Gd-based Contrast Agents Research Articles

Expression of GRP78 and its copartners in HEK293 and pancreatic cancer cell lines (BxPC-3/PANC-1) exposed to MRI and CT contrast agents

Endoplasmic reticulum (ER) stress-associated chaperones trigger a defense mechanism called as unfolded protein response (UPR) which can manage apoptosis and be determinative in cell fate. Both anticancer drug effects and potential toxicity effects of magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents were aimed to be evaluated. For this purpose, we investigated expression profiles of endoplasmic reticulum stress-associated chaperone molecules in human pancreatic tumor lines BxPC-3 and PANC-1 and control human embryonic kidney cells 293 (HEK293) induced with a variety of gadolinium and iohexol contrast agents. Protein expression levels of ER stress-associated chaperones (master regulator: GRP78/Bip and its copartners: Calnexin, Ero1, PDI, CHOP, IRE1α and PERK) were evaluated with Western blotting. Expression levels at mRNA level were also assessed for GRP78/Bip and CHOP with real-time PCR. Induction of cells was carried out with four different Gd-based contrast agents (GBCAs): (Dotarem, Optimark, Primovist and Gadovist) and two different iohexol agents (Omnipol, Omnipaque). CT contrast agents tested in the study did not result in significant ER stress in HEK293 cells. However, they do not seem to have theranostic potential in pancreas cancer through ER pathway. The potential efficiency of macrocyclic MRI contrast agents to provoke apoptosis via ER stress-associated chaperones in BxPC-3 cells lends credibility for their future theranostic use in pancreas cancer as long as undesired toxicity effects were carefully considered. ER stress markers and/or contrast agents seem to have promising potential to be translated into the clinical practice to manage pancreas cancer progression.

Advances in MRI: Peptide and peptidomimetic-based contrast agents.

Magnetic resonance imaging (MRI) is a common medical imaging technique that provides three-dimensional body images. MRI contrast agents improve image contrast by raising the rate of water proton relaxation in specific tissues. Peptides and peptidomimetics act as scaffolds for MRI imaging agents because of their increased size and offer the possibility to engine a higher hydration value within the design. The design of a new Gd-based contrast agent must take into account high stability constants to avoid free Gd(III), with the subsequent nephrotoxicity, and high relaxivity values. This review analyzes various synthetic approaches, reports studies of relaxometric parameters, and focuses on the description and application of Gd(III)-chelates based on peptide and peptidomimetic scaffolds. In addition, the X-ray molecular structures of three DOTA complexes will be reported to emphasize the necessity of using the X-ray diffraction analysis to identify the coordination sphere of the metals and the mechanism of action of the compounds.

Gadolinium Retention and Nephrotoxicity in a Mouse Model of Acute Ischemic Stroke: Linear Versus Macrocyclic Agents.

Gadolinium (Gd)-based contrast agents (GBCAs) have been widely used for acute ischemic stroke (AIS) patients. GBCAs or AIS alone may cause the adverse effects on kidney tissue, respectively. However, whether GBCAs and AIS would generate a synergistic negative effect remains undefined. To evaluate synergistic negative effects of AIS and GBCAs on renal tissues in a mouse model of AIS, and to compare the differences of these negative effects between linear and macrocyclic GBCAs. Animal study. Seventy-two healthy mice underwent transient middle cerebral artery occlusion (tMCAO) and sham operation to establish AIS and sham model (N = 36/model). 5.0 mmol/kg GBCAs (gadopentetate or gadobutrol) or 250 μL saline were performed at 4.5 hours and 1 day after model establishing (N = 12/group). Inductively coupled plasma mass spectrometry (ICP-MS) was performed to detect Gd concentrations. Serum biochemical analyzer was performed to measure the serum creatinine (Scr), uric acid (UA), and blood urea nitrogen (BUN). Pathological staining was performed to observe tubular injury, cell apoptosis, mesangial hyperplasia, and interstitial fibrosis. Two-way analysis of variances with post hoc Sidak's tests and independent-samples t-tests were performed. A P-value <0.05 was considered statistically significant. AIS groups showed higher Gd concentration than sham group on day 1 p.i. regardless of gadopentetate or gadobutrol used. Increased total Gd concentration was also found in AIS + gadopentetate group compared with the sham group on day 28 p.i. Significantly higher rates for renal dysfunction, higher tubular injury scores, and higher numbers of apoptotic cells on days 1 or 28 p.i. were found for AIS mice injected with GBCA. AIS + gadopentetate group displayed more severe renal damage than the AIS + gadobutrol group. AIS and GBCAs may cause increased total Gd accumulation and nephrotoxicity in a mouse, especially linear GBCAs were used. 1 TECHNICAL EFFICACY: Stage 4.

