Retention of Gadolinium in Brain Parenchyma: Pathways for Speciation, Access, and Distribution. A Critical Review.

The unexpected appearance of T1 hyperintensities, mostly in the dentate nucleus and the globus pallidus, during nonenhanced MRI was reported in 2014. This effect is associated with prior repeated administrations of gadolinium (Gd)-based contrast agents (GBCAs) in patients with a functional blood-brain barrier (BBB). It is widely assumed that GBCAs do not cross the intact BBB, but the observation of these hypersignals raises questions regarding this assumption. This review critically discusses the mechanisms of Gd accumulation in the brain with regard to access pathways, Gd species, tissue distribution, and subcellular location. We propose the hypothesis that there is early access of Gd species to cerebrospinal fluid, followed by passive diffusion into the brain parenchyma close to the cerebral ventricles. When accessing areas rich in endogenous metals or phosphorus, the less kinetically stable GBCAs would dissociate, and Gd would bind to endogenous macromolecules, and/or precipitate within the brain tissue. It is also proposed that Gd species enter the brain parenchyma along penetrating cortical arteries in periarterial pial-glial basement membranes and leave the brain along intramural peri-arterial drainage (IPAD) pathways. Lastly, Gd/GBCAs may access the brain parenchyma directly from the blood through the BBB in the walls of capillaries. It is crucial to distinguish between the physiological distribution and drainage pathways for GBCAs and the possible dissociation of less thermodynamically/kinetically stable GBCAs that lead to long-term Gd deposition in the brain. LEVEL OF EVIDENCE: 5. TECHNICAL EFFICACY STAGE: 3.

One-year Retention of Gadolinium in the Brain: Comparison of Gadodiamide and Gadoterate Meglumine in a Rodent Model.

Purpose To compare the long-term brain elimination kinetics and gadolinium species in healthy rats after repeated injections of the contrast agents gadodiamide (a linear contrast agent) or gadoterate (a macrocyclic contrast agent). Materials and Methods Nine-week-old rats received five doses of 2.4 mmol gadolinium per kilogram of body weight over 5 weeks and were followed for 12 months with T1-weighted MRI (n = 140 rats, corresponding to seven time points, two contrast agents, and 10 rats per group). Animals were sacrificed at 1 week, 1 month, and 2, 3, 4, 5, and 12 months after the last injection. Brain and plasma were sampled to determine the total gadolinium concentration by using inductively coupled plasma mass spectrometry (ICP-MS). For the cerebellum, gadolinium speciation analysis was performed after mild extraction at four time points (1 month and 3, 5, and 12 months after the last injection) by using size exclusion chromatography and hydrophilic interaction liquid chromatography, both coupled to ICP-MS. Tissue gadolinium kinetics were fitted to estimate the area under the curves and tissue elimination half-lives over the 12-month injection-free period. Results T1 hyperintensity of the deep cerebellar nuclei was observed only in gadodiamide-treated rats and remained stable from the 1st month after the last injection (the ratio of the signal intensity of the deep cerebellar nuclei to the signal intensity of the brain stem at 1 year: 1.101 ± 0.023 vs 1.037 ± 0.022 before injection, P < .001). Seventy-five percent of the total gadolinium detected after the last injection of gadodiamide (3.25 nmol/g ± 0.30) was retained in the cerebellum at 1 year (2.45 nmol/g ± 0.35), with binding of soluble gadolinium to macromolecules. No T1 hyperintensity was observed with gadoterate, consistent with a rapid, time-dependent washout of the intact gadolinium chelate down to background levels (0.07 nmol/g ± 0.03). Conclusion After repeated administration of gadodiamide, a large portion of gadolinium was retained in the brain, with binding of soluble gadolinium to macromolecules. After repeated injection of gadoterate, only traces of the intact chelated gadolinium were observed with time-dependent clearance. Online supplemental material is available for this article.

Transcatheter embolization therapy in liver cancer: an update of clinical evidences.

