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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., Competing Interests: Conflicts of interest and sources of funding: All authors are employees of Guerbet., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: Conflicts of interest and sources of funding: All authors are or were employees of Guerbet. This work is part of the Franco-German Project ISEULT and was funded in part by Banque Publique d'Investissement (France) and by Guerbet., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

The unexpected appearance of T 1 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., (© 2020 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

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.

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.

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.

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.

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.

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.

Objectives: The purpose of this preclinical study was to investigate whether moderate chronic kidney disease is a factor in potentiating gadolinium (Gd) uptake in the brain., Materials and Methods: A comparative study was performed on renally impaired (subtotal nephrectomy) rats versus rats with normal renal function. The animals received 4 daily injections of 0.6 mmol Gd/kg a week for 5 weeks (cumulative dose of 12 mmol Gd/kg) of gadodiamide or saline solution. The MR signal enhancement in the deep cerebellar nuclei was monitored by weekly magnetic resonance imaging examinations. One week after the final injection, the total Gd concentration was determined by inductively coupled plasma mass spectrometry in different regions of the brain including the cerebellum, plasma, cerebrospinal fluid, parietal bone, and femur., Results: After the administration of gadodiamide, the subtotal nephrectomy group presented a significantly higher T1 signal enhancement in the deep cerebellar nuclei and a major increase in the total Gd concentration in all the studied structures, compared with the normal renal function group receiving the same linear Gd-based contrast agent. Those potentiated animals also showed a pronounced hypersignal in the choroid plexus, still persistent 6 days after the last injection, whereas low concentration of Gd was found in the cerebrospinal fluid (<0.05 μmol/L) at this time point. Plasma Gd concentration was then around 1 μmol/L. Interestingly, plasma Gd was predominantly in a dissociated and soluble form (around 90% of total Gd). Total Gd concentrations in the brain, cerebellum, plasma, and bones correlated with creatinine clearance in both the gadodiamide-treated groups., Conclusions: Renal insufficiency in rats potentiates Gd uptake in the cerebellum, brain, and bones.

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., Competing Interests: Conflicts of Interest: JM Idée is an employee of Guerbet group, France. Guerbet group manufactures and markets a number of contrast agents for diagnostic and interventional imaging. And other author has no conflicts of interest to declare.

Objectives: The aim of this study was to evaluate Gd retention in the deep cerebellar nuclei (DCN) of linear gadolinium-based contrast agents (GBCAs) compared with a macrocyclic contrast agent., Materials and Methods: The brain tissue retention of Gd of 3 linear GBCAs (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) and a macrocyclic GBCA (gadoterate meglumine) was compared in healthy rats (n = 8 per group) that received 20 intravenous injections of 0.6 mmol Gd/kg (4 injections per week for 5 weeks). An additional control group with saline was included. T1-weighted magnetic resonance imaging was performed before injection and once a week during the 5 weeks of injections and for another 4 additional weeks after contrast period. Total gadolinium concentration was measured with inductively coupled plasma mass spectrometry. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data., Results: At completion of the injection period, all the linear contrast agents (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) induced a significant increase in signal intensity in DCN, unlike the macrocyclic GBCA (gadoterate meglumine) or saline. The T1 hypersignal enhancement kinetic was fast for gadodiamide. Total Gd concentrations for the 3 linear GBCAs groups at week 10 were significantly higher in the cerebellum (1.21 ± 0.48, 1.67 ± 0.17, and 3.75 ± 0.18 nmol/g for gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide, respectively) than with the gadoterate meglumine (0.27 ± 0.16 nmol/g, P < 0.05) and saline (0.09 ± 0.12 nmol/g, P < 0.05). No significant difference was observed between the macrocyclic agent and saline., Conclusions: Repeated administrations of the linear GBCAs gadodiamide, gadobenate dimeglumine, and gadopentetate dimeglumine to healthy rats were associated with progressive and significant T1 signal hyperintensity in the DCN, along with Gd deposition in the cerebellum. This is in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

