Gadolinium-based Agents Research Articles

Iron(III)-Quercetin Complex: In Vivo Acute Toxicity and Biodistribution of Novel MRI Agent.

The iron(III)-quercetin complex, known as "IronQ", is an innovative MRI contrast agent composed of one Fe(III) ion and two quercetin molecules. IronQ is efficiently internalized by cells, enabling T1-weighted MRI tracking. It has demonstrated therapeutic benefits in reducing inflammation in an intracerebral hemorrhage (ICH) mouse model and offers a safer alternative to gadolinium-based agents by avoiding cytotoxicity and genotoxicity. These properties make IronQ a promising candidate for safe and effective MRI contrast enhancement. This study aims to further the development of IronQ as an MRI contrast agent by investigating its biodistribution, pharmacokinetics, and acute toxicity in a preclinical animal model. The relaxivity of IronQ was measured in water and whole blood phantoms. Acute toxicity was evaluated in Sprague Dawley rats administered single intraperitoneal doses of IronQ (75, 150, and 225 µmol Fe/kg BW) over a 14-day period. Pharmacokinetic studies were performed at a dose of 150 µmol Fe/kg BW, with blood iron content analyzed using ICP-OES. For in vivo biodistribution, SD rats were administered an intravenous dose of IronQ (225 µmol Fe/kg BW), followed by MR imaging using a 1.5 T scanner and subsequent tissue-ICP analysis. The longitudinal relaxivity (r1) of IronQ was measured to be 2.17mm⁻¹s⁻¹ in ultrapure water and 3.56mm⁻¹s⁻¹ in whole blood. Acute toxicity studies showed no mortality, morbidity, or significant biochemical changes, with histopathology confirming no irreversible organ damage. Pharmacokinetics revealed peak blood iron content at 1.1hours post-administration and clearance within 24hours. MRI demonstrated enhanced T1 signal intensity, particularly in the liver and kidney. These findings provide valuable insights into the safety, pharmacokinetics, and imaging efficacy of IronQ, highlighting its potential as a robust and biocompatible MRI contrast agent.

Synthesis and Relaxivity study of amino acid-branched radical dendrimers as MRI contrast agents for potential brain tumor imaging.

This study introduces a series of water-soluble radical dendrimers (G0 to G5) as promising magnetic resonance imaging (MRI) contrast agents that could potentially address clinical safety concerns associated with current gadolinium-based contrast agents. By using a simplified synthetic approach based on a cyclotriphosphazene core and lysine-derived branching units, we successfully developed a G5 dendrimer containing up to 192 units of 2,2,6,6-Tetramethylpiperidinyloxy (TEMPO) radical. This synthesis offers advantages including ease of preparation, purification, and tunable water solubility through the incorporation of glutamic acid anion residues. Comprehensive characterization using 1H NMR, FT-IR, and SEC-HPLC confirmed the dendrimers' structures and purity. Electron paramagnetic resonance (EPR) spectroscopy revealed that TEMPO groups in higher generation dendrimers exhibited decreased mobility and stronger spin exchange in their local environments. In vitro MRI showed that relaxivity (r1) increased with higher dendrimer generations, with G5 exhibiting an exceptionally high r1 of over 24 mM-1s-1. Molecular dynamics simulations provided crucial insights into structure-property relationships, revealing the importance of water accessibility to TEMPO groups for enhancing relaxivity. Vero cell viability assay demonstrated G3 and G3.5 have good biocompatibility. In vivo MRI experiments in mice demonstrated that G3.5 was excreted through the kidneys and selectively accumulated in glioblastoma tumors. STATEMENT OF SIGNIFICANCE: This study explores a class of MRI contrast agents based on organic radical dendrimers as a potential alternative to gadolinium-based agents. We present a simplified synthesis method for water-soluble dendrimers containing up to 192 TEMPO radical units-the highest number achieved to date for this class of compounds-resulting in record-high relaxivity values. Our approach offers easier preparation, purification, and tunable water solubility, representing an improvement over existing methods. Through combined experimental and computational studies, we provide insights into the structure-property relationships governing relaxivity. In vivo experiments demonstrate the dendrimers' potential for glioblastoma imaging, with predominantly renal excretion. This work represents a step towards developing metal-free MRI contrast agents with promising relaxivity and biocompatibility, potentially opening new avenues for diagnostic imaging research.

