MR imaging of antigen‐induced arthritis with a new,folate receptor‐targeted contrast agent

The purpose of this study was to investigate if the new folate receptor‐targeted Gd‐chelate P866 may enhance immune‐mediated arthritis. A monoarthritis was induced in the right knee of 15 Sprague–Dawley rats. MR imaging of both knees was performed at 2 T before and up to 2 h and 24 h after injection (p.i.) of P866 (n = 3 dose finding study and n = 6, 0.02 mmol Gd/kg), the non‐FR targeted P866 analog P1001 (n = 3 at 24 h after P866‐administration, 0.02 mmol Gd/kg) or Gd‐DOTA (n = 6, 0.1 mmol Gd/kg). Pulse sequences comprised T₁‐SPGR 80°/50 ms/1.7 ms (flip angle/TR/TE) and inversion recovery 10°/3000 ms/1500 ms/50–3050, 10 000 ms (flip angle/TR/TE/TI) sequences. ΔSI‐data and T₁‐relaxation times of arthritic knees and contralateral normal knees were determined. Folate receptor expression was confirmed with histopathology. All three contrast agents showed an initial perfusion effect with significantly higher ΔSI‐data of arthritic knees compared with normal knees (p < 0.05). In addition, P866, but not P1001 or Gd‐DOTA, showed a prolonged enhancement of the synovitis. Compared with precontrast values, the T₁‐relaxation times of inflamed synovia were significantly decreased at 2 h p.i. of P866 (p < 0.05), but not P1001 or Gd‐DOTA (p > 0.05). Histopathology confirmed the presence of folate receptors in the inflamed joints, but not normal joints. Thus, results suggest a specific accumulation of the folate receptor‐targeted Gd‐chelate P866 in this arthritis model. Copyright © 2007 John Wiley & Sons, Ltd.     

Incorporation of an apoE‐derived lipopeptide in high‐density lipoprotein MRI contrast agents for enhanced imaging of macrophages in atherosclerosis

Magnetic resonance (MR) imaging is becoming a pivotal diagnostic method to identify and characterize vulnerable atherosclerotic plaques. We previously reported a reconstituted high‐density lipoprotein (rHDL) nanoparticle platform enriched with Gd‐based amphiphiles as a plaque‐specific MR imaging contrast agent. Further modification can be accomplished by inserting targeting moieties into this platform to potentially allow for improved intraplaque macrophage uptake. Since studies have indicated that intraplaque macrophage density is directly correlated to plaque vulnerability, modification of the rHDL platform may allow for better detection of vulnerable plaques. In the current study we incorporated a carboxyfluoresceine‐labeled apolipoprotein E‐derived lipopeptide, P2fA2, into rHDL. The in vitro macrophage uptake and in vivo MR efficacy were demonstrated using murine J774A.1 macrophages and the apolipoprotein E knock‐out (apoE^?/?) mouse model of atherosclerosis. The in vitro studies indicated enhanced association of murine macrophages to P2fA2 enriched rHDL (rHDL–P2A2) nanoparticles, relative to rHDL, using optical techniques and MR imaging. The in vivo studies showed a more pronounced and significantly higher signal enhancement of the atherosclerotic wall 24 h after the 50 µmol Gd/kg injection of rHDL–P2A2 relative to administration of rHDL. The normalized enhancement ratio for atherosclerotic wall of rHDL–P2A2 contrast agent injection was 90%, while that of rHDL was 53% 24 h post‐injection. Confocal laser scanning microscopy revealed that rHDL–P2A2 nanoparticles co‐localized primarily with intraplaque macrophages. The results of the current study confirm the hypothesis that intraplaque macrophage uptake of rHDL may be enhanced by the incorporation of the P2fA2 peptide into the modified HDL particle. Copyright © 2008 John Wiley & Sons, Ltd.     