Designing of theranostics and dual or multi-modality contrast agents are currently two of the hottest topics in biotechnology and biomaterials science. However, for single entity theranostics, a right ratio of their diagnostic component and their therapeutic component may not always be realized in a composite suitable for clinical application. For dual/multiple modality molecular imaging agents, after in vivo administration, there is an optimal time window for imaging, when an agent is imaged by one modality, the pharmacokinetics of this agent may not allow imaging by another modality. Due to reticuloendothelial system clearance, efficient in vivo delivery of nanoparticles to the lesion site is sometimes difficult. The toxicity of these entities also remains poorly understood. While the medical need of theranostics is admitted, the business model remains to be established. There is an urgent need for a global and internationally harmonized re-evaluation of the approval and marketing processes of theranostics. However, a reasonable expectation exists that, in the near future, the current obstacles will be removed, thus allowing the wide use of these very promising agents.

Objectives: To prospectively compare in healthy rats the effect of multiple injections of macrocyclic (gadoterate meglumine) and linear (gadodiamide) gadolinium-based contrast agents (GBCAs) on T1-weighted signal intensity in the deep cerebellar nuclei (DCN), including the dentate nucleus., Materials and Methods: Healthy rats (n = 7/group) received 20 intravenous injections of 0.6 mmol of gadolinium (Gd) per kilogram (4 injections per week during 5 weeks) of gadodiamide, gadoterate meglumine, or hyperosmolar saline (control group). Brain T1-weighted magnetic resonance imaging was performed before and once a week during the 5 weeks of injections and during 5 additional weeks (treatment-free period). Gadolinium concentrations were measured with inductively coupled plasma mass spectrometry in plasma and brain. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data., Results: A significant and persistent T1 signal hyperintensity in DCN was observed only in gadodiamide-treated rats. The DCN-to-cerebellar cortex signal ratio was significantly increased from the 12th injection of gadodiamide (1.070 ± 0.024) compared to the gadoterate meglumine group (1.000 ± 0.033; P < 0.001) and control group (1.019 ± 0.022; P < 0.001) and did not significantly decrease during the treatment-free period. Total Gd concentrations in the gadodiamide group were significantly higher in the cerebellum (3.66 ± 0.91 nmol/g) compared with the gadoterate meglumine (0.26 ± 0.12 nmol/g; P < 0.05) and control (0.06 ± 0.10 nmol/g; P < 0.05) groups., Conclusions: Repeated administrations of the linear GBCA gadodiamide to healthy rats are associated with progressive and persistent T1 signal hyperintensity in the DCN, with Gd deposition in the cerebellum in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

Objective: To assess the retention of gadolinium (Gd) in skin, liver, and bone following gadodiamide or gadoteric acid administration., Methods: Gd was measured in skin, liver and femur bone in female rats 10 weeks after administration of 17.5 mmol Gd/kg over 5 days of Gd agents. Rat skin microscopy, energy filtering transmission electron microscopy and elemental analysis were performed, and repeated after receiving the same dosage of gadodiamide in rats with osteoporosis induced with bilateral ovariectomy (OVX). The OVX was performed 60 days after the last injection of gadodiamide and animals sacrificed 3 weeks later., Results: Gd concentration was 180-fold higher in the skin, 25-fold higher in the femur, and 30-fold higher in the liver in rats received gadodiamide than rats received gadoteric acid. The retention of Gd in the skin with gadodiamide was associated with an increase in dermal cellularity, and Gd encrustation of collagen fibers and deposition inside the fibroblasts and other cells. No differences in Gd concentration in liver, skin, and femur were observed between rats receiving gadodiamide with or without OVX., Conclusions: Gd tissue retention with gadodiamide was higher than gadoteric acid. Tissues Gd deposition did not alter following gadodiamide administration to ovariectomized rats.

