How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo

Quyen, N.; Lenkinski, Robert E.; Tircsó, Gyula

doi:10.3390/molecules27010058

Cited by 14 publications

(16 citation statements)

References 149 publications

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“…The kinetic inertness combined with the thermodynamic stability is a good predictor for in vivo complex stability. 33 The ion exchange ICP-MS analytical investigation of the Gd complexes before and after 3 weeks incubation with human serum reflects both the kinetic inertness and the thermodynamic stability under physiological conditions. Gadoquatrane showed no release of Gd 3+ within 3 weeks at 37°C in pooled human serum, and the complex stability of gadoquatrane was in the same range to other macrocyclic ( q = 1) GBCAs.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Profile of Gadoquatrane

Lohrke¹,

Berger

Frenzel³

et al. 2022

Invest Radiol

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Objectives The aim of this report was to characterize the key physicochemical, pharmacokinetic (PK), and magnetic resonance imaging (MRI) properties of gadoquatrane (BAY 1747846), a newly designed tetrameric, macrocyclic, extracellular gadolinium-based contrast agent (GBCA) with high relaxivity and stability. Materials and Methods The r1-relaxivities of the tetrameric gadoquatrane at 1.41 and 3.0 T were determined in human plasma and the nuclear magnetic relaxation dispersion profiles in water and plasma. The complex stability was analyzed in human serum over 21 days at pH 7.4 at 37°C and was compared with the linear GBCA gadodiamide and the macrocyclic GBCA (mGBCA) gadobutrol. In addition, zinc transmetallation assay was performed to investigate the kinetic inertness. Protein binding and the blood-to-plasma ratio were determined in vitro using rat and human plasma. The PK profile was evaluated in rats (up to 7 days postinjection). Magnetic resonance imaging properties were investigated using a glioblastoma (GS9L) rat model. Results The new chemical entity gadoquatrane is a macrocyclic tetrameric Gd complex with one inner sphere water molecule per Gd ( q = 1). Gadoquatrane showed high solubility in buffer (1.43 mol Gd/L, 10 mM Tris-HCl, pH 7.4), high hydrophilicity (logP −4.32 in 1-butanol/water), and negligible protein binding. The r1-relaxivity of gadoquatrane in human plasma per Gd of 11.8 mM −1 ·s −1 (corresponding to 47.2 mM −1 ·s −1 per molecule at 1.41 T at 37°C, pH 7.4) was more than 2-fold (8-fold per molecule) higher compared with established mGBCAs. Nuclear magnetic relaxation dispersion profiles confirmed the more than 2-fold higher r1-relaxivity in human plasma for the clinically relevant magnetic field strengths from 0.47 to 3.0 T. The complex stability of gadoquatrane at physiological conditions was very high. The observed Gd release after 21 days at 37°C in human serum was below the lower limit of quantification. Gadoquatrane showed no Gd 3+ release in the presence of zinc in the transmetallation assay. The PK profile (plasma elimination, biodistribution, recovery) was comparable to that of gadobutrol. In MRI, the quantitative evaluation of the tumor-to-brain contrast in the rat glioblastoma model showed significantly improved contrast enhancement using gadoquatrane compared with gadobutrol at the same Gd dose administered (0.1 mmol Gd/kg body weight). In comparison to gadoterate meglumine, similar contrast enhancement was reached with gadoquatrane with 75% less Gd dose. In terms of the molecule dose, this was reduced by 90% when compared with gadoterate meglumine. Because of its tetrameric structure and hence lower number of molecules per volume, all prepared formulations of gadoquatrane were iso-osmolar to blood. Conclusions The tetrameric...

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Section: Discussionmentioning

confidence: 99%

Preclinical Profile of Gadoquatrane

Lohrke¹,

Berger

Frenzel³

et al. 2022

Invest Radiol

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“…The diagnostic application of GBCAs is currently considered largely safe in patients with normal renal function. However, after repeated administration of mainly linear GBCAs, retention of gadolinium (Gd) within different organs was reported to occur in patients without renal impairment 2,3 . This resulted in restrictions on the use of linear GBCAs by the European Medicines Agency (EMA/625317/2017) 4 and class warnings by the US Food and Drug Administration 5…”

mentioning

confidence: 99%

“…However, after repeated administration of mainly linear GBCAs, retention of gadolinium (Gd) within different organs was reported to occur in patients without renal impairment. 2,3 This resulted in restrictions on the use of linear GBCAs by the European Medicines Agency (EMA/625317/2017) 4 and class warnings by the US Food and Drug Administration. 5 Within central nervous system (CNS) structures, Kanda et al 6 revealed for the first time a positive correlation between previous administrations of linear GBCAs and T1 hyperintensities in unenhanced brain MRI scans, in particular in the dentate nucleus (DN).…”

mentioning

confidence: 99%

Different Impact of Gadopentetate and Gadobutrol on Inflammation-Promoted Retention and Toxicity of Gadolinium Within the Mouse Brain