Liver-targeting MRI contrast agent based on galactose functionalized o-carboxymethyl chitosan.

Commercial gadolinium (Gd)-based contrast agents (GBCAs) play important role in clinical diagnostic of hepatocellular carcinoma, but their diagnostic efficacy remained improved. As small molecules, the imaging contrast and window of GBCAs is limited by low liver targeting and retention. Herein, we developed a liver-targeting gadolinium (Ⅲ) chelated macromolecular MRI contrast agent based on galactose functionalized o-carboxymethyl chitosan, namely, CS-Ga-(Gd-DTPA)n, to improve hepatocyte uptake and liver retention. Compared to Gd-DTPA and non-specific macromolecular agent CS-(Gd-DTPA)n, CS-Ga-(Gd-DTPA)n showed higher hepatocyte uptake, excellent cell and blood biocompatibility in vitro. Furthermore, CS-Ga-(Gd-DTPA)n also exhibited higher relaxivity in vitro, prolonged retention and better T1-weighted signal enhancement in liver. At 10days post-injection of CS-Ga-(Gd-DTPA)n at a dose of 0.03mMGd/Kg, Gd had a little accumulation in liver with no liver function damage. The good performance of CS-Ga-(Gd-DTPA)n gives great confidence in developing liver-specifc MRI contrast agents for clinical translation.

Biotin-Conjugated Upconversion KMnF3/Yb/Er Nanoparticles for Metabolic Magnetic Resonance Imaging of the Invasive Margin of Glioblastoma

The incomplete detection of glioblastoma or the remnants of surgery constitute the primary reasons underlying glioblastoma recurrence. However, the current commercial MR Gd-based contrast agents (GBCAs) are not specialized, thus posing a potentially high risk of missed diagnosis or inaccurate boundary identification. MR contrast agents have been widely explored in conjugation with tumor-specific markers to preoperatively diagnose and identify the intraoperative positioning of glioblastoma. Herein, we developed a type of upconversion nanoparticle (UCNP), KMnF3:18%Yb, 2%Er, via the typical hydrothermal method, which possesses unique MR upconversion luminescence bimodal imaging. Furthermore, UCNPs were transformed to the aqueous phase by replacing oleic acid with amine–polyethylene glycol (PEG)–thiol (NH2–PEG–SH), further enabling the covalent conjugation of the glioblastoma metabolic ligand biotin. The as-prepared multifunctional biotin/PEG–UCNPs were characterized using various techniques. Moreover, their biocompatibility, especially with the brain, was systematically assessed via histological and hematological examinations. The results indicated negligible toxicity in vivo. As a proof of concept, biotin/PEG–UCNPs exhibited considerable potential for accurate definition of glioma infiltration boundaries for surgery as metabolic dual imaging contrast agents.

Gadolinium contrast agents: dermal deposits and potential effects on epidermal small nerve fibers