Gadolinium chelates (GC) are contrast agents widely used to facilitate or to enable diagnosis using magnetic resonance imaging (MRI). From a regulatory viewpoint, GC are drugs. GC have largely contributed to the success of MRI, which has become a major component of clinician's diagnostic armamentarium. GC are not metabolised and are excreted by the kidneys. They distribute into the extracellular compartment. Because of its high intrinsic toxicity, gadolinium must be administered as a chelate. GC can be classified according to two key molecular features: (a) nature of the chelating moiety: either macrocyclic molecules in which gadolinium is caged in the pre-organized cavity of the ligand, or linear, open-chain molecules, (b) ionicity: Gd chelates can be ionic (meglumine or sodium salts) or non-ionic. The thermodynamic and kinetic stabilities of the various GCs differ according to these structural characteristics. The kinetic stability of macrocyclic GCs is much higher than that of linear GCs and the thermodynamic stability of ionic GCs is generally higher than that of non-ionic GC, thus leading to a lower risk of gadolinium dissociation. This class of drugs has enjoyed an excellent reputation in terms of safety for a long time, until a causal link with a recently-described serious disease, nephrogenic systemic fibrosis (NSF), was evidenced. It is acknowledged that the vast majority of NSF cases are related to the administration of some linear CG in renally-impaired patients. Health authorities, worldwide, released recommendations which drastically reduced the occurrence of new cases., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

While not acutely toxic, chronic hepatic effect of certain gadolinium chelates (GC), used as contrast agent for magnetic resonance imaging, might represent a risk in renally-impaired patients due to free gadolinium accumulation in the liver. To answer this question, this study investigated the consequences of the presence of small amounts of either a soluble gadolinium salt ("free" Gd) or low-stability chelating impurity in the pharmaceutical solution of gadoteric acid, a macrocyclic GC with high thermodynamic and kinetic stabilities, were investigated in renally-impaired rats. Renal failure was induced by adding 0.75% adenine in the diet for three weeks. The pharmaceutical and commercial solution of gadoteric acid was administered (5 daily intravenous injections of 2.5 mmol Gd/kg) either alone or after being spiked with either "free" gadolinium (i.e., 0.04% w/v) or low-stability impurity (i.e., 0.06 w/v). Another GC, gadodiamide (low thermodynamic and kinetic stabilities) was given as its commercial solution at a similar dose. Non-chelated gadolinium was tested at two doses (0.005 and 0.01 mmol Gd/kg) as acetate salt. Gadodiamide induced systemic toxicity (mortality, severe epidermal and dermal lesions) and substantial tissue Gd retention. The addition of very low amounts of "free", non-chelated gadolinium or low thermodynamic stability impurity to the pharmaceutical solution of the thermodynamically stable GC gadoteric acid resulted in substantial capture of metal by the liver, similar to what was observed in "free" gadolinium salt-treated rats. Relaxometry studies strongly suggested the presence of free and soluble gadolinium in the liver. Electron microscopy examinations revealed the presence of free and insoluble gadolinium deposits in hepatocytes and Kupffer cells of rats treated with gadoteric acid solution spiked with low-stability impurity, free gadolinium and gadodiamide, but not in rats treated with the pharmaceutical solution of gadoteric acid. The presence of impurities in the GC pharmaceutical solution may have long-term biological consequences., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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.

Objectives: The purposes of this study were to evaluate the risk for analytical interference with gadolinium-based contrast agents (GBCAs) for the colorimetric measurement of serum iron (Fe³⁺) and to investigate the mechanisms involved., Materials and Methods: Rat serum was spiked with several concentrations of all molecular categories of GBCAs, ligands, or "free" soluble gadolinium (Gd³⁺). Serum iron concentration was determined by 2 different colorimetric methods at pH 4.0 (with a Vitros DT60 analyzer or a Cobas Integra 400 analyzer). Secondly, the cause of interference was investigated by (a) adding free soluble Gd³⁺ or Mn²⁺ to serum in the presence of gadobenic acid or gadodiamide and (b) electrospray ionization mass spectrometry., Results: Spurious decrease in serum Fe³⁺ concentration was observed with all linear GBCAs (only with the Vitros DT60 technique occurring at pH 4.0) but not with macrocyclic GBCAs or with free soluble Gd³⁺. Spurious hyposideremia was also observed with the free ligands present in the pharmaceutical solutions of the linear GBCAs gadopentetic acid and gadodiamide (ie, diethylene triamine pentaacetic acid and calcium-diethylene triamine pentaacetic acid bismethylamide, respectively), suggesting the formation of Fe-ligand chelate.Gadobenic acid-induced interference was blocked in a concentration-dependent fashion by adding a free soluble Gd³⁺ salt. Conversely, Mn²⁺, which has a lower affinity than Gd³⁺ and Fe³⁺ for the ligand of gadobenic acid (ie, benzyloxypropionic diethylenetriamine tetraacetic acid), was less effective (interference was only partially blocked), suggesting an Fe³⁺ versus Gd³⁺ transmetallation phenomenon at pH 4.0. Similar results were observed with gadodiamide. Mass spectrometry detected the formation of Fe-ligand with all linear GBCAs tested in the presence of Fe and the disappearance of Fe-ligand after the addition of free soluble Gd³⁺. No Fe-ligand chelate was found in the case of the macrocyclic GBCA gadoteric acid., Conclusions: Macrocyclic GBCAs induced no interference with colorimetric methods for iron determination, whereas negative interference was observed with linear GBCAs using a Vitros DT60 analyzer. This interference of linear GBCAs seems to be caused by the excess of ligand and/or an Fe³⁺ versus Gd³⁺ transmetallation phenomenon.