Theragnostic Gadolinium-Based Nanoparticles Safely Augment X-ray Radiation Effects in Patients with Cervical Cancer.

Activated guided irradiation by X-ray (AGuIX) nanoparticles are gadolinium-based agents that have the dual benefit of mimicking the effects of a magnetic resonance imaging (MRI) contrast agent used in a clinical routine and enhancing the radiotherapeutic activity of conventional X-rays (for cancer treatment). This "theragnostic" action is explained on the one hand by the paramagnetic properties of gadolinium and on the other hand by the generation of high densities of secondary radiation following the interaction of ionizing radiation and high-Z atoms, which leads to enhanced radiation dose deposits within the tumors where the nanoparticles accumulate. Here, we report the results of a phase I trial that aimed to assess the safety and determine the optimal dose of AGuIX nanoparticles in combination with chemoradiation and brachytherapy in patients with locally advanced cervical cancer. AGuIX nanoparticles were administered intravenously and appropriately accumulated within tumors on a dose-dependent manner, as assessed by T1-weighted MRI, with a rapid urinary clearance of uncaught nanoparticles. We show that the observed tumor accumulation of the compounds can support precise delineation of functional target volumes at the time of brachytherapy based on gadolinium enhancement. AGuIX nanoparticles combined with chemoradiation appeared well tolerated among the 12 patients treated, with no dose-limiting toxicity observed. Treatment yielded excellent local control, with all patients achieving complete remission of the primary tumor. One patient had a distant tumor recurrence. These results demonstrate the clinical feasibility of using theranostic nanoparticles to augment the accuracy of MRI-based treatments while focally enhancing the radiation activity in tumors.

Gadolinium-Based Magnetic Resonance Theranostic Agent with Gallic Acid as an Anti-Neuroinflammatory and Antioxidant Agent.

Studies in the field have actively pursued the incorporation of diverse biological functionalities into gadolinium-based contrast agents, aiming at the amalgamation of MRI imaging and therapeutic capabilities. In this research, we present the development of Gd-Ga, an anti-neuroinflammatory MR contrast agent strategically designed to target inflammatory mediators for comprehensive imaging diagnosis and targeted lesion treatment. Gd-Ga is a gadolinium complex composed of 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetylamide (DO3A) conjugated with gallic acid (3,4,5-trihydroxybenzoic acid). Upon intravenous administration in LPS-induced mouse models, Gd-Ga demonstrated a remarkable three-fold increase in signal-to-noise (SNR) variation compared to Gd-DOTA, particularly evident in both the cortex and hippocampus 30 min post-MR monitoring. In-depth investigations, both in vitro and in vivo, into the anti-neuroinflammatory properties of Gd-Ga revealed significantly reduced protein expression levels of pro-inflammatory mediators compared to the LPS group. The alignment between in silico predictions and phantom studies indicates that Gd-Ga acts as an anti-neuroinflammatory agent by directly binding to MD2. Additionally, the robust antioxidant activity of Gd-Ga was confirmed by its effective scavenging of NO and ROS. Our collective findings emphasize the immense potential of this theranostic complex, where a polyphenol serves as an anti-inflammatory drug, presenting an exceptionally efficient platform for the diagnosis and treatment of neuroinflammation.

CNN-based multi-modal radiomics analysis of pseudo-CT utilization in MRI-only brain stereotactic radiotherapy: a feasibility study

