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.     

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.     

In vitro Gd‐DTPA relaxometry studies in oxygenated venous human blood and aqueous solution at 3 and 7 T

In vitro T₁ and T₂^* relaxivities (r₁ and r₂^*) of Gd‐DTPA (GaD) in oxygenated human venous blood (OVB) and aqueous solution (AS) at 3 and 7 T were calculated. GaD concentrations ([GaD]) in OVB and AS were prepared in the range 0‐5 mM. All measurements were acquired at 37 ± 2 °C. At both 3 and 7 T, a linear relationship was observed between [GaD] and R₁ in both AS and OVB. At 7 T, r₁ in AS decreased by 7.5% (p = 0.045) while there was a negligible change in OVB. With respect to R₂^*, a linear relationship with [GaD] was only observed in AS, while a more complex relationship was observed in OVB; quadratic below and linear above 2 mM at both field strengths. There was a significant increase of over 4‐fold in r₂^* with GaD in OVB at 7 T (for [GaD] above 2 mM, p <<0.01) as compared with 3 T. Furthermore, in comparison to r₁, r₂^* in AS was less than 2‐fold higher at both field strengths while in OVB it was ~20‐fold and ~90‐fold higher at 3 and 7 T, respectively. This observation emphasizes the importance of r₂^* knowledge at high magnetic fields, ≥3 T. The comparison between r₁ and r₂^* presented in this work is crucial in the design and optimization of high‐field MRI studies making use of paramagnetic contrast agents. This is especially true in multiple compartment systems such as blood, where r₂^* dramatically increases while r₁ remains relatively constant with increasing magnetic field strength. Copyright © 2014 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.     

Aerosols and gaseous contrast agents for magnetic resonance imaging of the lung

Magnetic resonance imaging of lungs and the investigation of pulmonary pathologies with this technique are limited by low proton spin density, degraded magnetic homogeneity and motion. Inhaled contrast agents (gases or aerosols) can improve the diagnostic value of MRI for lung. Paramagnetic contrast agents such as gadolinium chelates aerosol or dioxygen gas increase the relaxivity of proton in lung parenchyma and can be used to assess the ventilated fraction of the bronchoalveolar space. Similarly, inhalation of non proton‐MRI nuclei such as perfluorinated gas or hyperpolarized gases (³He or ¹²⁹Xe) can provide functional ventilation image. In this review paper, the principles, the practical implementation, the limitations and possible safety issues of these different techniques are summarized. The main pre‐clinical and clinical applications of these approaches based on oral contrast agents are reviewed and illustrated with cutting‐edge lung MRI studies. Copyright © 2008 John Wiley & Sons, Ltd.     

Assessment of tumor angiogenesis: dynamic contrast‐enhanced MRI with paramagnetic nanoparticles compared with Gd‐DTPA in a rabbit Vx‐2 tumor model

The purpose of this study was to evaluate the suitability of a macromolecular MRI contrast agent (paramagnetic nanoparticles, PNs) for the characterization of tumor angiogenesis. Our aim was to estimate the permeability of PNs in developing tumor vasculature and compare it with that of a low molecular weight contrast agent (Gd‐DTPA) using dynamic contrast‐enhanced MRI (DCE). Male New Zealand white rabbits (n = 5) underwent DCE MRI 12–14 days after Vx‐2 tumor fragments were implanted into the left hind limb. Each contrast agent (PNs followed by Gd‐DTPA) was evaluated using a DCE protocol and transendothelial transfer coefficient (K_i) maps were calculated using a two‐compartment model. Two regions of interest (ROIs) were located within the tumor core and hindlimb muscle and five ROIs were placed within the tumor rim. Comparisons were performed using repeated measures analysis of variance (ANOVA). The K_i values estimated using PNs were significantly lower than those obtained for Gd‐DTPA (p = 0.018). When PNs and Gd‐DTPA data were analyzed separately, significant differences were identified among tumor rim ROIs for PNs (p < 0.0001), but not for Gd‐DTPA data (p = 0.34). The mean K_i for the tumor rim was significantly greater than that of either the core or the hindlimb muscle for both contrast agents (p < 0.05 for each comparison). In summary, the extravasation of Gd‐DTPA was far greater than that of PNs, suggesting that PNs can reveal regional differences in tumor vascular permeability that are not otherwise apparent with clinical contrast agents such as Gd‐DTPA. These results suggest that PNs show potential for the noninvasive delineation of tumor angiogenesis. Copyright © 2010 John Wiley & Sons, Ltd.     