This study was designed to compare the safety of two gadolinium chelates (GCs), used as contrast agents for magnetic resonance imaging, in juvenile rats. Juvenile rats received five intravenous administrations (between postnatal day [PND] 4 and 18) of gadoteric acid (macrocyclic ionic GC), gadodiamide (linear nonionic GC) or saline, and sacrificed at PND 25. Gadodiamide induced mortality, alopecia and hyperpigmentation of dorsal skin. Two gadodiamide-treated rats presented severe epidermal and dermal lesions. No abnormal signs were detected following administration of gadoteric acid. Higher tissue gadolinium concentrations were found in the gadodiamide group compared to the gadoteric acid group. Dissociation of gadodiamide was observed in skin and liver, with the presence of dissociated and soluble gadolinium. In conclusion, repeated administration of gadoteric acid was well tolerated by juvenile rats. In contrast, gadodiamide induced significant toxicity and more marked tissue gadolinium retention (at least partly in the dissociated and soluble form)., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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.

Hepatocellular carcinoma (HCC) remains a major public health problem. Transarterial chemoembolization (TACE) is recognized as the standard of care for patients with unresectable, asymptomatic, noninvasive and multinodular HCC. This procedure is based on percutaneous administration of a cytotoxic drug emulsified with Lipiodol followed by embolization of the tumour-feeding arteries. The standard procedure involves Lipiodol, an oily contrast medium which consists of a mixture of long-chain di-iodinated ethyl esters of poppy seed fatty acids. The aim of this review is to discuss the physical properties, tumour uptake behaviour and drug delivery effects of Lipiodol, the parameters influencing tumour uptake and future prospects. Lipiodol has a unique place in TACE as it combines three specific characteristics: drug delivery, transient and plastic embolization and radiopacity properties. Substantial heterogeneity in the physicochemical characteristics of Lipiodol/cytotoxic agent emulsions might reduce the efficacy of this procedure and justifies the current interest in Lipiodol for drug delivery., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Nephrogenic systemic fibrosis (NSF) is a scleroderma-like disease associated with prior administration of certain gadolinium chelates (GCs). NSF occurs in patients with severe renal failure. The purpose of this study was to set up a rat model of GC-associated NSF to elucidate the mechanism of this devastating disease. Firstly, after characterization of the model, male Wistar rats received a 0.75% adenine-enriched diet for 8, 14, or 16 days to obtain various degrees of renal failure. Rats received five consecutive daily iv injections of saline or gadodiamide (2.5 mmol/kg/day). Secondly, the safety profile and in vivo propensity to dissociate of all categories of marketed GCs (gadoterate, gadobutrol, gadobenate, gadopentetate, and gadodiamide) were compared in rats receiving adenine-enriched diet for 16 days. Serial skin biopsies were performed for blinded histopathological study. Total Gd concentration in tissues was measured by Inductively Coupled Plasma Mass Spectrometry. Relaxometry was used to evaluate the presence of dissociated Gd in skin and bone. Gadodiamide-induced high mortality and skin lesions (dermal fibrosis, calcification, and inflammation) were related to adenine diet duration. No skin lesions were observed with other molecules. Unlike macrocyclic GCs, gadodiamide, gadopentetate, and gadobenate gradually increased the r(1) relaxivity value, consistent with in vivo dissociation and release of soluble Gd (or, in the case of gadobenate, the consequence of protein binding). Gadodiamide-induced cutaneous and systemic toxicity depended on baseline renal function. We demonstrate in vivo dissociation of linear GCs, gadodiamide, and gadopentetate, whereas macrocyclic agents remained stable over the study period.