BackgroundPseudo-computed tomography (pCT) quality is a crucial issue in magnetic resonance image (MRI)-only brain stereotactic radiotherapy (SRT), so this study systematically evaluated it from the multi-modal radiomics perspective.Methods34 cases (< 30 cm³) were retrospectively included (2021.9-2022.10). For each case, both CT and MRI scans were performed at simulation, and pCT was generated by a convolutional neural network (CNN) from planning MRI. Conformal arc or volumetric modulated arc technique was used to optimize the dose distribution. The SRT dose was compared between pCT and planning CT with dose volume histogram (DVH) metrics and gamma index. Wilcoxon test and Spearman analysis were used to identify key factors associated with dose deviations. Additionally, original image features were extracted for radiomic analysis. Tumor control probability (TCP) and normal tissue complication probability (NTCP) were employed for efficacy evaluation.ResultsThere was no significant difference between pCT and planning CT except for radiomics. The mean value of Hounsfield unit of the planning CT was slightly higher than that of pCT. The Gadolinium-based agents in planning MRI could increase DVH metrics deviation slightly. The median local gamma passing rates (1%/1 mm) between planning CTs and pCTs (non-contrast) was 92.6% (range 63.5–99.6%). Also, differences were observed in more than 85% of original radiomic features. The mean absolute deviation in TCP was 0.03%, and the NTCP difference was below 0.02%, except for the normal brain, which had a 0.16% difference. In addition, the number of SRT fractions and lesions, and lesion morphology could influence dose deviation.ConclusionsThis is the first multi-modal radiomics analysis of CNN-based pCT from planning MRI for SRT of small brain lesions, covering dosiomics and radiomics. The findings suggest the potential of pCT in SRT plan design and efficacy prediction, but caution needs to be taken for radiomic analysis.

Incidental findings involving the temporomandibular joint on computed tomography and magnetic resonance imaging.

The temporomandibular joint (TMJ) is frequently imaged in head and neck computed tomography (CT) and magnetic resonance imaging (MRI) studies. Depending on the indication for the study, an abnormality of the TMJ may be an incidental finding. These findings encompass both intra- and extra-articular disorders. They may also be related to local, regional or systemic conditions. Familiarity with these findings along with pertinent clinical information helps narrow the list of differential diagnoses. While definitive diagnosis may not be immediately apparent, a systematic approach contributes to improved discussions between clinicians and radiologists and better patient management.

Stem cell–nanomedicine system as a theranostic bio-gadolinium agent for targeted neutron capture cancer therapy

The potential clinical application of gadolinium-neutron capture therapy (Gd-NCT) for glioblastoma multiforme (GBM) treatment has been compromised by the fast clearance and nonspecific biodistribution of gadolinium-based agents. We have developed a stem cell–nanoparticle system (SNS) to actively target GBM for advanced Gd-NCT by magnetizing umbilical cord mesenchymal stem cells (UMSCs) using gadodiamide-concealed magnetic nanoparticles (Gd-FPFNP). Nanoformulated gadodiamide shielded by a dense surface composed of fucoidan and polyvinyl alcohol demonstrates enhanced cellular association and biocompatibility in UMSCs. The SNS preserves the ability of UMSCs to actively penetrate the blood brain barrier and home to GBM and, when magnetically navigates by an external magnetic field, an 8-fold increase in tumor-to-blood ratio is achieved compared with clinical data. In an orthotopic GBM-bearing rat model, using a single dose of irradiation and an ultra-low gadolinium dose (200 μg kg−1), SNS significantly attenuates GBM progression without inducing safety issues, prolonging median survival 2.5-fold compared to free gadodiamide. The SNS is a cell-based delivery system that integrates the strengths of cell therapy and nanotechnology, which provides an alternative strategy for the treatment of brain diseases.

A Retrospective study of contrast media related adverse drug reactions at tertiary hospital in South India

: Adverse drug reaction not only occurs with curative, preventive and palliative drugs but also with diagnostic tools like radio contrast agents which are used for enhancement of images. Timely and incessant reporting of adverse drug reaction with various agents is necessary to reduce the incidence. The study aims to find out the trend of contrast media related adverse drug reactions from 2016 to 2021. A retrospective observational study was conducted on adverse drug reactions reported to the adverse drug reaction monitoring centre at tertiary care hospital in South India. All the adverse drug reactions related to various contrast agents used in computed tomography and magnetic resonance imaging were recorded. Patients’ demographic details, individual contrast agent, clinical manifestations of reactions, severity, causality were mentioned in descriptive statistics. : A total of 218 (16%) adverse drug reaction were reported due to various contrast media including non-ionic iodinated and gadolinium-based agents. The incidence of adverse drug reactions with radio contrast agents varies between 0.23% - 0.35%. 89% of symptoms were itching and rashes. Using the WHO-UMC (Uppsala monitoring centre) causality assessment scale, 87% of adverse drug reactions were categorized as ‘probable’. : Unavoidable and untoward reactions can happen in any patient with any contrast agent. With the introduction of newer agents for last six years reactions continue to occur in same proportion. There is no culprit agent, but being ‘vigilante’ on reactions and timely reporting is necessary.