A neutral polydisulfide containing Gd(III) DOTA monoamide as a redox‐sensitive biodegradable macromolecular MRI contrast agent

This work aims to develop safe and effective gadolinium (III)‐based biodegradable macromolecular MRI contrast agents for blood pool and cancer imaging. A neutral polydisulfide containing macrocyclic Gd‐DOTA monoamide (GOLS) was synthesized and characterized. In addition to studying the in vitro degradation of GOLS, its kinetic stability was also investigated in an in vivo model. The efficacy of GOLS for contrast‐enhanced MRI was examined with female BALB/c mice bearing 4T1 breast cancer xenografts. The pharmacokinetics, biodistribution, and metabolism of GOLS were also determined in mice. GOLS has an apparent molecular weight of 23.0 kDa with T₁ relaxivities of 7.20 mM^?1 s^?1 per Gd at 1.5 T, and 6.62 mM^?1 s^?1 at 7.0 T. GOLS had high kinetic inertness against transmetallation with Zn²⁺ ions, and its polymer backbone was readily cleaved by L‐cysteine. The agent showed improved efficacy for blood pool and tumor MR imaging. The structural effect on biodistribution and in vivo chelation stability was assessed by comparing GOLS with Gd(HP‐DO3A), a negatively charged polydisulfide containing Gd‐DOTA monoamide GODC, and a polydisulfide containing Gd‐DTPA‐bisamide (GDCC). GOLS showed high in vivo chelation stability and minimal tissue deposition of gadolinium. The biodegradable macromolecular contrast agent GOLS is a promising polymeric contrast agent for clinical MR cardiovascular imaging and cancer imaging. Copyright © 2015 John Wiley & Sons, Ltd.     

靶向对比剂CLT1-(Gd-DTPA)在小鼠乳腺癌磁共振分子成像效果的研究

本文研究了一个小肽靶向的对比剂CLT1-(Gd-DTPA) 对肿瘤基质中的纤维蛋白--链接纤维蛋白复和物的磁共振分子影像的效能.所用动物模型为带有MDA-MB-231乳腺癌的母系裸鼠,所用仪器为西门子3T磁共振成像仪,对比剂为Gd-(DTPA-BMA),所用CLT1-(Gd-DPTA)剂量为0.05 mmol/kg.该...     

MR imaging assessment of the kinetics of P846, a new gadolinium‐based MR contrast medium,in ischemically injured myocardium

The objectives of the study were: (1) to compare the kinetics of a new gadolinium‐based low‐diffusibility magnetic resonance (MR) contrast medium, P846 and Gd‐DOTA in left ventricular (LV) blood and in normal and ischemically injured myocardium using inversion recovery echo‐planar imaging (IR‐EPI) and (2) to compare the enhancement pattern after injection of P846 with Gd‐DOTA, using T₁‐weighted spin‐echo imaging (T₁‐SE). Sixteen rats were subjected to left descending artery (LAD) occlusion for 30 min, followed by 2.5 h reperfusion. MR imaging was performed before and after administration of the contrast medium in two different groups of animals: one group (n = 8) received 0.05 mmol kg^?1 P846 and the other (n = 8) 0.1 mmol kg^?1 Gd‐DOTA. A blipped IR‐EPI and a multislice T₁‐SE were performed before injection and for 90 min after injection. T₁‐values were derived by fitting regional signal intensity on the IR‐EPI images, the R₁, ΔR₁ (R_{1postcontrast} – R_1precontrast) and ΔR₁ ratios were calculated in LV blood, normal and injured myocardium. On SE‐T₁, the signal intensity ratio (SI) and extent of injury were measured. True infarct size was measured using histochemical staining. Changes in ΔR₁ were 4.8 times greater with 0.05 mmol kg^?1 P846 than with 0.1 mmol kg^?1 Gd‐DOTA in LV blood (6.3 ± 0.9 vs 0.9 ± 0.1 s^?1, p < 0.0001), normal (1.7 ± 0.2 vs 0.34 ± 0.03 s^?1, p < 0.0001) and ischemically injured myocardium (5.4 ± 0.4 vs 1.6 ± 0.1 s^?1, p < 0.0001). MR imaging experiments showed that the signal enhancement with P846 is longer (90 min), which might be explained by a lower diffusion of P846 compared with Gd‐DOTA (30 min). P846 differentiates viable and nonviable myocardium. Despite lower gadolinium dose, P846 permits differentiation of viable and nonviable myocardium owing to a high contrast and a long imaging window with conventional t₁‐weighted SE sequence. Copyright © 2008 John Wiley & Sons, Ltd.     