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., (© RSNA, 2012.)

Due to numerous technical developments, in vivo imaging is suitable for pharmacokinetic and metabolism studies of new chemical entities as well as for evaluating their pharmacological or biological effects. MRI, nuclear medicine, X-Ray, ultrasound and optical imaging are available for both clinical and experimental imaging with even higher performance. For all these imaging modalities, diagnostic agents are useful to improve contrast and specificity. Specific targeting of biological events is addressed by molecular imaging. From a pharmacodynamic perspective, radiolabeling of a new chemical entity allows in vivo visualization quantitative measure of its biodistribution, its elimination and its specific molecular binding. Non-invasive imaging methods are useful for longitudinal investigations of biological changes. Based on nanotechnologies, specificity of drug delivery can be monitored by imaging. New developments in hybrid imaging technologies as well as multimodal contrast agents reinforce in vivo experimental and clinical proof of mechanism of new chemical entities., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objectives: Nephrogenic systemic fibrosis occurs in patients with poor renal function who receive gadolinium-based contrast agents (Gd-CAs). Several reports suggest that this is more likely to occur with the less stable forms of Gd chelates, suggesting a release of cytotoxic free Gd ions from these. There is evidence that Gd can stimulate human fibroblast proliferation but the evidence is less clear concerning the production of collagen by these cells. Our aim was to assess effects of Gd chelates on human skin cell activity and collagen production., Materials and Methods: Keratinocytes and fibroblasts were cultured with 3 Gd chelates (Gd-EDTA, Omniscan [nonionic linear Gd-CA], and Dotarem [ionic macrocyclic Gd-CA]) for up to 7 days, and cell viability and collagen production were assessed using the colorimetric assays of MTT (3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide) and Sirius Red, respectively. The uptake of Gd by cultured fibroblasts was also undertaken using the techniques of inductively coupled plasma mass spectrometry and relaxometry., Results: Our data show that Gd-EDTA and Omniscan significantly stimulated both fibroblast and keratinocyte viability and fibroblast (but not keratinocyte) collagen production. In contrast, Dotarem had little, if any, effect on these cultured cells. The Omniscan-induced increase in fibroblast collagen was around 40% over 7 days-a similar increase to that seen for cell viability, suggesting that collagen production was secondary to an initial stimulatory effect on fibroblast viability. Studies of the uptake of Gd by the cultured fibroblasts showed that these took up Gd when cultured with Omniscan for 7 days, and our study also suggests that some of this Gd was in a free dissociated form., Conclusions: We conclude that these results support a simple nephrogenic systemic fibrosis causative role of low-stability nonionic linear Gd-CA inducing dermal collagen via the release of dissociated Gd which enters fibroblasts and stimulates their activity and associated collagen production.

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.