Transarterial chemoembolization (TACE) is a form of intra-arterial catheter-based chemotherapy that selectively delivers high doses of cytotoxic drug to the tumor bed combining with the effect of ischemic necrosis induced by arterial embolization. Chemoembolization and radioembolization are at the core of the treatment of liver hepatocellular carcinoma (HCC) patients who cannot receive potentially curative therapies such as transplantation, resection or percutaneous ablation. TACE for liver cancer has been proven to be useful in local tumor control, to prevent tumor progression, prolong patients' life and control patient symptoms. Recent evidence showed in patients with single-nodule HCC of 3 cm or smaller without vascular invasion, the 5-year overall survival (OS) with TACE was similar to that with hepatic resection and radiofrequency ablation. Although being used for decades, Lipiodol(®) (Lipiodol(®) Ultra Fluid(®), Guerbet, France) remains important as a tumor-seeking and radio-opaque drug delivery vector in interventional oncology. There have been efforts to improve the delivery of chemotherapeutic agents to tumors. Drug-eluting bead (DEB) is a relatively novel drug delivery embolization system which allows for fixed dosing and the ability to release the anticancer agents in a sustained manner. Three DEBs are available, i.e., Tandem(®) (CeloNova Biosciences Inc., USA), DC-Beads(®) (BTG, UK) and HepaSphere(®) (BioSphere Medical, Inc., USA). Transarterial radioembolization (TARE) technique has been developed, and proven to be efficient and safe in advanced liver cancers and those with vascular complications. Two types of radioembolization microspheres are available i.e., SIR-Spheres(®) (Sirtex Medical Limited, Australia) and TheraSphere(®) (BTG, UK). This review describes the basic procedure of TACE, properties and efficacy of some chemoembolization systems and radioembolization agents which are commercially available and/or currently under clinical evaluation. The key clinical trials of transcatheter arterial therapy for liver cancer are summarized.

The role of gadolinium chelates in the mechanism of nephrogenic systemic fibrosis: A critical update.

Nephrogenic systemic fibrosis (NSF) is an iatrogenic scleroderma-like fibrosing systemic disorder occurring in patients with severe or end-stage renal disease. It was established as a new clinical entity in the year 2000. A causal role for gadolinium chelates (GC), widely used as contrast agents for magnetic resonance imaging, was suggested six years later. It rapidly appeared that the occurrence of NSF was associated with prior administration of GCs with lower thermodynamic stability, leading to warnings being published by health authorities and learned societies worldwide. Although a role for the chelated form of the less stable GCs has been proposed, the most commonly accepted hypothesis involves the gradual release of dissociated gadolinium in the body, leading to systemic fibrosis. However, the entire chain of events is still not fully understood in a causal way and many uncertainties remain.

Skin gadolinium following use of MR contrast agents in a rat model of nephrogenic systemic fibrosis.

PURPOSE: To detect the ultrastructural site of gadolinium retention in skin by using an animal model of nephrogenic systemic fibrosis and compare a linear, low-stability gadolinium chelate (formulated gadodiamide) with a macrocylic, high-stability gadolinium chelate (gadoterate meglumine). MATERIALS AND METHODS: Experimental procedures were performed according to rules and regulations laid down by the UK Home Office (Animal Procedures Act of 1986). Male Wistar rats were subjected to 5/6 subtotal nephrectomy (creatinine clearance, 25% normal). Gadolinium-based contrast agents, formulated gadodiamide (n = 9) and gadoterate meglumine (n = 11), were administered intravenously (2.5 mmol/kg for 5 days). After 28 days, skin was analyzed by means of morphometric and immunohistochemical techniques and electron microscopy. Data were compared with the Student t test. Skin gadolinium was located by means of energy-filtered transmission electron microscopy. RESULTS: Formulated gadodiamide produced a 40-fold greater increase in gadolinium in skin than did gadoterate meglumine. An electron-dense filamentous material, detected within extracellular matrix, displayed a "halo" appearance, associated with collagen fibrils and electron-dense intracellular fragments of collagen fibrils within activated fibroblasts. Both electron-dense features demonstrated the presence of gadolinium but were much less apparent following gadoterate meglumine administration, where the presence of gadolinium was not detected. Formulated gadodiamide increased dermal cell count, dermal thickness, and collagen bundle density with enhanced immunostain for CD34, fibroblast-specific protein 1,4-hydroxy-prolyl-hydroxylase, and factor XIIIa. Circular staining for α-smooth muscle actin indicated new blood vessel formation. Skin of rats receiving gadoterate meglumine remained unchanged. CONCLUSION: Gadolinium retention in skin following formulated gadodiamide administration was located to the collagen fibril, in both the extracellular matrix and within activated fibroblasts.