Real‐time 3D MRI of contrast agents in whole living mice

A specific mouse whole body coil and a dedicated gradient system at 4.7 T were coupled with an ultra‐fast 3D gradient echo MRI and keyhole reconstruction technique to obtain 3D whole‐body dynamic T₁‐weighted or T₂*‐weighted imaging. The technique was used to visualize the real‐time distribution of non‐targeting T₁ and T₂* contrast agent (CA) in a glioma‐bearing mouse model. T₁ dynamic contrast‐enhancement imaging was performed with a fast imaging with steady‐state precession sequence [echo time/repetition time (TE/TR), 1.32/3.7 ms] before and after CA injection (Gd–DOTA and BSA–Gd–DOTA) for 21 min. The temporal resolution was 1 image/6.5 s. T₂* imaging (TE/TR, 4/8 ms) was performed before and after iron‐based (small and ultra‐small particles of iron oxide) CA injection for 45 min. The temporal resolution was 1 image/14 s. Signal‐to‐noise ratio curves were determined in various mouse organs. The whole‐body coil and gradient systems made it possible to acquire data with sufficient and homogeneous signal‐to‐noise ratio on the whole animal. The spatial resolution allowed adequate depiction of the major organs, blood vessels and brain glioma. The distribution and the time‐course of T₁ and T₂* contrasts upon contrast agent injection were also assessed. 3D whole‐body mouse MRI is feasible at high spatial resolution in movie mode and can be applied successfully to visualize real‐time contrast agent distribution. This method should be effective in future preclinical molecular imaging studies. Copyright © 2011 John Wiley & Sons, Ltd.     

A dual CT‐MR dendrimer contrast agent as a surrogate marker for convection‐enhanced delivery of intracerebral macromolecular therapeutic agents

The feasibility of using Gd dendrimer‐based macromolecules (Gd‐G8 dendrimer) as a dual CT and MR contrast agent for monitoring convection‐enhanced delivery of therapy in the brain is evaluated both in vitro and in vivo with optimal dosing established. In vitro CT attenuation values of the Gd‐based agents (～6.0 HU mM ^?1) were ～1.6 times greater than iodine‐based agents and the attenuation of the Gd‐DTPA was comparable to Gd‐G8 dendrimer. Visible enhancement was observed on both CT and MR using Gd‐G8 dendrimer over a range of 23–78 mM ; however, a concentration of at least 47 mM in Gd was required for adequate delineation of the injection site on both CT and MR. MR offers greater sensitivity than CT in estimating the volume of distribution (V_d) and effectively quantified the agent's concentration and diffusion using T₁ mapping at much lower concentrations of Gd (<10 mM in [Gd]). Copyright © 2008 John Wiley & Sons, Ltd.     

Pharmacokinetics of Gd(DO3A‐Lys) and MR imaging studies in an orthotopic U87MG glioma tumor model

Pharmacokinetics of Gd(DO3A‐Lys), a macrocyclic gadolinium‐based magnetic resonance imaging (MRI) contrast agent functionalized with a lysine derivative, was studied in Wistar rats. Kinetic data were fitted using a two‐compartment model and revealed Gd(DO3A‐Lys) to have a distribution half‐life, t_1/2(α), of 1.3 min, an elimination half‐life, t_1/2(β), of 24.9 min and a large volume of distribution, V_D, of 0.49 L/kg indicative of the agent being able to rapidly distribute into tissues and organs. Contrast‐enhanced magnetic resonance angiography (CE‐MRA) in an orthotopic U87MG glioma mouse model demonstrated considerable enhancement of both the tumor and surrounding vasculature after intravenous administration of Gd(DO3A‐Lys). Applying dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) in the glioma of different sizes further showed distinct uptake characteristics and patterns of enhancement, which suggests the potential for differentiating changes at different stages of tumor growth. Our results indicate that Gd(DO3A‐Lys) could be a promising candidate for glioma MR imaging. Copyright © 2015 John Wiley & Sons, Ltd.     

Synthesis and characterization of a porphyrazine–Gd(III) MRI contrast agent and in vivo imaging of a breast cancer xenograft model

