Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration

Davies, Julie; Siebenhandl-Wolff, Petra; Tranquart, F.; Jones, Paul B.; Evans, Paul M.

doi:10.1007/s00204-021-03189-8

Cited by 55 publications

(35 citation statements)

References 227 publications

(373 reference statements)

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“…30 Adult zebrafish GCA excretion rates are unknown; however, they are likely to be similar to or faster than those for rodents (half-life: rat, 18-20 min; mouse, 5-6 min). 31,32 In our study, the GCA concentration and immersion time were not optimized. The immersion time was taken for pragmatic reasons whilst one of the other fish treatment groups was scanned.…”

Section: Discussionmentioning

confidence: 98%

Longitudinal MRI brain studies in live adult zebrafish

2023

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Zebrafish (Danio rerio) has been successfully used for decades in developmental studies and disease modelling. The remarkable uptake of zebrafish as a model system is partly due to its transparency during the early weeks of its development, allowing in vivo imaging of cellular and molecular processes. However, this key advantage wears off when tissues become opaque as the animal reaches juvenile and adult stages, rendering access to tissues for live imaging and longitudinal studies difficult.Here we provide a novel approach to image and assess tissue integrity of adult zebrafish using MRI on live zebrafish suitable for longitudinal studies. We built a 3Dprinted life support chamber and designed a protocol-directed sedation regime to recover adult zebrafish after scanning in a 9.4 T MRI scanner. Our life support chamber is cheap and easy to create using 3D printing, allowing other groups to copy our template for quick setup. Additionally, we optimized the delivery of contrast agent to enhance brain signals in order to refine current delivery, usually delivered intravenously in rodents. We show here that immersion in gadolinium was a viable alternative to intraperitoneal injection to reduce T 1 relaxation times. This resulted in protocol refinement as per the 3Rs guidelines and improved image contrast in adult zebrafish disease models. In conclusion, we provide here a detailed methodology to allow longitudinal studies of brain tissue integrity of adult zebrafish, combining safe and efficient delivery of contrast agent and live MRI. This technique can be used to bridge the gap between in vivo studies and longitudinal brain analysis in adult zebrafish, and can be applied to the ever-growing number of adult zebrafish models of ageing and neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 98%

Longitudinal MRI brain studies in live adult zebrafish

2023

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“…3 Due to the lack of detectable endogenous fluorine in the human body (only present as inorganic fluorine in bones and teeth), 4 19 F-MRI does not suffer of any background signals (signals derive only from the fluorine atoms contained in the used fluorinated tracer), allowing for "hot-spot" images that add secondary independent information (i.e., biodistribution) in addition to the anatomical features provided by the anatomical/morphological 1 H-MRI. The absence of a proper background signal of 19 F-MRI is a strong feature that makes this technique suitable for unbiased localization and tracking of fluorinated probes over time, contrary to what is observed for other 1 H-based standard CAs. For example, superparamagnetic iron oxide nanoparticles (SPIONs) are characterized by poor specificity due to the absence of MRI signal linearity with CA concentration, thus preventing a quantitative and accurate analysis.…”

Section: Introductionmentioning

confidence: 94%

“…), determined the fast development of heteronuclear fluorine, sodium, phosphorus, and other tracers and imaging technologies. 2 The 19 F nucleus with its 100% natural abundance, high gyromagnetic ratio (40.06 MHz/T), wide range of chemical shift (<350 ppm), and 83% sensitivity of 1 H is considered one of the most promising imaging nuclei. Thus, 19 F-MRI emerged as an extremely powerful quantification and tracking technique providing complementary information to 1 H-MRI.…”

Section: Introductionmentioning

confidence: 99%

“…Hydrogen ( 1 H) nuclei in body water are the best target for in vivo MRI because, among all types of nuclei in the body, they provide the highest nuclear MR signal and achieve good contrast between different tissues. However, 1 H-MRI sensitivity issues require the administration of high concentrations of contrast agents (CA), possibly causing toxicity concerns, as recently emerged for gadolinium (Gd 3+ )-based ones. 1 Moreover, the urgent need to localize complex molecular activities in vivo, as well as track and quantify targets of biological interest (i.e., drugs, nanoparticles, etc.…”

Section: Introductionmentioning

confidence: 99%

“…However, 1 H-MRI sensitivity issues require the administration of high concentrations of contrast agents (CA), possibly causing toxicity concerns, as recently emerged for gadolinium (Gd 3+ )-based ones. 1 Moreover, the urgent need to localize complex molecular activities in vivo, as well as track and quantify targets of biological interest (i.e., drugs, nanoparticles, etc. ), determined the fast development of heteronuclear fluorine, sodium, phosphorus, and other tracers and imaging technologies.…”