Small Brain Lesion Enhancement and Gadolinium Deposition in the Rat Brain: Comparison Between Gadopiclenol and Gadobenate Dimeglumine.

OBJECTIVES: The aim of the set of studies was to compare gadopiclenol, a new high relaxivity gadolinium (Gd)-based contrast agent (GBCA) to gadobenate dimeglumine in terms of small brain lesion enhancement and Gd retention, including T1 enhancement in the cerebellum. MATERIALS AND METHODS: In a first study, T1 enhancement at 0.1 mmol/kg body weight (bw) of gadopiclenol or gadobenate dimeglumine was evaluated in a small brain lesions rat model at 2.35 T. The 2 GBCAs were injected in an alternated and cross-over manner separated by an interval of 4.4 ± 1.0 hours (minimum, 3.5 hours; maximum, 6.1 hours; n = 6). In a second study, the passage of the GBCAs into cerebrospinal fluid (CSF) was evaluated by measuring the fourth ventricle T1 enhancement in healthy rats at 4.7 T over 23 minutes after a single intravenous (IV) injection of 1.2 mmol/kg bw of gadopiclenol or gadobenate dimeglumine (n = 6/group). In a third study, Gd retention at 1 month was evaluated in healthy rats who had received 20 IV injections of 1 of the 2 GBCAs (0.6 mmol/kg bw) or a similar volume of saline (n = 10/group) over 5 weeks. T1 enhancement of the deep cerebellar nuclei (DCN) was assessed by T1-weighted magnetic resonance imaging at 2.35 T, performed before the injection and thereafter once a week up to 1 month after the last injection. Elemental Gd levels in central nervous system structures, in muscle and in plasma were determined by inductively coupled plasma mass spectrometry (ICP-MS) 1 month after the last injection. RESULTS: The first study in a small brain lesion rat model showed a ≈2-fold higher number of enhanced voxels in lesions with gadopiclenol compared with gadobenate dimeglumine. T1 enhancement of the fourth ventricle was observed in the first minutes after a single IV injection of gadopiclenol or gadobenate dimeglumine (study 2), resulting, in the case of gadopiclenol, in transient enhancement during the injection period of the repeated administrations study (study 3). In terms of Gd retention, T1 enhancement of the DCN was noted in the gadobenate dimeglumine group during the month after the injection period. No such enhancement of the DCN was observed in the gadopiclenol group. Gadolinium concentrations 1 month after the injection period in the gadopiclenol group were slightly increased in plasma and lower by a factor of 2 to 3 in the CNS structures and muscles, compared with gadobenate dimeglumine. CONCLUSIONS: In the small brain lesion rat model, gadopiclenol provides significantly higher enhancement of brain lesions compared with gadobentate dimeglumine at the same dose. After repeated IV injections, as expected for a macrocyclic GBCA, Gd retention is minimalized in the case of gadopiclenol compared with gadobenate dimeglumine, resulting in no T1 hypersignal in the DCN.

The role of phosphate on Omniscan(®) dechelation: an in vitro relaxivity study at pH 7.

