prompt gamma neutron activation analysis. In this paper we present the results of a pilot study where we show that we can measure Gd, quantitatively in vivo, in the lower leg muscle of 10 participants. A series of three neutron leg scans were performed. The effective radiation dose for a single neutron leg scan was very low, 0.6 µSv, so multiple scans were possible. Calibration phantom and in vivo detection limits were determined to be identical: 0.58 ppm. Gd was not detectable in muscle prior to exposure to the contrast agent Gadovist®. Gd was detected, at greater than 99% confidence, in 9 participants within 1 h of contrast administration and in 1 participant approximately 3.3 h post-contrast administration. The measured concentrations of Gd ranged from 2.0 to 17.3 ppm (6.9 to 56 uncertainties different from zero). No detectable Gd was measured in any participant in the third neutron scan (conducted 0.7 to 5.9 d post-contrast). The results of this study validate our new measurement technology. This technique could be used as a non-invasive monitoring procedure for exposure and retention of Gd from Gd-based chelates used in MRI.

Enhanced cytotoxic and genotoxic effects of gadolinium following ELF-EMF irradiation in human lymphocytes

Gadolinium (Gd) and its chelated derivatives are widely utilized for various industrial and medical purposes, particularly as a contrast agent for magnetic resonance imaging (MRI). There are many studies of Gd nephrotoxicity and neurotoxicity, whereas research on cyto- and genotoxicity in normal human lymphocytes is scarce. It is important to investigate the effect of extremely low-frequency electromagnetic fields (ELF-EMF) on Gd toxicity, as patients are co-exposed to Gd and ELF-EMF generated by MRI scanners. We investigated the cytotoxicity and genotoixcity of Gd and the possible enhancing effect of ELF-EMF on Gd toxicity in cultured human lymphocytes by performing a micronuclei (MN) assay, trypan blue dye exclusion, single cell gel electrophoresis, and apoptosis analyses using flow cytometry. Isolated lymphocytes were exposed to 0.2–1.2 mM of Gd only or in combination with a 60-Hz ELF-EMF of 0.8-mT field strength. Exposing human lymphocytes to Gd resulted in a concentration- and time-dependent decrease in cell viability and an increase in MN frequency, single strand DNA breakage, apoptotic cell death, and ROS production. ELF-EMF (0.8 mT) exposure also increased cell death, MN frequency, olive tail moment, and apoptosis induced by Gd treatment alone. These results suggest that Gd induces DNA damage and apoptotic cell death in human lymphocytes and that ELF-EMF enhances the cytotoxicity and genotoxicity of Gd.

An intravascular MRI contrast agent based on Gd(DO3A-Lys) for tumor angiography

An intravascular MRI contrast agent Gd(DO3A-Lys), Gadolinium(III) (2,2′,2″-(10-(3-(5-benzamido-6-methoxy-6-oxohexylamino)-3-oxopropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate), has been studied for tumor angiography based on its high relaxivity and long blood half-life. The preparation procedures of the contrast agent have been modified in order to achieve higher yield and improve the synthetic reproducibility. High relaxivity of Gd(DO3A-Lys) has been confirmed by measurements at 3 T, 7 T and 9.4 T magnetic fields. The relaxivity-dependent albumin binding study indicated that Gd(DO3A-Lys) partially bound to albumin protein. In vitro cell viability in HK2 cell indicated low cytotoxicity of Gd(DO3A-Lys) up to 1.2 mm [Gd] concentration. In vivo toxicity studies demonstrated no toxicity of Gd(DO3A-Lys) on kidney tissues up to 0.2 mm [Gd]. While the toxicity on liver tissue was not observed at low dosage (1.0 mm [Gd]), Gd(DO3A-Lys) cause certain damage on hepatic tissue at high dosage (2.0 mm [Gd]). The DO3A-Lys has been labeled with 68Ga radioisotope for biodistribution studies. 68Ga(DO3A-Lys) has high uptake in both HT1080 and U87MG xenograft tumors, and has high accumulation in blood. Contrast-enhanced MR angiography (CE-MRA) in mice bearing U87MG xenograft tumor demonstrated that Gd(DO3A-Lys) could enhance vascular microenvironment around the tumor, and displays promising characteristics of an MRI contrast agent for tumor angiography.