Small fiber neuropathy (SFN) affects unmyelinated and thinly myelinated nerve fibers causing neuropathic pain with distal distribution and autonomic symptoms. In idiopathic SFN (iSFN), 30% of the cases, the underlying aetiology remains unknown. Gadolinium (Gd)-based contrast agents (GBCA) are widely used in magnetic resonance imaging (MRI). However, side-effects including musculoskeletal disorders and burning skin sensations were reported. We investigated if dermal Gd deposits are more prevalent in iSFN patients exposed to GBCAs, and if dermal nerve fiber density and clinical parameters are likewise affected. 28 patients (19 females) with confirmed or no GBCA exposure were recruited in three German neuromuscular centers. ISFN was confirmed by clinical, neurophysiological, laboratory and genetic investigations. Six volunteers (two females) served as controls. Distal leg skin biopsies were obtained according to European recommendations. In these samples Gd was quantified by elemental bioimaging and intraepidermal nerve fibers (IENF) density via immunofluorescence analysis. Pain phenotyping was performed in all patients, quantitative sensory testing (QST) only in a subset (15 patients; 54%). All patients reported neuropathic pain, described as burning (n = 17), jabbing (n = 16) and hot (n = 11) and five QST scores were significantly altered. Compared to an equal distribution significantly more patients reported GBCA exposures (82%), while 18% confirmed no exposures. Compared to unexposed patients/controls significantly increased Gd deposits and lower z-scores of the IENF density were confirmed in exposed patients. QST scores and pain characteristics were not affected. This study suggests that GBCA exposure might alter IENF density in iSFN patients. Our results pave the road for further studies investigating the possible role of GBCA in small fiber damage, but more investigations and larger samples are needed to draw firm conclusions.

Intracellular Construction of Cathepsin B-Guided Gadolinium Nanoparticles for Enhanced T2 -Weighted MR Tumor Imaging.

Magnetic resonance imaging (MRI) is a superior and noninvasive imaging technique with unlimited tissue penetration depth and superb spatiotemporal resolution, however, using intracellular self-assembly of Gd-containing nanoparticles to enhance the T2 -weighted MR contrast of cancer cells in vivo for precise tumor MRI is rarely reported. The lysosomal cysteine protease cathepsin B (CTSB) is regarded as an attractive biomarker for the early diagnosis of cancers and metastasis. Herein, taking advantage of a biocompatible condensation reaction, a "smart" Gd-based CTSB-responsive small molecular contrast agent VC-Gd-CBT is developed, which can self-assemble into large intracellular Gd-containing nanoparticles by glutathione reduction and CTSB cleavage to enhance the T2 -weighted MR contrast of CTSB-overexpressing MDA-MB-231 cells at 9.4T. In vivo T2 -weighted MRI studies using MDA-MB-231 murine xenografts show that the T2 -weighted MR contrast change of tumors in VC-Gd-CBT-injected mice is distinctly larger than the mice injected with the commercial agent gadopentetate dimeglumine, or co-injected with CTSB inhibitor and VC-Gd-CBT, indicating that the accumulation of self-assembled Gd-containing nanoparticles at tumor sites effectively enhances the T2 -weighted MR tumor imaging. Hence, this CTSB-targeted small molecule VC-Gd-CBT has the potential to be employed as a T2 contrast agent for the clinical diagnosis of cancers at an early stage.

Silicone-based materials with tailored MR relaxation characteristics for use in reduced coil visibility and in tissue-mimicking phantom design.

The development of materials with tailored signal intensity in MR imaging is critically important both for the reduction of signal from non-tissue hardware, as well as for the construction of tissue-mimicking phantoms. Silicone-based phantoms are becoming more popular due to their structural stability, stretchability, longer shelf life, and ease of handling, as well as for their application in dynamic imaging of physiology in motion. Moreover, silicone can be also used for the design of stretchable receive radio-frequency (RF) coils. Fabrication of materials with tailored signal intensity for MRI requires knowledge of precise T1 and T2 relaxation times of the materials used. In order to increase the range of possible relaxation times, silicone materials can be doped with gadolinium (Gd). In this work, we aim to systematically evaluate relaxation properties of Gd-doped silicone material at a broad range of Gd concentrations and at three clinically relevant magnetic field strengths (1.5 T, 3 T, and 7 T). We apply the findings for rendering silicone substrates of stretchable receive RF coils less visible in MRI. Moreover, we demonstrate early stage proof-of-concept applicability in tissue-mimicking phantom development. Ten samples of pure and Gd-doped Ecoflex silicone polymer samples were prepared with various Gd volume ratios ranging from 1:5000 to 1:10, and studied using 1.5T and 3T clinical and 7T preclinical scanners. T1 and T2 relaxation times of each sample were derived by fitting the data to Bloch signal intensity equations. A receive coil made from Gd-doped Ecoflex silicone polymer was fabricated and evaluated in vitro at 3T. With the addition of a Gd-based contrast agent, it is possible to significantly change T2 relaxation times of Ecoflex silicone polymer (from 213ms to 20ms at 1.5T; from 135ms to 17ms at 3T; and from 111.4ms to 17.2ms at 7T). T1 relaxation time is less affected by the introduction of the contrast agent (changes from 608ms to 579ms; from 802.5ms to 713ms at 3T; from 1276ms to 979ms at 7T). First results also indicate that liver, pancreas, and white matter tissues can potentially be closely mimicked using this phantom preparation technique. Gd-doping reduces the appearance of the silicone-based coil substrate during the MR scan by up to 81%. Gd-based contrast agents can be effectively used to create Ecoflex silicone polymer-based phantoms with tailored T2 relaxation properties. The relative low cost, ease of preparation, stretchability, mechanical stability, and long shelf life of Ecoflex silicone polymer all make it a good candidate for "MR invisible" coil development and bears promise for tissue-mimicking phantom development applicability.