Nephrogenic systemic fibrosis (NSF), a disease occurring in patients with severe renal failure, may be linked to injections of gadolinium chelates, contrast agents used for magnetic resonance imaging. A hypothesis frequently proposed to explain NSF is dissociation of Gd(3+) from its chelate, possibly from a deep storage compartment. Numerous in vivo and in vitro studies have been performed in an attempt to determine the extent of this dechelation and to understand its mechanism. Proton-assisted dechelation and transmetallation are the most widely described mechanisms of dechelation. This study investigated the possible ligand exchange role played by phosphate in the dechelation mechanism. Omniscan(®) dechelation was monitored in vitro by relaxivity measurements performed at physiological pH with different concentrations of phosphate buffer and in the presence of endogenous cations. Dechelation experiments performed on phosphate buffer alone showed that phosphate may induce gadolinium release by ligand exchange when the phosphate concentration in the buffer is higher than 130 mM for an Omniscan(®) concentration of 1.25 mM. This corresponds to a Gd/phosphate ratio of 10(-2). This ratio could be reached in vivo, especially in deep compartments such as bone. The presence of endogenous cations (Zn(2+), Cu(2+) or Ca(2+)) has also been demonstrated to accelerate the kinetics of gadolinium release, either by catalysing ligand exchange or by inducing a transmetallation mechanism. The Omniscan(®) formulation was also tested and the added Ca-DTPA-BMA was shown to increase dechelation kinetics in these experiments. This striking result may question the value of the Omniscan(®) formulation in the context of NSF.

Safety and Gadolinium Distribution of the New High-Relaxivity Gadolinium Chelate Gadopiclenol in a Rat Model of Severe Renal Failure.

OBJECTIVE: The aim of this study was to investigate the toxicological profile of gadopiclenol, a new high-relaxivity macrocyclic gadolinium-based contrast agent (GBCA), in renally impaired rats, in comparison with 2 other macrocyclic GBCAs, gadoterate meglumine and gadobutrol, and 1 linear and nonionic GBCA, gadodiamide. METHODS: Renal failure was induced by adding 0.75% wt/wt adenine to the diet for 3 weeks. During the second week of adenine-enriched diet, the animals (n = 8/group × 5 groups) received 5 consecutive intravenous injections of GBCA at 2.5 mmol/kg per injection, resulting in a cumulative dose of 12.5 mmol/kg or saline followed by a 3-week treatment-free period after the last injection. The total (elemental) gadolinium (Gd) concentration in different tissues (brain, cerebellum, femoral epiphysis, liver, skin, heart, kidney, spleen, plasma, urine, and feces) was measured by inductively coupled plasma mass spectrometry. Transmission electron microscopy (and electron energy loss spectroscopy analysis of metallic deposits) was used to investigate the presence and localization of Gd deposits in the skin. Relaxometry was used to evaluate the presence of dissociated Gd in the skin, liver, and bone. Skin histopathology was performed to investigate the presence of nephrogenic systemic fibrosis-like lesions. RESULTS: Gadodiamide administrations were associated with high morbidity-mortality but also with macroscopic and microscopic skin lesions in renally impaired rats. No such effects were observed with gadopiclenol, gadoterate, or gadobutrol. Overall, elemental Gd concentrations were significantly higher in gadodiamide-treated rats than in rats treated with the other GBCAs for all tissues except the liver (where no significant difference was found with gadopiclenol) and the kidney and the heart (where statistically similar Gd concentrations were observed for all GBCAs). No plasma biochemical abnormalities were observed with gadopiclenol or the control GBCAs. Histopathology revealed a normal skin structure in the rats treated with gadopiclenol, gadoterate, and gadobutrol, contrary to those treated with gadodiamide. No evidence of Gd deposits on collagen fibers and inclusions in fibroblasts was found with gadopiclenol and its macrocyclic controls, unlike with gadodiamide. Animals of all test groups had Gd-positive lysosomal inclusions in the dermal macrophages. However, the textures differed for the different products (speckled texture for gadodiamide and rough-textured appearance for the 2 tested macrocyclic GBCAs). CONCLUSIONS: No evidence of biochemical toxicity or pathological abnormalities of the skin was observed, and similar to other macrocyclic GBCAs, gadoterate and gadobutrol, tissue retention of Gd was found to be low (except in the liver) in renally impaired rats treated with the new high-relaxivity GBCA gadopiclenol.