ANGI-05. VASCULAR NORMALIZATION IN MURINE GLIOBLASTOMA IS CONTROLLED BY APLN-SIGNALING AND CAN BE MONITORED BY DCE-MR IMAGING IN VIVO

Abstract OBJECTIVE Glioblastoma (GBM) expansion is accompanied by aberrant tumor vascularization. We demonstrated that the peptide hormone Apelin (APLN) controls GBM neo-vascularization and that the APLN-receptor antagonist Apelin-F13A improved the efficiency and reduced the invasive side effect of established antiangiogenic therapy. Here we investigated if Apelin-F13A blunts the formation of vasogenic edema, which can be monitored by MRI in vivo. METHODS To investigate the role of APLN -signaling in regulating the tightness of the tumor vasculature we performed in vivo leakage assays using Evans-Blue dye and fluorescent dextran. By confocal immunofluorescence, we characterized the maturation of the tumor vasculature with respect to pericyte-coverage and established a dynamic contrast enhanced (DCE) MR imaging protocol to follow vascular edema formation. RESULTS We found that Evans-Blue extravasation is significantly increased by 3-fold in APLNKO tumors compared to controls. Uptake of fluorescent Dextran by CD31+ endothelia was quantified and increased massively from 200μm2 per high magnification field (HMF) in wildtype to 3500μm2 per HMF in APLNKO tumors. Interestingly, intracerebral infusion of Apelin-F13A enhanced pericyte coverage of the tumor vasculature by 50%, decreased Evans-Blue extravasation from 25 μg/ml in controls to 8 μg/ml in treated tumors significantly and efficiently reversed the APLN-dependent vasogenic edema assessed by comparison of T2w-MRI to HE tumor volumes. To follow vasogenic edema formation in vivo, T1w 3D FLASH images were acquired every second over a 360s time course after gadolinium-based MR-contrast agent injection and demonstrated a delayed washout of the contrast in APLN-deficient GBM. CONCLUSION Together, our study shows that DCE-MRI can document APLN-dependent intratumoral vascular normalization and allows inspecting vasogenic edema formation in vivo. In addition to its anti-angiogenic / anti-invasive effect, Apelin-F13A can potently reduce vasogenic edema and might thus serve as a multimodal therapy for the treatment of human GBM in the future.

Stability testing of gadoteridol and gadobenate dimeglumine formulations under exposure to high-intensity focused ultrasound.

Contrast-enhanced MRI could be useful to guide high-intensity focused ultrasound treatment (HIFU), but the effects of HIFU on gadolinium-based agents is not known. Here, we tested in vitro the stability of gadoteridol and gadobenate dimeglumine, two widely used MR contrast agents, after exposure to HIFU at power levels typically applied in the clinical practice. 0.5 M (gadoteridol and gadobenate dimeglumine) and diluted formulations (1:10 gadoteridol in saline) were exposed to different HIFU sequences. Unexposed and exposed solutions were characterized by high-performance liquid chromatography in terms of concentration of gadolinium complex, free gadolinium and free ligand. Gadoteridol formulation after treatment showed concentrations of the complex not significantly different from control. Free Gd and/or free ligand concentrations in the order of 0.002/0.004% w/w, were observed occasionally without significant correlation with intensity and duration of exposure to HIFU. Gadobenate dimeglumine formulation after treatment showed complex assay content values, by-products (0.24-0.26%) and free BOPTA levels (0.07%) comparable to control sample within the experimental error. In the range of conditions explored, HIFU exposure did not induce significant dissociations of gadoteridol and gadobenate dimeglumine, nor a detectable increase in the concentration of free species. Our study strengthens the hypothesis that gadolinium-based contrast agents are stable during HIFU treatment for body applications (e.g. thermal ablation of uterine fibroids).