Purpose: Investigation of dissociated versus chelated gadolinium (Gd) in plasma, skin, and bone of rats with impaired renal function after administration of ionic macrocyclic (gadoterate or Dotarem) or nonionic linear (gadodiamide or Omniscan) Gd chelates., Materials and Methods: Subtotally nephrectomized Wistar rats were subjected to receive daily injections of 2.5 mmol/kg of Omniscan, gadodiamide without excess ligand caldiamide, Dotarem, or saline (n = 7-10 rats/group) for 5 consecutive days. The Gd concentration was measured by inductively coupled plasma mass spectrometer in skin, femur epiphysis, and plasma on completion of the study (day 11), and dissociated Gd(3+) was measured in the plasma at day 11 (liquid chromatography inductively coupled plasma mass spectrometry). The r(1) relaxivity constant was measured in skin (at day 4 and day 11) and bone (day 11) to investigate the dissociated or chelated form of Gd found in tissue samples. Clinical and skin histopathologic studies were performed., Results: Subtotal nephrectomy decreased creatinine clearance by 60%. No macroscopic skin lesions were observed in the Dotarem and Omniscan groups in contrast with the gadodiamide group (2 rats survived the study period and 4 of 10 rats showed skin ulcerations and scabs). Skin histopathologic lesions were in the range gadodiamide > Omniscan > Dotarem (similar to control rats). At day 11, the skin Gd concentration was lower in the Dotarem group (161.0 ± 85.5 nmol/g) as compared with the Omniscan (490.5 ± 223.2 nmol/g) and gadodiamide groups (mean value, 776.1 nmol/g; n = 2 survivors). The total Gd concentration in the femur was significantly higher in the Omniscan group than in the Dotarem group. At day 11, the dissociated Gd(3+) concentration in plasma was below the limit of detection in the Dotarem group and was 1.5 ± 0.7 μmol/L in the Omniscan group corresponding to 62% ± 15% of the total Gd concentration. The dissociated Gd(3+) concentration was 1.1 μmol/L in gadodiamide rats (n = 2 survivors). In the skin, the in vivo r1 relaxivity value increased from 4.8 ± 0.7 mM(-1)s(-1) at day 4 to 10.5 ± 3.9 mM(-1)s(-1) at day 11 in the Omniscan group, P < 0.05 (in vitro r(1) in skin, 3.5 mM(-1)s(-1)) and gadodiamide group, whereas no significant change was observed in the Dotarem group (2.8 ± 0.2 and 4.9 ± 2.8 mM(-1)s(-1) at day 4 and 11, respectively, NS) (in vitro value in the skin, 3.2 mM(-1)s(-1)). In the femur, the in vivo r1 relaxivity was higher in the Omniscan group (8.9 ± 2.1 mM(-1)s(-1)) (in vitro relaxivity, 4.5 mM(-1)s(-1)) and gadodiamide group (8.8 mM(-1)s(-1), n = 2 survivors) than in the Dotarem group (3.8 mM(-1)s(-1), n = 1 rat with measurable r(1), since for 7 rats, 1/T(1) - 1/T(1(diamagnetic)) <10% of 1/T(1(diamagnetic)) because of low Gd concentration) (in vitro relaxivity value in the femur matrix, 3.1 mM(-1)s(-1))., Conclusions: Unlike Dotarem, Omniscan and gadodiamide induced histologic skin lesions. At day 11, a higher Gd concentration was found in both skin and femur of Omniscan- and gadodiamide-treated rats than in Dotarem-treated rats. Relaxometry results indicate gradual in vivo dechelation and release of dissociated Gd(3+) in a soluble form in renally impaired rats receiving Omniscan and gadodiamide, whereas Dotarem remained stable over the study period.

Objective: the purpose of this study was to compare the clinical, pathologic, and biochemical effects of repeated administrations of ionic macrocyclic or nonionic linear gadolinium chelates (GC) in rats with impaired renal function., Material and Methods: rats submitted to subtotal nephrectomy were allocated to single injections of 2.5 mmol/kg of gadodiamide (nonionic linear chelate), nonformulated gadodiamide (ie, without the free ligand caldiamide), gadoterate (ionic macrocyclic chelate), or saline for 5 consecutive days. Blinded semi-quantitative histopathologic and immunohistochemical examinations of the skin were performed, as well as clinical, hematological, and biochemical follow-up. Rats were killed at day 11. Long-term (up to day 32) follow-up of rats was also performed in an auxiliary study., Results: epidermal lesions (ulcerations and scabs) were found in 4 of the 10 rats treated with nonformulated gadodiamide. Two rats survived the study period. Inflammatory signs were observed in this group. No clinical, hematological, or biochemical signs were observed in the saline and gadoterate- or gadodiamide-treated groups. Plasma fibroblast growth factor-23 levels were significantly higher in the gadodiamide group than in the gadoterate group (day 11). Decreased plasma transferrin-bound iron levels were measured in the nonformulated gadodiamide group. Histologic lesions were in the range: nonformulated gadodiamide (superficial epidermal lesions, inflammation, necrosis, and increased cellularity in papillary dermis) > gadodiamide (small superficial epidermal lesions and signs of degradation of collagen fibers in the dermis) > gadoterate (very few pathologic lesions, similar to control rats)., Conclusions: repeated administration of the nonionic linear GC gadodiamide to renally impaired rats is associated with more severe histologic lesions and higher FGF-23 plasma levels than the macrocyclic GC gadoterate.