Transmission electron microscopy of lipid vesicles for drug delivery: comparison between positive and negative staining.

Lipid-containing nanostructures, in the form of solid lipid nanoparticles or iron oxide nanoparticles (NPs) coated with a lipid shell, were used as case studies for assessing and optimizing staining for transmission electron microscopy structural and compositional characterization. These systems are of paramount importance as drug delivery systems or as bio-compatible contrast agents. In particular, we have treated the systems with a negative (phospshotungstic acid) or with a positive (osmium tetroxide) staining agent. For iron-oxide NPs coated with the lipid shell, negative staining was more efficient with respect to the positive one. Nevertheless, in particular cases the combination of the two staining procedures provided more complete morphological and compositional characterization of the particles.

Role of thermodynamic and kinetic parameters in gadolinium chelate stability.

In recent years there has been a renewed interest in the physicochemical properties of gadolinium chelates (GC). The aim of this review is to discuss the physicochemical properties of marketed GC with regard to possible biological consequences. GC can be classified according to three key molecular features: 1) the nature of the chelating moiety: either macrocyclic molecules in which Gd(3+) is caged in the preorganized cavity of the ligand, or linear, open-chain molecules; 2) ionicity: the ionicity of the molecule varies from neutral to tri-anionic agents; and 3) the presence or absence of an aromatic lipophilic moiety, which has a profound impact on the biodistribution of the GC. These parameters can also explain why GC differ considerably with regard to their thermodynamic stability constants and kinetic stability, as demonstrated by numerous studies. The concept of thermodynamic and kinetic stability is critically discussed, as it remains somewhat controversial, especially in predicting the amount of free gadolinium that may result from decomplexation of chelates in physiologic or pathologic situations. This review examines the possibility that the high kinetic stability provided by the macrocyclic structure combined with a high thermodynamic stability (reinforced by ionicity for macrocyclic chelates) can minimize the amount of free Gd(3+) released in the body. J. Magn. Reson. Imaging 2009;30:1249-1258. (c) 2009 Wiley-Liss, Inc.

Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?: A Comparative Gadoterate Versus Gadodiamide Study in Juvenile and Adult Rats.

OBJECTIVES: The main objective of the study was to assess the effect of age on target tissue total gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective was to assess the potential developmental and long-term consequences of GBCA administration during neonatal and juvenile periods. MATERIALS AND METHODS: A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either gadoterate or gadodiamide were administered concurrently by the intravenous route to healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the blood-brain barrier is functional as in humans after birth. The tests were conducted on 5 juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats. Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats were characterized by histopathological examination (including immunohistochemistry for glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by fluorescence microscopy. All tests were performed blindly on randomized animals. RESULTS: Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in adult rats having received gadodiamide. Persisting (up to completion of the study) T1 hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem ratio was observed in adult rats compared with juvenile rats, whereas no difference was noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in the gadodiamide-treated groups than in the gadoterate groups. No age-related differences were observed except in bone marrow where total Gd concentrations in gadodiamide-treated juvenile rats were higher than those measured in adults and similar to those measured in cortical bone tissue. No significant treatment-related effects were observed in histopathological findings or in development, behavior, and biochemistry parameters. However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the balance beam test, a high number of trials were excluded in the gadodiamide group because rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic effect. CONCLUSIONS: No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide. Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect, whereas Gd distribution in bone marrow was influenced by age. Further studies are required to assess the form of the retained Gd and to investigate the potential risks associated with Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of age, total Gd concentration in the brain and bone was 10- to 30-fold higher after administration of gadodiamide compared with gadoterate.

Physicochemical and Pharmacokinetic Profiles of Gadopiclenol: A New Macrocyclic Gadolinium Chelate With High T1 Relaxivity.