Using micro-synchrotron radiation x-ray fluorescence (µ-SRXRF) for trace metal imaging in the development of MRI contrast agents for prostate cancer imaging

BackgroundContrast agents (CA) are administered in magnetic resonance imaging (MRI) clinical exams to measure tissue perfusion, enhance image contrast between adjacent tissues, or provide additional biochemical information in molecular MRI. The efficacy of a CA is determined by the tissue distribution of the agent and its concentration in the extracellular space of all tissues. MethodsIn this work, micro-synchrotron radiation x-ray fluorescence (µ-SRXRF) was used to examine and characterize a gadolinium-based zinc-sensitive agent (GdL2) currently under development for detection of prostate cancer (PCa) by MRI. Prostate tissue samples were collected from control mice and mice with known PCa after an MRI exam that included injection of GdL2. The samples were raster scanned to investigate trends in Zn, Gd, Cu, Fe, S, P, and Ca. ResultsSignificant Zn and Gd co-localization was observed in both healthy and malignant tissues. In addition, a marked decrease in Zn was found in the lateral lobe of the prostate obtained from mice with PCa. ConclusionWe demonstrate here that µ-SRXRF is a useful tool for monitoring the distribution of several elements including Zn and Gd in animal models of cancer. The optimized procedures for tissue preparation, processing, data collection, and analysis are described.

Myocardial Approximate Spin-lock Dispersion Mapping using a Simultaneous T2 and TRAFF2 Mapping at 3T MRI.

Ischemic heart disease (IHD) is one of the leading causes of death worldwide. Myocardial infarction (MI) represents a third of all IHD cases, and cardiac magnetic resonance imaging (MRI) is often used to assess its damage to myocardial viability. Late gadolinium enhancement (LGE) is the current gold standard, but the use of gadolinium-based agents limits the clinical applicability in some patients. Spin-lock (SL) dispersion has recently been proposed as a promising non-contrast biomarker for the assessment of MI. However, at 3T, the required range of SL preparations acquired at different amplitudes suffers from specific absorption rate (SAR) limitations and off-resonance artifacts. Relaxation Along a Fictitious Field (RAFF) is an alternative to SL preparations with lower SAR requirements, while still sampling relaxation in the rotating frame. In this study, a single breath-hold simultaneous TRAFF2 and T2 mapping sequence is proposed for SL dispersion mapping at 3T. Excellent reproducibility (coefficient of variations lower than 10%) was achieved in phantom experiments, indicating good intrascan repeatability. The average myocardial TRAFF2, T2, and SL dispersion obtained with the proposed sequence (68.0±10.7 ms, 44.0±4.0 ms, and 0.4±0.2 ×10-4 s2, respectively) were comparable to the reference methods (62.7±11.7 ms, 41.2±2.4 ms, and 0.3±0.2x 10-4s2, respectively). High visual map quality, free of B0 and B1+ related artifacts, for T2, TRAFF2, and SL dispersion maps were obtained in phantoms and in vivo, suggesting promise in clinical use at 3T. Clinical relevance - and imaging promises non-contrast assessment of scar and focal fibrosis in a single breath-hold using approximate spin-lock dispersion mapping.

Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218.