Porphyrazines (Pz), or tetraazaporphyrins, are being studied for their potential use in detection and treatment of cancer. Here, an amphiphilic Cu–Pz–Gd(III) conjugate has been prepared via azide–alkyne Huisgen cycloaddition or ‘click’ chemistry between an azide functionalized Pz and alkyne functionalized DOTA–Gd(III) analog for use as an MRI contrast agent. This agent, Cu–Pz–Gd(III), is synthesized in good yield and exhibits solution‐phase ionic relaxivity (r₁ = 11.5 mm ^?1 s^?1) that is approximately four times higher than that of a clinically used monomeric Gd(III) contrast agent, DOTA–Gd(III). Breast tumor cells (MDA‐MB‐231) associate with Cu–Pz–Gd(III) in vitro, where significant contrast enhancement (9.336 ± 0.335 contrast‐to‐noise ratio) is observed in phantom cell pellet MR images. This novel contrast agent was administered in vivo to an orthotopic breast tumor model in athymic nude mice and MR images were collected. The average T₁ of tumor regions in mice treated with 50 mg kg^?1 Cu–Pz–Gd(III) decreased relative to saline‐treated controls. Furthermore, the decrease in T₁ was persistent relative to mice treated with the monomeric Gd(III) contrast agent. An ex vivo biodistribution study confirmed that Cu–Pz–Gd(III) accumulates in the tumors and is rapidly cleared, primarily through the kidneys. Differential accumulation and T₁ enhancement by Cu–Pz–Gd(III) in the tumor's core relative to the periphery offer preliminary evidence that this agent would find application in the imaging of necrotic tissue. Copyright © 2014 John Wiley & Sons, Ltd.     

Contrast enhancement by lipid‐based MRI contrast agents in mouse atherosclerotic plaques; a longitudinal study

The use of contrast‐enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of two differently sized gadolinium‐based contrast agents to enhance atherosclerotic plaques in ApoE^?/? mice was evaluated with MRI. We obtained a kinetic profile for contrast enhancement, as the literature data on optimal imaging time points is scarce, and assessed the longer‐term kinetics. Signal enhancement in the wall of the aortic arch, following intravenous injection of paramagnetic micelles and liposomes, was followed for 1 week. In vivo T₁‐weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy of NIR₆₆₄ incorporated in the contrast agents and quantification of tissue and blood Gd–DTPA. Both micelles and liposomes enhanced contrast in T₁‐weighted MR images of plaques in the aortic arch. The average contrast‐to‐noise ratio increased after liposome or micelle injection to 260 or 280% respectively, at 24 h after injection, compared with a pre‐scan. A second wave of maximum contrast enhancement was observed around 60–72 h after injection, which only slowly decreased towards the 1 week end‐point. Confocal fluorescence microscopy and whole body fluorescence imaging confirmed MRI‐findings of accumulation of micelles and liposomes. Plaque permeation of contrast agents was not strongly dependent on the contrast agent size in this mouse model. Our results show that intraplaque accumulation over time of both contrast agents leads to good plaque visualization for a long period. This inherent intraplaque accumulation might make it difficult to discriminate passive from targeted accumulation. This implies that, in the development of targeted contrast agents on a lipid‐based backbone, extensive timing studies are required. Copyright © 2012 John Wiley & Sons, Ltd.     

A new type of susceptibility‐artefact‐based magnetic resonance angiography: intra‐arterial injection of superparamagnetic iron oxide particles (SPIO) A Resovist® in combination with TrueFisp imaging: a feasibility study

The goal of this study was to evaluate the use of super paramagnetic particles of iron oxide (SPIO) as a dark blood contrast agent, in combination with a bright blood steady‐state free precession sequence for magnetic resonance angiography (MRA), in an animal model. The original concentration of the SPIO of 500 mmol Fe/l and dilutions to 250, 125, 60, 30, 10 and 5 mmol Fe/l were intra‐arterially injected into the aorta of a pig. Then the dilution of 10 mmol Fe/l was chosen for repeated intra‐arterial injections into two pigs. During these intra‐arterial SPIO injections MR images were acquired with a 1.5 T scanner. Signal intensity measurements were performed in the aorta. The signal‐to‐noise ratio during SPIO bolus passage was significantly less than during baseline conditions (Fisher's F‐ratio 159.8, p < 0.005) or the recovery signal‐to‐noise ratio (Fisher's F‐ratio 144.6, p < 0.005). Also, confirmation of flow distal to the catheter‐tip position was possible. The use of SPIO as a dark blood agent in combination with a bright blood MR imaging sequence is feasible. Temporary loss of intraluminal signal occurs due to local decrease of the signal because of induction of local inhomogeneities after mixture the present blood and SPIO solution. It provides immediate information about blood flow distal to the catheter and is a potentially useful to guide intravascular MR‐interventional procedures. Copyright © 2006 John Wiley & Sons Ltd.     