OBJECTIVES: We aimed to evaluate gadopiclenol, a newly developed extracellular nonspecific macrocyclic gadolinium-based contrast agent (GBCA) having high relaxivity properties, which was designed to increase lesion detection and characterization by magnetic resonance imaging. METHODS: We described the molecular structure of gadopiclenol and measured the r1 and r2 relaxivity properties at fields of 0.47 and 1.41 T in water and human serum. Nuclear magnetic relaxation dispersion profile measurements were performed from 0.24 mT to 7 T. Protonation and complexation constants were determined using pH-metric measurements, and we investigated the acid-assisted dissociation of gadopiclenol, gadodiamide, gadobutrol, and gadoterate at 37°C and pH 1.2. Applying the relaxometry technique (37°C, 0.47 T), we investigated the risk of dechelation of gadopiclenol, gadoterate, and gadodiamide in the presence of ZnCl2 (2.5 mM) and a phosphate buffer (335 mM). Pharmacokinetics studies of radiolabeled Gd-gadopiclenol were performed in Beagle dogs, and protein binding was measured in rats, dogs, and humans plasma and red blood cells. RESULTS: Gadopiclenol [gadolinium chelate of 2,2',2″-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid); registry number 933983-75-6] is based on a pyclen macrocyclic structure. Gadopiclenol exhibited a very high relaxivity in water (r1 = 12.2 mM·s at 1.41 T), and the r1 value in human serum at 37°C did not markedly change with increasing field (r1 = 12.8 mM·s at 1.41 T and 11.6 mM·s at 3 T). The relaxivity data in human serum did not indicate protein binding. The nuclear magnetic relaxation dispersion profile of gadopiclenol exhibited a high and stable relaxivity in a strong magnetic field. Gadopiclenol showed high kinetic inertness under acidic conditions, with a dissociation half-life of 20 ± 3 days compared with 4 ± 0.5 days for gadoterate, 18 hours for gadobutrol, and less than 5 seconds for gadodiamide and gadopentetate. The pharmacokinetic profile in dogs was typical of extracellular nonspecific GBCAs, showing distribution in the extracellular compartment and no metabolism. No protein binding was found in rats, dogs, and humans. CONCLUSIONS: Gadopiclenol is a new extracellular and macrocyclic Gd chelate that exhibited high relaxivity, no protein binding, and high kinetic inertness. Its pharmacokinetic profile in dogs was similar to that of other extracellular nonspecific GBCAs.

Possible involvement of gadolinium chelates in the pathophysiology of nephrogenic systemic fibrosis: a critical review.

Nephrogenic systemic fibrosis (NSF) is a recently described, highly debilitating scleroderma-like disease occurring in patients with severe or end-stage renal failure. NSF is characterized by cutaneous papules and coalescing plaques ("peau d'orange" appearance) and a wooden consistency. It may ultimately cause disabling contractures of several joints, thus making many patients wheelchair-dependent. NSF has been associated to prior administration of gadolinium chelates (GC) used as contrast agents for magnetic resonance imaging. The best available treatment option at the present time is renal transplantation. The mechanism of NSF has not been fully elucidated. Several hypotheses have been proposed so far and are critically discussed in the present review article. Gadolinium has been found in skin biopsy samples of patients. The most widely accepted hypothesis is related to dechelation of less stable GC, progressively releasing free Gd3+ which may subsequently lead to the attraction of CD34+, CD45+, pro-collagen+ circulating fibrocytes via the release of chemokines, thereby inducing systemic fibrosing disorders. Pre-existing renal failure may facilitate the process by delaying the excretion of GC. A complex interplay between gadolinium and co-factors (pro-inflammatory status, vascular injury, high dose of erythropoietin, high levels of calcium, phosphorus, etc.) may occur in patients with impaired renal function. This and other hypotheses remain to be investigated, as well as the role and independence of co-factors.

Gadolinium Retention, Brain T1 Hyperintensity, and Endogenous Metals: A Comparative Study of Macrocyclic Versus Linear Gadolinium Chelates in Renally Sensitized Rats.