Gadolinium‐based contrast agents for magnetic resonance cancer imaging

AbstractMagnetic resonance imaging (MRI) is a clinical imaging modality effective for anatomical and functional imaging of diseased soft tissues, including solid tumors. MRI contrast agents (CA) have been routinely used for detecting tumor at an early stage. Gadolinium‐based CA are the most commonly used CA in clinical MRI. There have been significant efforts to design and develop novel Gd(III) CA with high relaxivity, low toxicity, and specific tumor binding. The relaxivity of the Gd(III) CA can be increased by proper chemical modification. The toxicity of Gd(III) CA can be reduced by increasing the agents' thermodynamic and kinetic stability, as well as optimizing their pharmacokinetic properties. The increasing knowledge in the field of cancer genomics and biology provides an opportunity for designing tumor‐specific CA. Various new Gd(III) chelates have been designed and evaluated in animal models for more effective cancer MRI. This review outlines the design and development, physicochemical properties, and in vivo properties of several classes of Gd(III)‐based MR CA tumor imaging. WIREs Nanomed Nanobiotechnol 2013, 5:1–18. doi: 10.1002/wnan.1198This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

Recent Progress of Molecular Imaging Probes Based on Gadofullerenes

Abstract Paramagnetic gadofullerenes and their derivatives exhibit more advantages than commercial Magnevist™ (Gd-DTPA) therefore have become competitive candidates for MR imaging probes. One of the most important properties is the stable fullerene cages are believed to hinder both chemical attacks on the inner clusters and the escape of the toxic lanthanide ions, which should effectively suppress the toxicity of naked Gd 3+ ions. Some functionalized gadofullerides are also available for further conjugation to fabricate multifunctional probes. This review presented the latest findings of MRI imaging probes based on various gadofullerenes, including Gd@C 60 , Gd@C 82 and Gd 3 N@C 80 and discussed the derivative strategy of gadofullerenes determining their relaxivity properties, biodistributions as well as their potential applications as nanoplatform for multifunctional probes.

Biosafety assessment of Gd@C82(OH)22 nanoparticles on Caenorhabditis elegans

Gd@C(82)(OH)(22), a water-soluble endohedral metallofullerene derivative, has been proven to possess significant antineoplastic activity in mice. Toxicity studies of the nanoparticle have shown some evidence of low or non toxicity in mice and cell models. Here we employed Caenorhabditis elegans (C. elegans) as a model organism to further evaluate the short- and long-term toxicity of Gd@C(82)(OH)(22) and possible behavior changes under normal and stress culture conditions. With treatment of Gd@C(82)(OH)(22) at 0.01, 0.1, 1.0 and 10 μg ml(-1) within one generation (short-term), C. elegans showed no significant decrease in longevity or thermotolerance compared to the controls. Furthermore, when Gd@C(82)(OH)(22) treatment was extended up to six generations (long-term), non-toxic effects to the nematodes were found. In addition, data from body length measurement, feeding rate and egg-laying assays with short-term treatment demonstrated that the nanoparticles have no significant impact on the individual growth, feeding behavior and reproductive ability, respectively. In summary, this work has shown that Gd@C(82)(OH)(22) is tolerated well by worms and it has no apparent toxic effects on longevity, stress resistance, growth and behaviors that were observed in both adult and young worms. Our work lays the foundations for further developments of this anti-neoplastic agent for clinical applications.

MRI gadolinium-based contrast agents. Radiologists beware!

Gadolinium (Gd) is used in contrast agents as it enhances magnetic resonance imaging (MRI) signals. To reduce Gd toxicity, it is chelated into linear or macrocyclic complexes. Eight Gd-containing contrast agents have been approved by the European Medicines Agency (EMEA) for use in MRI, and six by the US Food and Drug Administration. Stability depends upon its physicochemical properties. When renal function is normal, the Gd is quickly cleared from the body by the kidneys. For patients with chronic kidney disease, the elimination is greatly reduced and Gd may be released from its chelate and deposit in body tissues, leading to nephrogenic systemic fibrosis (NSF). More than 200 cases of NSF have been reported in the world. NSF is characterized by an extensive fibrosis of skin and tissues, a very severe affection with possible lethal outcome. We propose recommendations to avoid the risk of NSF.