Hindered diffusion of MRI contrast agents in rat brain extracellular micro‐environment assessed by acquisition of dynamic T1 and T2 maps

The knowledge of brain tissues characteristics (such as extracellular space and tortuosity) represents valuable information for the design of optimal MR probes for specific biomarkers targeting. This work proposes a methodology based on dynamic acquisition of relaxation time maps to quantify in vivo MRI contrast agent concentration after intra‐cerebral injection in rat brain. It was applied to estimate the hindered diffusion in brain tissues of five contrast agents with different hydrodynamic diameters (Dotarem® ≈ 1 nm, P846 ≈ 4 nm, P792 ≈ 7 nm, P904 ≈ 22 nm and Gd‐based emulsion ≈ 170 nm). In vivo apparent diffusion coefficients were compared with those estimated in an obstacle‐free medium to determine brain extracellular space and tortuosity. At a 2 h imaging timescale, all contrast agents except the Gd‐based emulsion exhibited significant diffusion through brain tissues, with characteristic times compatible with MR molecular imaging (<70 min to diffuse between two capillaries). In conclusion, our experiments indicate that MRI contrast agents with sizes up to 22 nm can be used to perform molecular imaging on intra‐cerebral biomarkers. Our quantification methodology allows a precise estimation of apparent diffusion coefficients, which is helpful to calibrate optimal timing between contrast agent injection and MRI observation for molecular imaging studies. Copyright © 2012 John Wiley & Sons, Ltd.     

Multi‐modal magnetic resonance imaging and histology of vascular function in xenografts using macromolecular contrast agent hyperbranched polyglycerol (HPG‐GdF)

Macromolecular gadolinium (Gd)‐based contrast agents are in development as blood pool markers for MRI. HPG‐GdF is a 583 kDa hyperbranched polyglycerol doubly tagged with Gd and Alexa 647 nm dye, making it both MR and histologically visible. In this study we examined the location of HPG‐GdF in whole‐tumor xenograft sections matched to in vivo DCE‐MR images of both HPG‐GdF and Gadovist. Despite its large size, we have shown that HPG‐GdF extravasates from some tumor vessels and accumulates over time, but does not distribute beyond a few cell diameters from vessels. Fractional plasma volume (fPV) and apparent permeability–surface area product (aPS) parameters were derived from the MR concentration–time curves of HPG‐GdF. Non‐viable necrotic tumor tissue was excluded from the analysis by applying a novel bolus arrival time (BAT) algorithm to all voxels. aPS derived from HPG‐GdF was the only MR parameter to identify a difference in vascular function between HCT116 and HT29 colorectal tumors. This study is the first to relate low and high molecular weight contrast agents with matched whole‐tumor histological sections. These detailed comparisons identified tumor regions that appear distinct from each other using the HPG‐GdF biomarkers related to perfusion and vessel leakiness, while Gadovist‐imaged parameter measures in the same regions were unable to detect variation in vascular function. We have established HPG‐GdF as a biocompatible multi‐modal high molecular weight contrast agent with application for examining vascular function in both MR and histological modalities. Copyright © 2015 John Wiley & Sons, Ltd.     

Nature‐inspired nanoformulations for contrast‐enhanced in vivo MR imaging of macrophages

Magnetic resonance imaging (MRI) of macrophages in atherosclerosis requires the use of contrast‐enhancing agents. Reconstituted lipoprotein particles that mimic native high‐density lipoproteins (HDL) are a versatile delivery platform for Gd‐based contrast agents (GBCA) but require targeting moieties to direct the particles to macrophages. In this study, a naturally occurring methionine oxidation in the major HDL protein, apolipoprotein (apo) A‐I, was exploited as a novel way to target HDL to macrophages. We also tested if fully functional GBCA–HDL can be generated using synthetic apo A‐I peptides. The fluorescence and MRI studies reveal that specific oxidation of apo A‐I or its peptides increases the in vitro macrophage uptake of GBCA–HDL by 2–3 times. The in vivo imaging studies using an apo E‐deficient mouse model of atherosclerosis and a 3.0 T MRI system demonstrate that this modification significantly improves atherosclerotic plaque detection using GBCA–HDL. At 24 h post‐injection of 0.05 mmol Gd kg^?1 GBCA–HDL containing oxidized apo A‐I or its peptides, the atherosclerotic wall/muscle normalized enhancement ratios were 90 and 120%, respectively, while those of GBCA–HDL containing their unmodified counterparts were 35 and 45%, respectively. Confocal fluorescence microscopy confirms the accumulation of GBCA–HDL containing oxidized apo A‐I or its peptides in intraplaque macrophages. Together, the results of this study confirm the hypothesis that specific oxidation of apo A‐I targets GBCA–HDL to macrophages in vitro and in vivo. Furthermore, our observation that synthetic peptides can functionally replace the native apo A‐I protein in HDL further encourages the development of these contrast agents for macrophage imaging. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis and evaluation of a polydisulfide with Gd–DOTA monoamide side chains as a biodegradable macromolecular contrast agent for MR blood pool imaging