Experimental findings in vitro and in vivo illustrate enhanced hypoxia and the formation of reactive oxygen species (ROS) within the kidney following the administration of iodinated contrast media, which may play a role in the development of contrast media-induced nephropathy. Clinical studies indeed support this possibility, suggesting a protective effect of ROS scavenging or reduced ROS formation with the administration of N-acetyl cysteine and bicarbonate infusion, respectively. Furthermore, most risk factors, predisposing to contrast-induced nephropathy are prone to enhanced renal parenchymal hypoxia and ROS formation. In this review, the association of renal hypoxia and ROS-mediated injury is outlined. Generated during contrast-induced renal parenchymal hypoxia, ROS may exert direct tubular and vascular endothelial injury and might further intensify renal parenchymal hypoxia by virtue of endothelial dysfunction and dysregulation of tubular transport. Preventive strategies conceivably should include inhibition of ROS generation or ROS scavenging.

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.

Nephrogenic systemic fibrosis (NSF) is a highly debilitating scleroderma-like disease occurring exclusively in patients with severe or end-stage renal failure. Since the recognition of a link between gadolinium chelates (GCs) used as contrast agents for MR imaging and NSF by two independent European teams in 2006, numerous studies have described the clinical issues and investigated the mechanism of this disease. So far the most commonly reported hypothesis is based on the in vivo dechelation of GCs. The physicochemical properties of GCs, especially their thermodynamic and kinetic stabilities, are described in the present article. High kinetic stability provided by the macrocyclic structure, combined with high thermodynamic stability, minimizes the amount of free gadolinium released in the body. The current hypotheses regarding the pathophysiologic mechanism are critically discussed.

Gadolinium-based contrast agents are widely used to enhance image contrast in magnetic resonance imaging (MRI) procedures. Over recent years, there has been a renewed interest in the physicochemical properties of gadolinium chelates used as contrast agents for MRI procedures, as it has been suggested that dechelation of these molecules could be involved in the mechanism of a recently described disease, namely nephrogenic systemic fibrosis (NSF). The aim of this paper is to discuss the structure-physicochemical properties relationships of marketed gadolinium chelates in regards to their biological consequences. Marketed gadolinium chelates can be classified according to key molecular design parameters: (a) nature of the chelating moiety: macrocyclic molecules in which Gd3+ is caged in the pre-organized cavity of the ligand, or linear open-chain molecules, (b) ionicity: the ionicity of the complex varies from neutral to tri-anionic agents, and (c) the presence or absence of an aromatic lipophilic residue responsible for protein binding. All these molecular characteristics have a profound impact on the physicochemical characteristics of the pharmaceutical solution such as osmolality, viscosity but also on their efficiency in relaxing water protons (relaxivity) and their biodistribution. These key molecular parameters can also explain why gadolinium chelates differ in terms of their thermodynamic stability constants and kinetic stability, as demonstrated by numerous in vitro and in vivo studies, resulting in various formulations of pharmaceutical solutions of marketed contrast agents. The concept of kinetic and thermodynamic stability is critically discussed as it remains a somewhat controversial topic, especially in predicting the amount of free gadolinium which may result from dechelation of chelates in physiological or pathological situations. A high kinetic stability provided by the macrocyclic structure combined with a high thermodynamic stability (reinforced by ionicity for macrocyclic chelates) will minimize the amount of free gadolinium released in tissue parenchymas.

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-based contrast agents (CAs) are widely used to enhance the contrast of images in magnetic resonance imaging procedures. Two categories of gadolinium chelates exist: the macrocyclic molecules where Gd3+ is caged in the pre-organized cavity of the ligand and the linear molecules. Gadolinium chelates differ in their thermodynamic stability constants and in their kinetic stability. In general, macrocyclic chelates such as Gd-DOTA or Gd-HP-DO3A are more stable than linear molecules. Even among linear agents, differences can be found. There is increasing evidence that transmetallation can be found in vivo, in the case of certain CAs (especially linear chelates), with body cations such as zinc, calcium or iron. Furthermore, analytical interference with colorimetric determination of calcium has been clinically evidenced with two linear chelates, Gd-DTPA-BMA and Gd-DTPA-BMEA. Clinical cases of spurious hypocalcaemia have been reported with these molecules. Such interference with some colorimetric assays for calcium is clinically relevant in that it can lead to unnecessary and potentially harmful treatment for hypocalcaemia.