Investigation of anthropogenic gadolinium in tap water of polish cities: Gdańsk, Kraków, Warszawa, and Wrocław

In urban areas where tap water is often produced by a purification of water supplied from a river bank filtration, a significant fraction of gadolinium (Gd) total pool is of an anthropogenic origin. It happens because Gd-based contrast agents used in Magnetic Resonance Imaging (MRI) are not removed during wastewater treatment and they are discharged to the environment and returned to the water cycle. Despite the growing number of MRI examinations worldwide, little is known about the anthropogenic Gd in Polish surface water as well as drinking water. The aim of this pilot study was to gain information about the occurrence of emergent pollution as Gd in potable water available for inhabitants of Polish municipal areas. Tap water samples from Gdańsk, Kraków, Wrocław and Warszawa were analyzed by an inductively coupled plasma quadrupole mass spectrometry after their preconcentration by a seaFAST-pico chromatographic system. In this study, the sum of REE was in the range registered in the drinking waters of European urban regions (usually below 100 ng/L). The highest values of the sum of REE total concentrations were observed in the tap water samples collected in Warszawa (37.7 ng/L) and Wrocław (35.9 ng/L and 32.9 ng/L), where water supplies originate from the Wisła River and Oława River, respectively. The highest total Gd concentration was observed in the tap water of Warszawa city where the anthropogenic Gd fraction represented about 90% of the total Gd. The lowest values of the sum REE were registered in tap waters of Gdańsk (sum of REE below 2.2 ng/L) with up to 17% of the anthropogenic Gd. Thus, our study showed the occurrence of the anthropogenic Gd in all analyzed tap waters.

Rapid In Vitro Quantification of a Sensitized Gadolinium Chelate via Photoinduced Triplet Harvesting.

Gadolinium (Gd) based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI) and are paramount to cancer diagnostics and tumor pharmacokinetic analysis. Accurate quantification of gadolinium concentration is essential to monitoring the biodistribution, clearance, and pharmacodynamics of GBCAs. However, current methods of quantifying gadolinium in blood or plasma (biological media) are both low throughput and clinically unavailable. Here, we have demonstrated the use of a sensitized gadolinium chelate, Gd[DTPA-cs124], as an MRI contrast agent that can be used to measure the concentration of gadolinium via luminescence quantification in biological media following transmetalation with a terbium salt. Gd[DTPA-cs124] was synthesized by conjugating carbostyril-124 (cs124) to diethylenetriaminepentaacetic acid (DTPA) and chelating to gadolinium. We report increases in both stability and relaxivity compared to the clinically approved analog Gd[DTPA] (gadopentetic acid or Magnevist). In vivo MRI experiments were conducted using C57BL6 mice in order to further illustrate the performance of Gd[DTPA-cs124] as an MRI contrast agent in comparison to Magnevist. Our results indicate that similar chemical modification to existing clinically approved GBCA may likewise provide favorable property changes, with the ability to be used in a gadolinium quantification assay. Furthermore, our assay provides a straightforward and high-throughput method of measuring gadolinium in biological media using a standard laboratory plate reader.