ObjectivesPreclinical assessments were performed according to the US Food and Drug Administration guidelines to determine the physicochemical properties, pharmacokinetics, clearance, safety, and tumor-specific magnetic resonance (MR) imaging of MT218, a peptidic gadolinium-based MR imaging agent targeting to extradomain B fibronectin for MR molecular imaging of aggressive tumors.Materials and MethodsRelaxivity, chelation stability, binding affinity, safety-related target profiling, and effects on CYP450 enzymes and transporters were evaluated in vitro. Magnetic resonance imaging was performed with rats bearing prostate cancer xenografts, immunocompetent mice bearing murine pancreatic cancer allografts, and mice bearing lung cancer xenografts at different doses of MT218. Pharmacological effects on cardiovascular, respiratory, and central nervous systems were determined in rats and conscious beagle dogs. Pharmacokinetics were tested in rats and dogs. Biodistribution and excretion were studied in rats. Single and repeated dosing toxicity was evaluated in rats and dogs. In vitro and in vivo genotoxicity, in vitro hemolysis, and anaphylactic reactivity were also performed.ResultsAt 1.4 T, the r1 and r2 relaxivities of MT218 were 5.43 and 7.40 mM−1 s−1 in pure water, 6.58 and 8.87 mM−1 s−1 in phosphate-buffered saline, and 6.54 and 8.70 mM−1 s−1 in aqueous solution of human serum albumin, respectively. The binding affinity of MT218 to extradomain B fragment is 3.45 μM. MT218 exhibited no dissociation of the Gd(III) chelates under physiological conditions. The peptide degradation half-life (t1/2) of MT218 was 1.63, 5.85, and 2.63 hours in rat, dog, and human plasma, respectively. It had little effect on CYP450 enzymes and transporters. MT218 produced up to 7-fold increase of contrast-to-noise ratios in the extradomain B fibronectin–rich tumors with a dose of 0.04 mmol/kg for at least 30 minutes. MT218 had little pharmacological effect on central nervous, cardiovascular, or respiratory systems. MT218 had a mean plasma elimination half-life (t1/2) of 0.31 and 0.89 hours in rats and dogs at 0.1 mmol/kg, respectively. No detectable Gd deposition was observed in the brain at 6 hours postinjection of MT218 at 0.1 mmol/kg in rats. MT218 was not mutagenic and had no mortality or morbidity in the rats or dogs up to 1.39 and 0.70 mmol/kg/d, respectively. The no observed adverse effect level of MT218 in Sprague-Dawley rats was 1.39 mmol/kg for single dosing and 0.46 mmol/kg/d for repeated dosing. The no observed adverse effect level in dogs was 0.07 mmol/kg/d. MT218 exhibited no genotoxicity, hemolysis, and anaphylactic reactivity.ConclusionThe preclinical assessments showed that the targeted contrast agent MT218 has high r1 and r2 relaxivities, satisfactory physicochemical properties, pharmacokinetic, and safety profiles and produces effective tumor enhancement in multiple cancer types in rats and mice at reduced doses.

Assessment of genetic damage induced by gadolinium-based radiocontrast agents

BackgroundToday, although gadolinium based contrast agents have been frequently used in the field of medicine, there is limited data available whether gadolinium based agents affect the genome. AimThe present study aimed to investigate the genotoxic and cytotoxic potentials of gadoteric acid and gadoversetamide used as gadolinium-based contrast agents for magnetic resonance (MR) imaging. Material and methodsThe cytokinesis-block micronucleus assay was applied to human peripheral blood lymphocytes to assess the genotoxicity measured as micronucleus (MN), nucleoplasmic bridge (NPBs) and nuclear bud (NBUDs) frequencies. Furthermore, cytokinesis-block proliferation index (CBPI) was calculated to determine cytostasis. Lymphocytes were treated with gadoteric acid at concentrations of 1.0, 2.5, 5.0, and 25 mM and with gadoversetamide at concentrations of 0.25, 1.0, 2.5, and 5.0 mM for 48 h. ResultsGadoteric acid did not cause significant increase in MN, NBPs and NBUDs frequencies and CBPI values at any concentration. Gadoversetamide induced significantly increase MN formation at concentration of 2.5 mM, NBP formation at concentrations of 1.0 and 2.5 mM, and NBUD formation at concentrations of 0.25, 1.0 and 2.5 mM. Additionally, gadoversetamide exposure resulted in statistically significant decrease in CBPI values compared to the control at concentrations of 2.5 and 5.0 mM. In addition, CBPI levels in response to concentrations of gadoversetamide was negatively and significantly associated with concentration. ConclusionThese findings show that gadoteric acid does not have genotoxic or cytotoxic potential, while gadoversetamide might have both genotoxic and cytotoxic potential on human peripheral blood lymphocytes. As a comparison, gadoversetamide was found more genotoxic and cytotoxic.

Tolerance of peritoneal and residual renal function to intraperitoneal gadolinium-based agents: An animal experimental study of magnetic resonance peritoneography.