OBJECTIVES: This preclinical study was designed to compare gadolinium (Gd) brain uptake after repeated injections of a macrocyclic Gd-based contrast agent (GBCA) (gadoterate meglumine) or 2 linear GBCAs (L-GBCAs) (gadobenate dimeglumine or gadodiamide) on a translational model of moderate renal impairment in rats. METHODS: The study was carried out in subtotally nephrectomized rats. Animals received 4 intravenous injections per week of GBCA (gadoterate meglumine, gadobenate dimeglumine, or gadodiamide) for 5 weeks, resulting in a cumulative dose of 12 mmol/kg, followed by a 1-month injection-free period. T1 hyperintensity in the deep cerebellar nuclei (DCNs) was investigated, and brain structures were carefully dissected to determine elemental Gd, iron (Fe), copper (Cu), and zinc (Zn) distribution by mass spectrometry. Urinary excretion of endogenous metals was also investigated soon after GBCA administration and several days later in order to assess a potential transmetalation phenomenon. RESULTS: Unlike gadoterate, repeated injections of L-GBCAs gadobenate and gadodiamide both induced T1 hyperintensity in the DCNs. Fine dissection of cerebral and cerebellar structures demonstrated very low levels or absence of Gd after repeated injections of gadoterate, in contrast to the two L-GBCAs, for which the highest total Gd concentration was demonstrated in the DCNs (Gd concentration in DCNs after 4.5 weeks of injection-free period: 27.1 ± 6.5 nmol/g for gadodiamide [P < 0.01 vs saline and P < 0.05 vs gadoterate]; 12.0 ± 2.6 nmol/g for gadobenate [P < 0.09 vs saline]; compared with 1.4 ± 0.2 nmol/g for gadoterate [ns vs saline]). The distribution of Gd concentration among the various brain structures dissected was also well correlated with the Fe distribution in these structures. No difference in endogenous metal levels in brain structures was observed. However, injection of gadobenate or gadodiamide resulted in an increase in urinary Zn excretion (urinary Zn concentrations: 57.9 ± 20.5 nmol/mL with gadobenate [P < 0.01 vs gadoterate and saline] and 221.6 ± 83.3 nmol/L with gadodiamide [P < 0.0001 vs all other treatments] vs 8.1 ± 2.3 nmol/L with saline and 10.6 ± 4.8 nmol/L with gadoterate]). CONCLUSIONS: In a model of renally impaired rats, only traces of gadoterate meglumine were detected in the brain with no T1 hyperintensity of the DCNs, whereas marked Gd retention was observed in almost all brain areas after injections of the L-GBCAs, gadobenate dimeglumine and gadodiamide. Brain structures with higher Gd uptake corresponded to those structures containing more Fe. Urinary Zn excretion was significantly increased after a single injection of L-GBCAs.

Multimodal Imaging Study of Gadolinium Presence in Rat Cerebellum: Differences Between Gd Chelates, Presence in the Virchow-Robin Space, Association With Lipofuscin, and Hypotheses About Distribution Pathway.