Non-invasive diagnosis of acute kidney injury using Mn-doped carbon dots-based magnetic resonance imaging.

As Gd-based contrast agents suffer from the risk of causing nephrogenic systemic fibrosis, less toxic contrast agents are urgently needed in contrast-enhanced magnetic resonance imaging (CE-MRI) of kidney injury. Herein, we develop a non-invasive diagnosis method for acute kidney injury using CE-MRI based on manganese-doped carbon dots (Mn-CDs). The synthesized Mn-CDs possess an ultrasmall size of 5 nm, good biocompatibility, and a high T1 relaxation rate (10.8 mM-1 s-1), which can produce effective positive enhancement in the kidneys and clearly show the fine structures of the kidneys including the cortex, outer medulla, and inner medulla. In an acute kidney injury model, Mn-CDs-based CE-MRI can not only accurately and intuitively reveal the site of kidney injury consistent with the pathological analysis, but also reflect the functional changes in the injured kidney. Collectively, our study provides a new strategy for the non-invasive diagnosis of acute kidney injury using CE-MRI based on Mn-CDs.

Effect of gadopentetate dimeglumine on bone growth in zebrafish caudal fins

Compared with MR plain scanning, gadolinium (Gd)-enhanced MR scanning can provide more diagnostic information. Gadopentetate dimeglumine is generally used as an MR enhancement contrast agent in some countries. It is a member of linear Gd-based contrast agents (GBCAs) which are considered more likely to release free Gd ions (Gd3+) than macrocyclic GBCAs. Gd3+ is one of the most effective known calcium antagonists, and can compete with calcium ions (Ca2+) in Ca2+-related biological reactions. In this study, animal models of tissue regeneration were established by cutting the caudal fins of zebrafish, and the models were exposed with gadopentetate dimeglumine solution for different immersion times of 1, 3, and 5 min. Three GBCA exposures per week were performed in the first 3 weeks of the follow-up time. Morphological parameters such as regenerative area (RA), bone density, bone thickness and regenerative bone volume (RBV) were quantified using a camera and synchrotron radiation micro CT. RA decreased as total Gd intake increased in both the female group (ρ = −0.784, P < 0.0001) and the male group (ρ = −0.471, P = 0.011). The bone density of the regenerated bone increased after Gd exposure in the treated groups. The morphology of the regenerated bone from the treated groups became shorter and thicker. Our results showed that gadopentetate dimeglumine had osteogenic toxicity in zebrafish.

Exploring EPR Parameters of 187Re Complexes for Designing New MRI Probes: From the Gas Phase to Solution and a Model Protein Environment

Breast cancer is one of the major types of cancer around the world, and early diagnosis is essential for successful treatment. New contrast agents (CAs), with reduced toxicology, are needed to improve diagnosis. One of the most promising Magnetic Resonance Imaging (MRI) CA is based on rhenium conjugated with a benzothiazole derivate (ReABT). In this sense, DFT has been used to evaluate the best methodology for calculating the hyperfine coupling constant (Aiso) of ReABT. Then, a thermodynamic analysis was performed to confirm the stability of the complex. Furthermore, a docking study of ReABT at the enzyme PI3K active site and Aiso calculations of ReABT in the enzyme environment were carried out. The best methodology for the Aiso calculation of ReABT was using the M06L functional, SARC-ZORA-TZVP (for Re) and TZVP (for all other atoms) basis set, relativistic Hamiltonian, and the CPCM solvation model with water as the solvent which confirm that the relativistic effects are important for calculating the Aiso values. In addition, thermodynamic analysis indicates that ReABT presents a higher stability and a lower toxicity than Gd-based CAs. The docking studies point out that ReABT interacts with amino acids residues of alanine, aspartate, and lysine from the PI3K active site. Considering the enzyme environment, Aiso values decrease significantly. These findings indicate that the CA candidate ReABT could be a good candidate for a new contrast agent.

Facile Synthesis of Weakly Ferromagnetic Organogadolinium Macrochelates-Based T1 -Weighted Magnetic Resonance Imaging Contrast Agents.