MR (Magnetic resonance) peritoneography is sensible for continuous ambulatory peritoneal dialysis (CAPD)-related complications, which could offer excellent soft-tissue contrast and allows a multiplanar imaging evaluation of complications. However, there is no study about the optimal concentration of the gadolinium-based agents nor the side effects of gadolinium-based agents on peritoneum and residual renal function. Five different groups of uremic rats and two groups of normal rats were injected with a 40-ml mixture of peritoneal dialysate and gadolinium-based agents at varying concentrations prior to MR peritoneography. Thereafter, MR image obtained was evaluated by two experienced radiologists blinded to the concentrations. Peritoneal morphology and thickness of the uremic rats were also assessed using hematoxylin and eosin and Masson staining. Residual renal function was evaluated using serum creatinine levels and hematoxylin and eosin (HE) staining of pathological kidney sections. The gadolinium-based agents used in this experiment have no significant effect on residual renal function. There is no obvious difference in the image quality at the different gadolinium-based agents concentration. Due to the adverse effects of gadolinium-based agents in the previous studies, we suggest reducing the dose of gadolinium-based agents during MR peritoneography to the lowest limits.

Quantification of Gastric Contractions Using MRI with a Natural Contrast Agent.

Gastric motility has an essential role in mixing and the breakdown of ingested food. It can affect the digestion process and the efficacy of the orally administered drugs. There are several methods to image, measure, and quantify gastric motility. MRI has been shown to be a suitable non-invasive method for gastric motility imaging. However, in most studies, gadolinium-based agents have been used as an oral contrast agent, making it less desirable for general usage. In this study, MRI scans were performed on 4 healthy volunteers, where pineapple juice was used as a natural contrast agent for imaging gastric motility. A novel method was developed to automatically estimate a curved centerline of the stomach. The centerline was used as a reference to quantify contraction magnitudes. The results were visualized as contraction magnitude-maps. The mean speed of each contraction wave on the lesser and greater curvatures of the stomach was calculated, and the variation of the speeds in 4 regions of the stomach were quantified. There were 3-4 contraction waves simultaneously present in the stomach for all cases. The mean speed of all contractions was 2.4±0.9 mm/s, and was in agreement with previous gastric motility studies. The propagation speed of the contractions in the greater curvature was higher in comparison to the lesser curvature (2.9±0.8 vs 1.9±0.5 mm/s); however, the speeds were more similar near to the pylorus. This study shows the feasibility of using pineapple juice as a natural oral contrast agent for the MRI measurements of gastric motility. Also, it demonstrated the viability of the proposed method for automatic curved centerline estimation, which enables practical clinical translation.Clinical Relevance- MRI is able to non-invasively provide dynamic images of the contraction patterns of the stomach, providing a novel clinical tool for assessing functional motility disorders. The use of a natural oral contrast agent such as pineapple juice, as opposed to a gadolinium-based contrast agent, makes MRI more widely accessible. Our semi-automated methods for quantifying contraction magnitude and speed will streamline analysis and clinical diagnosis.

Gadolinium-Based Paramagnetic Relaxation Enhancement Agent Enhances Sensitivity for NUS Multidimensional NMR-Based Metabolomics.

Gadolinium is a paramagnetic relaxation enhancement (PRE) agent that accelerates the relaxation of metabolite nuclei. In this study, we noted the ability of gadolinium to improve the sensitivity of two-dimensional, non-uniform sampled NMR spectral data collected from metabolomics samples. In time-equivalent experiments, the addition of gadolinium increased the mean signal intensity measurement and the signal-to-noise ratio for metabolite resonances in both standard and plasma samples. Gadolinium led to highly linear intensity measurements that correlated with metabolite concentrations. In the presence of gadolinium, we were able to detect a broad array of metabolites with a lower limit of detection and quantification in the low micromolar range. We also observed an increase in the repeatability of intensity measurements upon the addition of gadolinium. The results of this study suggest that the addition of a gadolinium-based PRE agent to metabolite samples can improve NMR-based metabolomics.

Investigating plasma volume expanders as novel macromolecular MRI-CEST contrast agents for tumor contrast-enhanced imaging.