Abstract 3625: Targeted Ultra-Small Iron Oxide Particles for In Vivo MR Detection of Atherosclerotic Lesions Using Antibodies against Oxidized Low Density Lipoprotein

Background: Oxidized low-density lipoprotein (OxLDL) plays a key role in the progression and destabilization of atherosclerotic plaque. Preliminary studies indicate that gadolinium (Gd) micelles labeled with oxidation-specific antibodies allow for specific targeting of vulnerable plaque. Due to issues associated with Gd toxicity (caused by retention and bio-transformation of the micelles), clinical translation of this platform may be limited. Iron oxides are recognized as safe and effective contrast agents for MRI. As a result, it was hypothesized that lipid coated ultra-small iron oxide particles (LUSPIOs) containing murine antibodies that bind malondialde-hyde lysine (MDA2) or oxidized phospholipids (EO6) associated with oxLDL may allow for the development of a safe platform for in vivo detection of vulnerable plaque. Materials and Results: Untargeted, MDA2, and EO6 labeled LUSPIOs were prepared and characterized with respect to efficacy, pharmacokinetics, and biodistribution in Apolipoprotein deficient mice (ApoE−/−). MRI was performed at 9.4T prior to and 24 hrs after LUSPIO administration (4 mg Fe/kg) using both gradient echo and positive contrast GRASP sequences. MDA2 and EO6 increased the particle size, blood half-life, and MR efficacy of the LUSPIOs, relative to untargeted particles. Only limited signal attenuation was observed following administration of untargeted LUSPIO. MRI and microscopy revealed that MDA2 and EO6 LUSPIOs accumulate within oxLDL rich foam cells (Fig.1 ). Conclusions: This study suggests that biocompatible LUSPIOs may provide a clinically translatable platform for the MR detection of oxLDL rich foam cells in humans. This research has received full or partial funding support from the American Heart Association, AHA National Center.

Tissue distribution and kinetics of gadolinium and nephrogenic systemic fibrosis

Gadolinium (Gd) released from Gd-based MR contrast agents is the likely etiologic agent of nephrogenic systemic fibrosis (NSF). The biodistribution and kinetics of both chelated Gd and free Gd 3+ are reviewed, including demonstrations of Gd in tissues of NSF patients. The purpose of this review is to consolidate the available information on distribution, metabolism, excretion and retention of Gd with particular emphasis on the possible mechanisms in the development of NSF. We also raise serious concern about the growing tissue burden of Gd with the release of Gd from its chelates and its yet unknown consequences. The development of NSF as well as potential long-term consequences of tissue Gd retention represent a part of the spectrum of Gd toxicity.

Stability of gadolinium complexes in vitro and in vivo.

Gd(III) toxicity is such that, for in vivo use, the ion must be incorporated into stable, ionically bound complexes with organic chelating agents. Although metal-chelate-based contrast agents have been demonstrated safe in phase I-III studies, their potential toxicities must be considered, particularly in the development of new contrast media. The potential for adverse effects is thought to arise from in vivo dissociation into constituent metal ion and ligand. Release of Gd(III) from ligand may also be facilitated by endogenous metals [e.g., Zn(II)] that compete with Gd(III) for ligand-binding sites. In vivo complex stability toward dissociation depends on several closely balanced characteristics of the metal and ligand that maintain metal-chelate integrity during residence in the body. Among design strategies explored to minimize the potential for in vivo Gd(III) release are the use of ligands that: form Gd(III) complexes with high thermodynamic stabilities; have binding selectivity for Gd(III) over endogenous metal ions; incorporate rigid cyclic structures and form Gd(III) complexes with greater kinetic stabilities than their open-chain homologs; or incorporate slight excess ligand to "scavenge" loosely bound or free endogenous metal ions that might otherwise compete with Gd(III) for ligand binding.