To surmount the major concerns of commercial small molecule Gd chelates and reported Gd-based contrast agents (GBCAs) for magnetic resonance imaging (MRI), a new concept of organogadolinium macrochelates (OGMCs) constructed from the coordination between Gd3+ and macromolecules is proposed. A library of macromolecules were screened for Gd3+ coordination, and two candidates [i.e., poly(acrylic acid) (PAA), and poly(aspartic acid) (PASP)] succeeded in OGMC formation. Under optimized synthesis conditions, both Gd-PAA12 and Gd-PASP11 OGMCs are outstanding T1 -weighted CAs owing to their super high r1 values (> 50mm-1 s-1 , 3.0T) and ultralow r2 /r1 ratios (< 1.6, 3.0T). The ferromagnetism of OGMCs is completely different from the paramagnetism of commercial and reported GBCAs. The ferromagnetism is very weak (Ms <1.0emug-1 ) leading to a low r2 , which is preferred for T1 MRI. Gd3+ is not released from the OGMC Gd-PAA12 and Gd-PASP11, ensuring biosafety for in vivo applications. The safety and T1 -weighted MRI efficiencies of the OGMC Gd-PAA12 and Gd-PASP11 are tested in cells and mice. The synthesis method of the OGMCs is facile and easy to be scaled up. Consequently, the OGMC Gd-PAA12 and Gd-PASP11 are superior T1 -weighted CAs with promising translatability to replace the commercial Gd chelates.

Rare earth elements and yttrium in suspension-feeding bivalves (dog cockle, Glycymeris glycymeris L.): Accumulation, vital effects and pollution

Rare earth element (REE) and Y (REY) concentrations were determined in soft tissues and shells prepared from 9 to 93 years old dog cockles sampled alive from a marine site in NW Brittany, France. The concentrations shown by the different soft tissues and shells are extremely variable ranging from 9·10−5 to 10−1 × PAAS. The mantle is the organ with the highest concentrations, while the feet, the adductor muscles and the digestive glands display the lowest ones. Relative to the masses of the different organs, we show that the shell concentrates >85% of the REY contained in an animal, and the mantle, which represents less than 0.5% of the total animal mass (on a dry basis), contains 10% of the total REY. Organs accumulate REY throughout the life of the animal. REY concentrations in soft tissues increase by more than one order of magnitude in 90 years. The shells mirror the REY abundances of the mantle but are slightly less light-REE enriched than the latter. Furthermore, shells as well as feet and adductor muscles show a striking correlation between animal age and Ce/Ce* ratios. Ce/Ce* ratios evolve from 0.8 for animals aged ∼10 years to 1 for the oldest, with most of the variation during the first 25 years, indicating that Ce also accompanies biochemical reactions probably related to the growth or maturity of the animals.Soft tissues also show extremely variable positive Gd anomalies (Gd/Gd*= 1.04–1.94) which indicate environmental pollution by Gd based contrast agents (GBCA) used in medical imaging. Anomalies tend to be more important for organs poor in REY (like muscles and digestive glands). Low excesses of Gd, on the order of 1–3 ng/g (on a dry basis), account for these anomalies. There is no correlation between the age of the animals and the amount of anthropogenic Gd or Gd/Gd* ratios suggesting that GBCAs do not accumulate in the bivalve body on a long-term basis.

Signal Amplification Pretargeted PET/Fluorescence Imaging Based on Human Serum Albumin-Encapsulated GdF3 Nanoparticles for Diagnosis of Ovarian Cancer.

Different modal imaging techniques could be complementary in tumor diagnosis. Human serum albumin (HSA)-encapsulated GdF3 nanoparticles were developed as T1 magnetic resonance imaging (MRI) contrast agents. However, no significant T1 enhancement in the tumor site of the SKOV3 human ovarian cancer xenograft tumor model was observed within 3 h after injection of tetrazine-modified GdF3@HSA NPs through small-animal MRI. After intravenous injection of 18F (or Cy7)-labeled Reppe anhydride, pretargeted positron emission tomography (PET) (near-infrared (NIR) fluorescence) imaging was used to reveal the pharmacokinetics of GdF3@HSA NPs in the SKOV3 xenograft mouse model to locate the tumor. The probe based on Reppe anhydride achieved rapid ligation with tetrazine-modified GdF3@HSA nanoparticles (NPs), which accumulated in tumor through Reppe anhydride/tetrazine bioorthogonal chemistry. This pretargeting strategy enabled excellent tumor visualization and quantification at an early period after nanoparticle injection (3 h p.i.), while the MRI images with significant T1 enhancement could be obtained until 24 h after injection of Gd-based contrast agents only. In vivo pretargeted multimodal imaging based on the tetrazine/Reppe anhydride system using HSA-encapsulated GdF3 nanoparticles would be beneficial for amplification of the imaging signal in the disease site and enhancing diagnostic efficiency.