The design and synthesis of new synthetic low‐molecular‐weight heparins

Low‐molecular‐weight heparin (LMWH) has remained the most favorable form of heparin in clinics since the 1990s owing to its predictable pharmacokinetic properties. However, LMWH is mainly eliminated through the kidney, which limits its use in renal‐impaired patients. In addition, the anticoagulant activity of LMWH is only partially neutralized by protamine. LMWH is obtained from a full‐length, highly sulfated polysaccharide harvested from porcine mucosal tissue. The depolymerization involved in LMWH production generates a broad distribution of LMWH fragments (6–22 sugar residues). This, combined with the various methods used to produce commercial LMWHs, results in variable pharmacological and pharmacokinetic properties. An alternative chemoenzymatic approach offers a method for the synthesis of LMWH that has the potential to overcome the limitations of current LMWHs. This review summarizes the application of a chemoenzymatic approach to generate LMWH and the rationale for development of a synthetic LMWH.     

Functionalized single‐walled carbon nanotubes containing traces of iron as new negative MRI contrast agents for in vivo imaging

Single‐walled carbon nanotubes (SWCNTs) containing traces of iron oxide were functionalized by noncovalent lipid‐PEG or covalent carboxylic acid function to supply new efficient MRI contrast agents for in vitro and in vivo applications. Longitudinal (r₁) and transversal (r₂) water proton relaxivities were measured at 300 MHz, showing a stronger T₂ feature as an MRI contrast agent (r₂/r₁ = 190 for CO₂H functionalisation). The r₂ relaxivity was demonstrated to be correlated to the presence of iron oxide in the SWNT‐carboxylic function COOH, in comparison to iron‐free ones. Biodistribution studies on mice after a systemic injection showed a negative MRI contrast in liver, suggesting the presence of the nanotubes in this organ until 48 h after i.v. injection. The presence of carbon nanotubes in liver was confirmed after ex vivo carbon extraction. Finally, cytotoxicity studies showed no apparent effect owing to the presence of the carbon nanotubes. The functionalized carbon nanotubes were well tolerated by the animals at the dose of 10 µg g^?1 body weight. Copyright © 2012 John Wiley & Sons, Ltd.     

Enhanced MRI relaxivity of Gd3+‐based contrast agents geometrically confined within porous nanoconstructs

Gadolinium chelates, which are currently approved for clinical MRI use, provide relaxivities well below their theoretical limit, and they also lack tissue specificity. Recently, the geometrical confinement of Gd³⁺‐based contrast agents (CAs) within porous structures has been proposed as a novel, alternative strategy to improve relaxivity without chemical modification of the CA. Here, we have characterized and optimized the performance of MRI nanoconstructs obtained by loading [Gd(DTPA)(H₂O)]^2? (Magnevist®) into the pores of injectable mesoporous silicon particles. Nanoconstructs with three different pore sizes were studied, and at 60 MHz, they exhibited longitudinal relaxivities of ~24 m m ^?1 s^?1 for 5–10 nm pores and ~10 m m ^?1 s^?1 for 30 – 40 nm pores. No enhancement in relaxivity was observed for larger pores sizes. Using an outer‐sphere compound, [GdTTHA]^3?, and mathematical modeling, it was demonstrated that the relaxivity enhancement is due to the increase in rotational correlation times (CA adsorbed on the pore walls) and diffusion correlation times (reduced mobility of the water molecules), as the pore sizes decreases. It was also observed that extensive CA adsorption on the outer surface of the silicon particles negates the advantages offered by nanoscale confinement. Upon incubation with HeLa cells, the nanoconstructs did not demonstrate significant cytotoxicity for up to 3 days post incubation, at different particle/cell ratios. In addition, the nanoconstructs showed complete degradation after 24 h of continuous agitation in phosphate‐buffered saline. These data support and confirm the hypothesis that the geometrical confinement of Gd³⁺‐chelate compounds into porous structures offers MRI nanoconstructs with enhanced relaxivity (up to 6 times for [Gd(DTPA)(H₂O)]^2?, and 4 times for [GdTTHA]^3?) and, potentially, improved stability, reduced toxicity and tissue specificity. Copyright © 2012 John Wiley & Sons, Ltd.     