PURPOSE: The aim of this study was to investigate, based on in-depth multimodal imaging, the presence of Gd deposits, their ultrastructure, location, and co-location with endogenous elements, in the cerebellum, after repeated administrations of gadolinium-based contrast agents (GBCAs). METHODS: Rats sensitized by subtotal nephrectomy received 20 daily intravenous injections of 0.6 mmol Gd/kg for 5 weeks of commercial forms of either gadoterate, gadobenate or gadodiamide, or saline (n = 2/group). The study was randomized and blinded. Magnetic resonance imaging examination was performed weekly. One month after the last injection, electron microscopy analysis of the deep cerebellar nuclei, the granular layer of cerebellar cortex, and the choroid plexus was performed. Elemental analysis of deposits was carried out by electron energy loss spectroscopy. Secondary ion mass spectroscopy was used for complementary chemical mapping. RESULTS: A T1 hypersignal was evidenced in the deep cerebellar nuclei of rats treated with linear GBCAs, and Gd deposits were identified in all the studied cerebellar structures with gadobenate and gadodiamide (except in the granular layer in gadobenate-treated rats). No such effect was found with the macrocyclic GBCA gadoterate. Most of the Gd deposits revealed a characteristic spheroid "sea urchin-like" morphology, rich in phosphorus, and were localized in the basal lamina of microvessels, in the perivascular Virchow-Robin space, and in the interstitium. Gd was also identified in the glial cells, associated with lipofuscin pigments, for these same groups. CONCLUSIONS: Transmission electron microscopy analysis of cerebellums of renally impaired rats repeatedly injected with gadobenate and gadodiamide revealed the presence of Gd. Spheroid Gd depositions consisting of a filamentous meshwork were observed in the wall of microvessels, in perivascular Virchow-Robin space, and in the interstitium. Gd was also found in choroid plexus and was associated with pigments (likely lipofuscin) in glial cells. This is consistent with the involvement of the glymphatic distribution pathway for GBCAs. No insoluble Gd deposits were detected in rats injected with the macrocyclic GBCA gadoterate and controls.

Methodological Aspects for Preclinical Evaluation of Gadolinium Presence in Brain Tissue: Critical Appraisal and Suggestions for Harmonization-A Joint Initiative.

Gadolinium (Gd)-based contrast agents (GBCAs) are pharmaceuticals that have been approved for 30 years and used daily in millions of patients worldwide. Their clinical benefits are indisputable. Recently, unexpected long-term presence of Gd in the brain has been reported by numerous retrospective clinical studies and confirmed in preclinical models particularly after linear GBCA (L-GBCA) compared with macrocyclic GBCA (M-GBCA). Even if no clinical consequences of Gd presence in brain tissue has been demonstrated so far, in-depth investigations on potential toxicological consequences and the fate of Gd in the body remain crucial to potentially adapt the clinical use of GBCAs, as done during the nephrogenic systemic fibrosis crisis. Preclinical models are instrumental in the understanding of the mechanism of action as well as the potential safety consequences. However, such models may be associated with risks of biases, often related to the protocol design. Selection of adequate terminology is also crucial. This review of the literature intends to summarize and critically discuss the main methodological aspects for accurate design and translational character of preclinical studies.

A comprehensive literatures update of clinical researches of superparamagnetic resonance iron oxide nanoparticles for magnetic resonance imaging.

This paper aims to update the clinical researches using superparamagnetic iron oxide (SPIO) nanoparticles as magnetic resonance imaging (MRI) contrast agent published during the past five years. PubMed database was used for literature search, and the search terms were (SPIO OR superparamagnetic iron oxide OR Resovist OR Ferumoxytol OR Ferumoxtran-10) AND (MRI OR magnetic resonance imaging). The literature search results show clinical research on SPIO remains robust, particularly fuelled by the approval of ferumoxytol for intravenously administration. SPIOs have been tested on MR angiography, sentinel lymph node detection, lymph node metastasis evaluation; inflammation evaluation; blood volume measurement; as well as liver imaging. Two experimental SPIOs with unique potentials are also discussed in this review. A curcumin-conjugated SPIO can penetrate brain blood barrier (BBB) and bind to amyloid plaques in Alzheime's disease transgenic mice brain, and thereafter detectable by MRI. Another SPIO was fabricated with a core of Fe3O4 nanoparticle and a shell coating of concentrated hydrophilic polymer brushes and are almost not taken by peripheral macrophages as well as by mononuclear phagocytes and reticuloendothelial system (RES) due to the suppression of non-specific protein binding caused by their stealthy ''brush-afforded'' structure. This SPIO may offer potentials for the applications such as drug targeting and tissue or organ imaging other than liver and lymph nodes.

Erratum to a comprehensive literatures update of clinical researches of superparamagnetic resonance iron oxide nanoparticles for magnetic resonance imaging.

[This corrects the article DOI: 10.21037/qims.2017.02.09.].