The aim of this study was to investigate two clinically approved plasma volume expanders (dextran 70 and voluven) as macromolecular MRI-chemical exchange saturation transfer (CEST) contrast agents to assess tumor vascular properties. CEST contrast efficiency of both molecules (6% w/v) was measured in vitro at various irradiation saturation powers (1-6 μT for 5 s) and pH values (range, 5.5-7.9) and the exchange rate of hydroxyl protons was calculated. In vivo studies in a murine adenocarcinoma model (n = 4 mice for each contrast agent) upon i.v. injection provided CEST-derived perfusion tumor properties that were compared with those obtained with a gadolinium-based blood-pool agent (Gd-AAZTA-Madec). In vitro measurements showed a marked CEST contrast dependency to pH, with higher CEST contrast at lower pH values for both molecules. The measured prototropic exchange rates confirmed a base-catalyzed exchange rate that was faster for dextran 70 in comparison to voluven. Both molecules showed a similar CEST contrast increase (ΔST% > 3%) in the tumor tissue up to 30 min postinjection, with heterogeneous accumulation. In tumors receiving both CEST and T1 -weighted agents, a voxel-by-voxel analysis indicated moderate spatial correlation of perfusion properties between voluven/dextran 70 and Gd-AAZTA-Madec, suggesting different distribution patterns according to their molecular size. The obtained results showed that both voluven and dextran 70 can be exploited as MRI-CEST contrast agents for evaluating tumor enhancement properties. Their increased accumulation in tumors and prolonged contrast enhancement promote their use as blood-pool MRI-CEST agents to examine tumor vascularization.

Ultracompact Iron Oxide Nanoparticles with a Monolayer Coating of Succinylated Heparin: A New Class of Renal-Clearable and Nontoxic T1 Agents for High-Field MRI.

Herein, we present a new magnetic iron oxide nanoparticle (MION) with a succinylated heparin monolayer coating, which exhibits the highest T1 relaxivity at 7 T and the lowest r2/r1 reported for any MION at these high-field conditions. While the recent proliferation of 7 T MRI instruments in hospitals worldwide has enabled widespread access to higher quality, more finely detailed, diagnostic imaging, clinically available contrast agents have not kept pace due to the general phenomenon of reduced efficacy of T1 relaxation as magnetic field strength is increased. Development of new MION agents is one strategy to address this need, and to this end, we demonstrate the in vitro magnetic properties of the MIONs reported here to extend to in vivo applications, providing greatly increased contrast in tumor imaging in a murine xenograft subject at 7 T. While MION-based contrast agents can have side effects in clinical application, these are generally thought to be less than those of gadolinium-based agents and here are further reduced by the small size allowing direct glomerular filtration from the blood followed by renal-excretion. Finally, we show the succinylated heparin monolayer coating to provide class leading magnetic properties over a homologous series of particles with core size ranging from 2 to 18 nm and show the properties to be strongly related to the surface area. We suggest the increased porosity and hydrophilicity of the coating to increase water accessibility to the surface resulting in the increased magnetic properties.

Gadolinium-Based Neuroprognostic Magnetic Resonance Imaging Agents Suppress COX-2 for Prevention of Reperfusion Injury after Stroke.

Advancements in recanalization therapies have rendered reperfusion injury an important challenge for stroke management. It is essential to work toward effective therapeutics that protect the ischemic brain from reperfusion injury. Here, we report a new concept of neuroprognostic agents, which combine molecular diagnostic imaging and targeted neuroprotection for treatment of reperfusion injury after stroke. These neuroprognostic agents are inflammation-targeted gadolinium compounds conjugated with nonsteroidal anti-inflammatory drugs (NSAIDs). Our results demonstrated that gadolinium-based MRI contrast agents conjugated with NSAIDs suppressed the increase in cyclooxygenase-2 (COX-2) levels, ameliorated glial activation, and neuron damage that are phenotypic for stroke by mitigating neuroinflammation, which prevented reperfusion injury. In addition, this study showed that the neuroprognostic agents are promising T1 molecular MRI contrast agents for detecting precise reperfusion injury locations at the molecular level. Our results build on this new concept of neuroprognostics as a novel management strategy for ischemia-reperfusion injury, combining neuroprotection and molecular diagnostics.