Section: Introductionmentioning

confidence: 99%

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Multibranched-Based Fluorinated Materials: Tailor-Made Design of ¹⁹F-MRI Probes

et al. 2022

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Conspectus Future medicine is primarily aiming at the development of novel approaches for an early diagnosis of diseases and a personalized therapy for patients. For achieving these objectives, a key role is played by medical imaging. Among available noninvasive imaging techniques, Fluorine-19 (19F) Magnetic Resonance Imaging (MRI) is emerging as a powerful quantitative detection modality for clinical use both for molecular imaging and for cell tracking. The strength of using 19F-MRI is mainly related to the lack of endogenous organic fluorine in tissues, with no background, enabling the visualization of fluorinated tracers as hot-spot images, adding secondary independent information to the anatomical features provided by the grayscale 1H-MRI. The main challenge for 19F-MRI clinical application is the intrinsic reduced sensitivity of MRI. To improve sensitivity, undoubtedly the use of a high field MRI scanner and cryogenic radiofrequency probes is advantageous, but there is a clear need of developing increasingly effective fluorinated tracers. The ideal tracer should bear as many as possible magnetically equivalent fluorine atoms and show optimal magnetic resonance relaxivity properties (i.e., T 1 and T 2), which enable reduced acquisition time with the possibility to apply fast imaging methods. Moreover, it should be biocompatible with reduced tendency to bioaccumulate in tissues, which is one of the main drawbacks in using perfluorocarbons (PFCs), together with their difficulty to be chemically modified with functional groups. In fact, PFCs such as perfluorooctyl bromide (PFOB), perfluoro-15-crown-5-ether (PFCE), and linear perfluoropolyethers (PFPE) are currently the most used tracers in 19F-MRI preclinical and clinical studies, with the above-mentioned limitations. In this regard, molecules bearing short branched fluorinated chains gained a lot of attention for their high number of equivalent fluorines and expected capability of reducing bioaccumulation concerns. A valuable building block for branched fluorinated tracers is perfluoro-tert-butanol (PFTB), with nine magnetically equivalent fluorines and easy availability and modification. In this Account we will discuss the main challenges that 19F-MRI has to overcome for increasing its clinical use, highlighting on one hand the need of developing customized fluorinated materials for increasing sensitivity and enabling multimodal properties, and on the other hand, the importance of the ultrastructure of the final formulation for the final biological response (i.e., clearance). In this context, our group has been focusing on the synthesis and development of branched fluorinated tracers, for which the originator is a molecule called PERFECTA (from suPERFluorinatEdContrasT Agent), bearing 36 equiv 19F atoms, which showed not only optimal relaxometry properties but also a very specific and intense Raman signal. Thus, PERFECTA and its derivatives represent a new family of multimodal tracers enabling multiscale analysis, from whole body imaging (19F-MRI) to microsco...

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Structurally Optimized Fluorinated Small‐Sized Graphene Oxide for Enhanced Magnetic Resonance Imaging during Pregnancy

Xu,

Chen,

Wang

et al. 2023

Adv Funct Materials

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Gadolinium‐based complex contrast agents (GBCAs), frequently applied in magnetic resonance imaging (MRI), are associated with severe acute anaphylactic shock and incurable nephrogenic systemic fibrosis. Besides, the repeated use of GBCAs may result in the accumulation in various tissues. Given these potential adverse effects, GBCAs have not been well used during pregnancy. Herein, a novel metal‐free T2‐weighted MRI nanoprobe, designated fluorinated small‐sized graphene oxide with optimized fluorine content (LF‐sGO), is developed via graphene oxide materials. By introducing specific polar C─F bonds onto the small‐sized graphene oxide (sGO) skeleton, the prepared nanoprobe exhibits excellent water solubility, as well as superior MRI capabilities, thereby furnishing high‐resolution MRI anatomical information. Furthermore, the free radicals on LF‐sGO stabilized by C─F bonds confer LF‐sGO enrichment in the tumor region, enabling comprehensive imaging capability. The cytotoxicity study in vitro indicates that LF‐sGO has the potential to serve as a biocompatible imaging probe. Moreover, detailed in vivo studies on pregnant mice and zebrafish adequately demonstrate that microinjection of LF‐sGO does not induce dysontogensis and teratogenesis. This study successfully showcases a metal‐free nanoprobe that exhibits exceptional MRI capabilities for the purpose of tumor diagnosis. Notably, this nanoprobe holds promise for safe and effective tumor diagnosis during pregnancy.

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Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration

Cited by 55 publications

References 227 publications

Longitudinal MRI brain studies in live adult zebrafish

Longitudinal MRI brain studies in live adult zebrafish

Multibranched-Based Fluorinated Materials: Tailor-Made Design of ¹⁹F-MRI Probes

Structurally Optimized Fluorinated Small‐Sized Graphene Oxide for Enhanced Magnetic Resonance Imaging during Pregnancy

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Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration

Cited by 55 publications

References 227 publications

Longitudinal MRI brain studies in live adult zebrafish

Longitudinal MRI brain studies in live adult zebrafish

Multibranched-Based Fluorinated Materials: Tailor-Made Design of 19F-MRI Probes

Structurally Optimized Fluorinated Small‐Sized Graphene Oxide for Enhanced Magnetic Resonance Imaging during Pregnancy

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Multibranched-Based Fluorinated Materials: Tailor-Made Design of ¹⁹F-MRI Probes