Gadolinium and Bio-Metal Association: A Concentration Dependency Tested in a Renal Allograft and Investigated by Micro-Synchrotron XRF.

Aims: This study aimed to investigate gadolinium (Gd) and bio-metals in a renal allograft of a patient who was shortly after transplantation repeatedly exposed to a Gd-based contrast agent (GBCA), with the purpose of determining whether Gd can be proven and spatially and quantitatively imaged. Further elemental associations between Gd and bio-metals were also investigated. Materials and Methods: Archival paraffin-embedded kidney tissue (eight weeks after transplantation) was investigated by microscopic synchrotron X-ray fluorescence (µSRXRF) at the DORIS III storage ring, beamline L, at HASYLAB/DESY (Hamburg, Germany). For the quantification of elements, X-ray spectra were peak-fitted, and the net peak intensities were normalized to the intensity of the incoming monochromatic beam intensity. Concentrations were calculated by fundamental parameter-based program quant and external standardization. Results: Analysis of about 15,000 µSRXRF spectra (comprising allograft tissue of four cm2) Gd distribution could be quantitatively demonstrated in a near histological resolution. Mean Gd resulted in 24 ± 55 ppm with a maximum of 2363 ppm. The standard deviation of ±55 ppm characterized the huge differences in Gd and not in detection accuracy. Gd was heterogeneously but not randomly distributed and was mostly found in areas with interstitial fibrosis and tubular atrophy. Concentrations of all other investigated elements in the allograft resembled those found in normal kidney tissue. No correlations between Gd and bio-metals such as calcium, strontium or zinc below ~40 ppm Gd existed. In areas with extremely high Gd, Gd was associated with iron and zinc. Conclusions: We could show that no dose-dependent association between Gd and bio-metals exists—least in renal tissue—at Gd concentrations below ~40 ppm Gd. This was proven compared with a GBCA-exposed end-stage renal failure in which the mean Gd was ten-fold higher. Our results could shed additional light on Gd metabolism.

Gadolinium retention in the ischemic cerebrum: Implications for pain, neuron loss, and neurological deficits.

To investigate the effects of gadolinium (Gd) retention of macrocyclic (gadobutrol) or linear (gadopentetate) Gd-based contrast agents (GBCAs) on neuron loss, neurological deficits, and sensory behavior in mice with or without stroke. Ninety C57BL/6 mice underwent sham (n=36) or transient middle cerebral artery occlusion (tMCAO) (n=54) surgery and then received intraperitoneal injections of 5.0 mmol/kg gadobutrol, 5.0 mmol/kg gadopentetate or saline (10ml/kg/administration) per day for 3 consecutive days. The Gd concentration in the ischemic cerebrum was quantified by inductively coupled plasma mass spectrometry on Day 1 and Day 28 after the last injection (post-injection, p. i.). Neuron loss, glia activation and neurological deficits were assessed on Day 1 and 28 p. i. Sensory behavior was also assessed on Day 28 p. i. Gd concentrations were higher in the brains of tMCAO mice than in those of sham mice on Days 1 p. i. of both GBCAs (gadobutrol, p&amp;lt; 0.05; gadopentetate, p&amp;lt; 0.001) and 28 p. i of gadopentetate. (p&amp;lt; 0.001). Sham or tMCAO mice injected with GBCAs showed no significant difference in neuron loss, glia activation, neurological deficits, brain atrophy, or hippocampus-dependent memory (all p&amp;gt; 0.05). Both gadobutrol and gadopentetate induced mechanical and heat hyperalgesia in sham mice (all p&amp;lt; 0.05). However, mechanical hyperalgesia but rather heat hyperalgesia was found in tMCAO mice with the highest force tested (1.0g) and statistically significant in both paws (right and left) with gadopentetate only (p&amp;lt; 0.05). Neither gadobutrol nor gadopentetate worsened neuron loss, glia activation, brain atrophy, neurological deficits, or hippocampus-dependent memory after tMCAO. However, GBCA administration induced mechanical hyperalgesia in sham and tMCAO mice although in the same level, which may be an important consideration for patients with central post-stroke pain and those who are sensitive to pain and about to receive multiple GBCA administrations.