Macromolecular Gd(III)‐based contrast agents are effective for contrast‐enhanced blood pool and cancer MRI in preclinical studies. However, their clinical applications are impeded by potential safety concerns associated with slow excretion and prolonged retention of these agents in the body. To minimize the safety concerns of macromolecular Gd contrast agents, we have developed biodegradable macromolecular Gd contrast agents based on polydisulfide Gd(III) complexes. In this study, we designed and synthesized a new generation of the polydisulfide Gd(III) complexes containing a macrocyclic Gd(III) chelate, Gd–DOTA monoamide, to improve the in vivo kinetic inertness of the Gd(III) chelates. (N₆‐Lysyl)lysine‐(Gd–DOTA) monoamide and 3‐(2‐carboxyethyldisulfanyl)propanoic acid copolymers (GODC) were synthesized by copolymerization of (N₆‐lysyl)lysine DOTA monoamide and dithiobis(succinimidylpropionate), followed by complexation with Gd(OAc)₃. The GODC had an apparent molecular weight of 26.4 kDa and T₁ relaxivity of 8.25 m m ^?1 s^?1 per Gd at 1.5 T. The polymer chains of GODC were readily cleaved by l ‐cysteine and the chelates had high kinetic stability against transmetallation in the presence of an endogenous metal ion Zn²⁺. In vivo MRI study showed that GODC produced strong and prolonged contrast enhancement in the vasculature and tumor periphery of mice with breast tumor xenografts. GODC is a promising biodegradable macromolecular MRI contrast agent with high kinetic stability for MR blood pool imaging. Copyright © 2013 John Wiley & Sons, Ltd.     

Automated colorimetric gadolinium assay for verification of clearance and estimation of glomerular filtration rate

BACKGROUND: NSF (nephrogenic systemic fibrosis) is a potentially serious adverse effect for renal patients undergoing MRI (magnetic resonance imaging) procedures using gadolinium-containing contrast agents. There is therefore a need to verify clearance of these agents and to confirm appropriate renal status of patients treated with these drugs. METHODS: Serum samples from canine and feline subjects dosed with 0.1 mmol/kg of gadolinium agent, or from spiked samples were assayed for gadopentetate (Magnevist), gadodiamide (Omniscan) or gadoversetamide (OptiMARK) using a new dye reagent on the Olympus AU400. Accuracy was verified by ICP-MS. RESULTS: The reportable dynamic range is 3-600 micromol/l Gd. Split serum samples from animals dosed with 0.1 mmol/kg of gadopentetate ranged from 7-458 micromol/l Gd: y=1.121x+0.267, r=0.996, for the Olympus method as a function of Gd measurement by ICP-MS. Between-day imprecision was 1.3% CV-3.6% CV for samples ranging from 12-400 micromol/l Gd. CONCLUSIONS: The assay is useful to verify the clearance of gadolinium and for evaluation of renal status by estimation of GFR using gadopentetate.     

First in vivo MRI assessment of a self‐assembled metallostar compound endowed with a remarkable high field relaxivity

{Fe[Gd₂bpy(DTTA)₂(H₂O)₄]₃}^4? is a self‐assembled, metallostar‐structured potential MRI contrast agent, with six efficiently relaxing Gd³⁺ centres confined into a small molecular space. Its proton relaxivity is particularly remarkable at very high magnetic fields (r₁ = 15.8 mM ^?1 s^?1 at 200 MHz, 37°C, in H₂O). Here we report the first in vivo MRI feasibility study, complemented with dynamic γ scintigraphic imaging and biodistribution experiments using the ¹⁵³Sm‐enriched compound. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small molecular weight contrast agent gadolinium(III)‐1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetate ([Gd(DOTA)(H₂O)]^? = GdDOTA). The metallostar was well tolerated by the animals at the concentrations of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg^?1 body weight; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high‐dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg^?1 BW), despite the higher dose of the latter. The high‐dose metallostar injection resulted in a greater drop in the spin‐lattice relaxation time (T₁), as calculated from the inversion recovery true fast imaging with steady‐state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approximately four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate molecular weight, the metallostar does not function as a blood pool agent. The dynamic γ scintigraphic studies performed in Wistar rats with the metallostar compound having ¹⁵³Sm enrichment also proved the renal elimination pathway. The biodistribution experiments are in full accordance with the MR and scintigraphic imaging. At 15 min post‐injection the activity is primarily localized in the urine, while at 24 h post‐injection almost all radioactivity is cleared from tissues and organs. Copyright © 2006 John Wiley & Sons, Ltd.     