Anderhalten

Silva²,

Morr

et al. 2022

Invest Radiol

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Objectives Using a murine model of multiple sclerosis, we previously showed that repeated administration of gadopentetate dimeglumine led to retention of gadolinium (Gd) within cerebellar structures and that this process was enhanced with inflammation. This study aimed to compare the kinetics and retention profiles of Gd in inflamed and healthy brains after application of the macrocyclic Gd-based contrast agent (GBCA) gadobutrol or the linear GBCA gadopentetate. Moreover, potential Gd-induced neurotoxicity was investigated in living hippocampal slices ex vivo. Materials and Methods Mice at peak of experimental autoimmune encephalomyelitis (EAE; n = 29) and healthy control mice (HC; n = 24) were exposed to a cumulative dose of 20 mmol/kg bodyweight of either gadopentetate dimeglumine or gadobutrol (8 injections of 2.5 mmol/kg over 10 days). Magnetic resonance imaging (7 T) was performed at baseline as well as at day 1, 10, and 40 post final injection (pfi) of GBCAs. Mice were sacrificed after magnetic resonance imaging and brain and blood Gd content was assessed by laser ablation-inductively coupled plasma (ICP)-mass spectrometry (MS) and ICP-MS, respectively. In addition, using chronic organotypic hippocampal slice cultures, Gd-induced neurotoxicity was addressed in living brain tissue ex vivo, both under control or inflammatory (tumor necrosis factor α [TNF-α] at 50 ng/μL) conditions. Results Neuroinflammation promoted a significant decrease in T1 relaxation times after multiple injections of both GBCAs as shown by quantitative T1 mapping of EAE brains compared with HC. This corresponded to higher Gd retention within the EAE brains at 1, 10, and 40 days pfi as determined by laser ablation-ICP-MS. In inflamed cerebellum, in particular in the deep cerebellar nuclei (CN), elevated Gd retention was observed until day 40 after last gadopentetate application (CN: EAE vs HC, 55.06 ± 0.16 μM vs 30.44 ± 4.43 μM). In contrast, gadobutrol application led to a rather diffuse Gd content in the inflamed brains, which strongly diminished until day 40 (CN: EAE vs HC, 0.38 ± 0.08 μM vs 0.17 ± 0.03 μM). The analysis of cytotoxic effects of both GBCAs using living brain tissue revealed an elevated cell death rate after incubation with gadopentetate but not gadobutrol at 50 mM. The cytotoxic effect due to gadopentetate increased in the presence of the inflammatory mediator TNF-α (with vs without TNF-α, 3.15% ± 1.18% vs 2.17% ± 1.14%; P = 0.0345). Conclusions In the EAE model, neuroinflammation promoted increased Gd retention in the brain for both GBCAs. Whereas in the inflamed brains, efficient clearance of macrocyclic gadobutrol during the investigated time period was observed, the Gd retention after application of linear gadopentetate persisted over the entire observational period. Gadopentetate but not gadubutrol appeared to be neurotoxic in an ex vivo paradigm of neuronal inflammation.

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“…However, when using these systems, potential toxic effects of the gadolinium salts should be considered as well as effects of the strong magnetic field and its gradient that are described above. Gadolinium derivatives are widely used as contrast agents in magnetic resonance imaging (MRI) techniques so their toxicity has been extensively studied [61][62][63]. An ability of the Gd 3+ to compete with Ca 2+ in active centers of Ca 2+ -binding enzymes underlies gadolinium toxicity because Ca 2+ substitution with Gd 3+ can interrupt critically important Ca 2+ -dependent pathways [61].…”

Section: Maglev Systems Based On Permanent Magnetsmentioning

confidence: 99%

“…Gadolinium derivatives are widely used as contrast agents in magnetic resonance imaging (MRI) techniques so their toxicity has been extensively studied [61][62][63]. An ability of the Gd 3+ to compete with Ca 2+ in active centers of Ca 2+ -binding enzymes underlies gadolinium toxicity because Ca 2+ substitution with Gd 3+ can interrupt critically important Ca 2+ -dependent pathways [61]. To decrease toxicity, gadolinium-based substances, which are used in MRI, enclose Gd 3+ in the complex that is expected to remain chelated in the human body and be excreted intact.…”

Section: Maglev Systems Based On Permanent Magnetsmentioning

confidence: 99%

Experimentally Created Magnetic Force in Microbiological Space and On-Earth Studies: Perspectives and Restrictions

Sа¹,

Parfenov

Каралкин

et al. 2023

Cells

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Magnetic force and gravity are two fundamental forces affecting all living organisms, including bacteria. On Earth, experimentally created magnetic force can be used to counterbalance gravity and place living organisms in conditions of magnetic levitation. Under conditions of microgravity, magnetic force becomes the only force that moves bacteria, providing an acceleration towards areas of the lowest magnetic field and locking cells in this area. In this review, we consider basic principles and experimental systems used to create a magnetic force strong enough to balance gravity. Further, we describe how magnetic levitation is applied in on-Earth microbiological studies. Next, we consider bacterial behavior under combined conditions of microgravity and magnetic force onboard a spacecraft. At last, we discuss restrictions on applications of magnetic force in microbiological studies and the impact of these restrictions on biotechnological applications under space and on-Earth conditions.

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How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo

Cited by 14 publications

References 149 publications

Preclinical Profile of Gadoquatrane

Preclinical Profile of Gadoquatrane

Different Impact of Gadopentetate and Gadobutrol on Inflammation-Promoted Retention and Toxicity of Gadolinium Within the Mouse Brain

Experimentally Created Magnetic Force in Microbiological Space and On-Earth Studies: Perspectives and Restrictions

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