Solution Structure and Relaxivity of Ln‐DOTXAZA Derivatives

AbstractHerein we report the synthesis and structural analysis of tunable 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA)‐derivatives bearing azidoethyl side chains. According to the number of azidoethyl side chains, the compounds are termed DOTXAZA (with X=1–4). All derivatives retain the well‐approved DOTA scaffold for metal complexation with 8 coordinating functionalities and are applicable to Cu‐catalyzed alkyne‐azide cycloaddition (CuAAC). They may thus be used to assemble new Gd‐based contrast agents (GBCAs) with tailored pharmacokinetic or MRI properties retaining the high stability of clinically used DOTA‐derived GBCAs. The complex geometry of all DOTXAZA derivatives was investigated in solution with NMR‐spectroscopy of the corresponding Eu‐complexes. A correlation of complex geometry with the longitudinal relaxivity of corresponding Gd‐complexes revealed an increase in relaxivity with increasing substitution number in the DOTXAZA series. Moreover, CuAAC‐modified DOTAZA‐derivatives with neutral, charged, and zwitterionic groups were prepared. Although of similar molecular mass, the corresponding Gd‐complexes revealed pronounced differences in relaxivities from r1=3.9–7.9 mm−1 s−1 in water at 1.5 T and 37 °C. Relaxivities of these complexes were found to be strongly dependent on side chain charge and are most likely determined by second‐sphere water effects.

Metal-Free Radical Dendrimers as MRI Contrast Agents for Glioblastoma Diagnosis: Ex Vivo and In Vivo Approaches

Simultaneously being a nonradiative and noninvasive technique makes magnetic resonance imaging (MRI) one of the highly required imaging approaches for the early diagnosis and follow-up of tumors, specifically for brain cancer. Paramagnetic gadolinium (Gd)-based contrast agents (CAs) are the most widely used ones in brain MRI acquisitions with special interest when assessing blood–brain barrier (BBB) integrity, a characteristic of high-grade tumors. However, alternatives to Gd-based contrast agents (CAs) are highly required to overcome their established toxicity. Organic radicals anchored on a dendrimer macromolecule surface (radical dendrimers) are promising alternatives since they also exhibit paramagnetic properties and can act as T1 CAs like Gd-based CAs while being organic species (mitigating concerns about toxic metal accumulation). Here, we studied the third generation of a water-soluble family of poly(phosphorhydrazone) radical dendrimers, with 48 PROXYL radical units anchored on their branches, exploring their potential of ex vivo and in vivo contrast enhancement in brain tumors (in particular, of immunocompetent, orthotopic GL261 murine glioblastoma (GB)). Remarkably, this radical species provides suitable contrast enhancement on murine GL261 GB tumors, which was comparable to that of commercial Gd-based CAs (at standard dose 0.1 mmol/kg), even at its 4 times lower administered dose (0.025 mmol/kg). Importantly, no signs of toxicity were detected in vivo. In addition, it showed a selective accumulation in brain tumor tissues, exhibiting longer retention within the tumor, which allows performing imaging acquisition over longer time frames (≥2.5 h) as opposed to Gd chelates. Finally, we observed high stability of the radicals in biological media, on the order of hours instead of minutes, characteristic of the isolated radicals. All of these features allow us to suggest that the G3-Tyr-PROXYL-ONa radical dendrimer could be a viable alternative to metal-based MRI contrast agents, particularly on MRI analysis of GB, representing, to the best of our knowledge, the first case of organic radical species used for this purpose and one of the very few examples of these types of radical species working as MRI CAs in vivo.