Evaluation of rHA labeled with Gd–DTPA for blood pool imaging and targeted contrast delivery

A new contrast agent was developed by linking Gd–DTPA chelate to recombinant human albumin in the laboratory. The molar relaxivity of the new agent was tested in aqueous solution at B₀ 1.5 T and temperature 20°C. The soluble compound had a higher molar longitudinal relaxivity and molar transverse relaxivity in water (r₁ = 7.2 s^?1 mM ^?1, r₂ = 18.4 s^?1 mM ^?1) than those measured for Gd–DTPA solution (r₁ = 3.5 s^?1 mM ^?1, r₂ = 5.5 s^?1 mM ^?1). The performance of the compound as a blood pool agent was investigated with soluble and microparticulate forms of the compound and comparisons were made with Gd–DTPA and the polymeric blood‐pool agent, Gadomer. T₁‐weighted imaging experiments show that the soluble compound acts as a highly effective blood pool agent with hyperintensity in the vasculature persisting beyond 2 h post administration, compared with free Gd–DTPA, which was cleared from the blood pool after approximately 10 min. The clearance kinetics of the new agents were examined, due to the incomplete elimination within 14 days post injection; both rHA labeled compounds are probably not suitable for development as routine blood pool contrast media. However, with free sites on the Gd‐loaded rHA molecule, there are possibilities for binding the agent to antibodies in the laboratory, which was demonstrated, and thus there exist potential applications for in vivo molecular imaging with this agent. Copyright © 2010 John Wiley & Sons, Ltd.     

A novel one‐step synthesis of Gd3+‐incorporated mesoporous SiO2 nanoparticles for use as an efficient MRI contrast agent

Molecular imaging has generated a demand for more sensitive contrast agents for magnetic resonance (MR) imaging. We synthesized, by a novel one‐step method, Gd³⁺ incorporated mesoporous SiO₂ nanoparticles, Gd₂O₃@SiO₂, for use as an efficient contrast agent. The prepared nanoparticles were also coated with poly(lactic‐co‐glycolic acid) (PLGA). The size, morphology, composition and Brunauer–Emmett–Teller specific surface area of the nanoparticles were evaluated. The Gd₂O₃@SiO₂ nanoparticles possess intragranular network morphology with a uniform size distribution and an average size of approximately 20–40 nm. The PLGA‐coated nanoparticles were spherical or near‐spherical in shape with a diameter of approximately 120 nm, a smooth surface, and neither aggregation nor adhesion tendencies. No free Gd ions were detected to dissociate from Gd₂O₃@SiO₂ even up to the limit (<0.03 mg/l) of the ICP equipment (IRIS Advantage). Our theoretical computation based on density functional theory (using DMol3, Materials Studio) revealed that the Gd₂O₃ molecules are fully absorbed on the interface of mesoporous SiO₂ with a stable state of lower energy. Both Gd₂O₃@SiO₂ and PLGA‐coated Gd₂O₃@SiO₂ samples have a larger T₁ relaxivitiy than commercial gadolinium diethylene triaminepentaacetate (Gd‐DTPA). In vitro and in vivo MR images using the Gd₂O₃@SiO₂ nanoparticles were observed with a 1.5 T clinical MR scanner and compared with the images using Gd‐DTPA. The Gd₂O₃@SiO₂ nanoparticles display a better magnetic property than commercial Gd‐DTPA. In vivo MR imaging demonstrated that the nanoparticles were mainly distributed in the liver. Strong enhancement was also detected in nasopharyngeal carcinoma CNE‐2 xenografted tumors. The Gd₂O₃@SiO₂ nanoparticles are not only potential candidates for highly efficient contrast agents for MR imaging, but also might be developed into potent targeted probes for in vivo molecular imaging of cancer. Copyright © 2010 John Wiley & Sons, Ltd.