Superparamagnetic iron oxide particles (SPIO and USPIO) have a variety of applications in molecular and cellular imaging. Most of the recent research has concerned cellular imaging with imaging of in vivo macrophage activity. According to the iron oxide nanoparticle composition and size which influence their biodistribution, several clinical applications are possible: detection liver metastases, metastatic lymph nodes, inflammatory and/or degenerative diseases. USPIO are investigated as blood pool agents with T1 weighted sequence for angiography, tumour permeability and tumour blood volume or steady-state cerebral blood volume and vessel size index measurements using T2 weighted sequences. Stem cell migration and immune cell trafficking, as well as targeted iron oxide nanoparticles for molecular imaging studies, are at the stage of proof of concept, mainly in animal models.

Magnetic resonance imaging (MRI) of normal and diseased kidneys shows great promise because of the combined value of anatomical and functional information provided, as well as of specific contrast patterns that can be observed non-invasively. Multicontrast MRI is able to show infiltrative kidney disorders. Diffusion-weighted imaging can assess alterations in renal function and can suggest obstruction or inflammation when present. Due to the low nephrotoxicity, contrast-enhanced MR studies using serial dynamic enhancement with non-specific gadolinium chelates are able to provide information on glomerular filtration. Furthermore, contrast agents such as ultrasmall particles of iron oxide, specific of inflammation, should be used in the near future to detect active from quiescent involvement, both in native kidneys and renal allografts. Early results should indicate that these compounds might differentiate acute tubular necrosis from other acute nephropathies, as well as active proliferative nephropathies from chronic ones. Ongoing studies will obviously demonstrate the value of the combination of these various MRI sequences in the diagnosis of acute renal failure and chronic kidney disease., (Copyright 2006 S. Karger AG, Basel.)

Allergy-like reactions may occur following administration of iodinated contrast media (CM), mostly in at-risk patients (patients with history of previous reaction, history of allergy, co-treated with interleukin-2 or beta-blockers, etc.) but remain generally unpredictable. Severe and fatal reactions are very rare events. All categories of CM may induce such reactions, although first generation (high osmolar CM) have been found to induce a higher rate of adverse events than low osmolar CM. However, no differences were found between the two categories of CM with respect to mortality. Delayed reactions can also occur. There are no differences between the various categories of CM except for non-ionic dimers, which are more likely to induce such effect. Numerous clinical studies have evaluated the prophylactic value of drugs (mostly antihistamines and corticosteroids). Results are unclear and highly variable. Any prevention depends upon the mechanism involved. However, the mechanism of CM-induced allergy-like reaction remains disputed. Relatively recent data revived the hypothesis of a type-I hypersensitivity mechanism. Positive skin tests to CM have been reported. However, the affinity of IgE towards CM has been found to be very low in the only study which actually evaluated it. Other pathophysiological mechanisms (involving direct secretory effects on mast cells or basophils, or activation of the complement system associated or not with the plasma contact system) are also much debated. Anaphylaxis and anaphylactoid reactions are, in the end, clinically undistinguishable.

Rationale and Objectives: To compare the effects of two iodinated contrast media, iodixanol and ioxaglate, on outer medullary blood flow (MBF) and oxygen tension (MPO(2)) in the dog kidney., Methods: Iodixanol and ioxaglate were injected selectively into the renal artery (320 mgI/kg) of anesthetized Beagle dogs. MBF and MPO(2) were measured with a laser-Doppler probe and an oxygen-sensing microelectrode implanted in the outer medulla. Urine samples were collected for viscosity and osmolality measurements., Results: Both contrast media produced a moderate decrease in MBF and MPO(2). The hypoperfusion and hypoxia lasted significantly longer with iodixanol than with ioxaglate. Theophylline, an adenosine receptor antagonist, partially prevented iodixanol-induced hypoxia. Urine viscosity was dramatically increased by iodixanol but not by ioxaglate. Urine osmolality did not differ significantly between groups., Conclusion: Iodixanol produced a more sustained medullary hypoxia than ioxaglate when injected selectively into the dog renal artery. This may lead to hypoxic cellular damage and subsequent impairment of kidney functions.