Utilization of nanoparticles as X‐ray contrast agents for diagnostic imaging applications

Among all the diagnostic imaging modalities, X‐ray imaging techniques are the most commonly used owing to their high resolution and low cost. The improvement of these techniques relies heavily on the development of novel X‐ray contrast agents, which are molecules that enhance the visibility of internal structures within the body in X‐ray imaging. To date, clinically used X‐ray contrast agents consist mainly of small iodinated molecules that might cause severe adverse effects (e.g. allergies, cardiovascular diseases and nephrotoxicity) in some patients owing to the large and repeated doses that are required to achieve good contrast. For this reason, there is an increasing interest in the development of alternative X‐ray contrast agents utilizing elements with high atomic numbers (e.g. gold, bismuth, ytterbium and tantalum), which are well known for exhibiting high absorption of X‐rays. Nanoparticles (NPs) made from these elements have been reported to have better imaging properties, longer blood circulation times and lower toxicity than conventional iodinated X‐ray contrast agents. Additionally, the combination of two or more of these elements into a single carrier allows for the development of multimodal and hybrid contrast agents. Herein, the limitations of iodinated X‐ray contrast agents are discussed and the parameters that influence the efficacy of X‐ray contrast agents are summarized. Several examples of the design and production of both iodinated and iodine‐free NP‐based X‐ray contrast agents are then provided, emphasizing the studies performed to evaluate their X‐ray attenuation capabilities and their toxicity in vitro and in vivo. Copyright © 2014 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.     

Neuroprotective effects of ultra‐low‐molecular‐weight heparin in vitro and vivo models of ischemic injury

This study was conducted to demonstrate ultra‐low‐molecular‐weight heparin’s neuroprotective effects on ischemic injury both in vivo and in vitro studies. In vitro, the effect of ultra‐low‐molecular‐weight heparin was tested in cultured PC12 cells exposed to Earle’s solution containing sodium dithionite, to identify its neuroprotection to PC12 cells damaged by oxygen‐glucose deprivation (OGD). The cell injury was detected by the tetrazolium salt 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5 diphenyl‐2H tetrazolium bromide (MTT) assay. In vivo, male Wistar rats with middle cerebral artery occlusion were evaluated for infarct volume followed by the treatment with ultra‐low‐molecular‐weight heparin. The results in vitro showed that ultra‐low‐molecular‐weight heparin significantly inhibited PC12 cells damage induced by OGD. Results in vivo showed that vein injection of Ultra‐Low‐molecular‐weight heparin at doses of 0.5 and 1.0 mg/kg exerted significant neuroprotective effects on rats with focal cerebral ischemic injury by significantly reducing the infarct volume compared with the injury group. All the findings suggest that ultra‐low‐molecular‐weight heparin might act as a neuroprotective agent useful in the treatment of cerebral ischemia.     

Prolonged in vivo circulation time by zwitterionic modification of magnetite nanoparticles for blood pool contrast agents

Long circulation time is critical for blood pool contrast agents used in high‐resolution magnetic resonance angiography. For iron oxide particle contrast agents, size and surface properties significantly influence their in vivo performance. We developed a novel long‐circulating blood pool contrast agent by introducing zwitterionic structure onto the particle surface. Zwitterionic structure was fabricated by 3‐(diethylamino)propylamine (DEAPA) grafted onto the surface of ployacrylic acid coated magnetite nanoparticles via EDC/NHS [N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbo‐diimide hydrochloride/N‐hydroxysuccinimide] coupling chemistry. Zwitterionic particles demonstrated five times lower macrophage cell uptake than the original particles and low cell toxicity. Magnetic resonance angiography indicated that zwitterionic nanoparticles had much longer in vivo circulation time than the original particles and were an ideal candidate for blood pool contrast agent. We suppose that zwitterionic modification by DEAPA and EDC/NHS can be used generally for coating nanoparticles with carboxyl surface and to prolong their circulating time. Copyright © 2012 John Wiley & Sons, Ltd.     

Quantitative imaging of the tissue contrast agent [Gd(DTPA)]2− in articular cartilage by laser ablation inductively coupled plasma mass spectrometry

Laser ablation inductively coupled plasma mass spectrometry (LA‐ICP‐MS) is an emerging analytical technique in the generation of quantitative images of MR contrast agent distribution in thin tissue sections of articular cartilage. An analytical protocol is described that includes sample preparation by cryo‐cutting of tissue sections, mass spectrometric measurements by LA‐ICP‐MS and quantification of gadolinium images by one‐point calibration, standard addition method (employing matrix‐matched laboratory standards) and isotope dilution analysis using highly enriched stable Gd‐155 isotope (abundance 92 vs 14.8% in the [Gd(DTPA)]^2? contrast agent). The tissue contrast agent concentrations of [Gd(DTPA)]^2? in cartilage measured in this work are in agreement with findings obtained by magnetic resonance imaging and other analytical methodologies. The LA‐ICP‐MS imaging data also confirm the observation that the spatial distribution of [Gd(DTPA)]^2? in the near‐equilibrium state is highly inhomogeneous across cartilage thickness with the highest concentration measured in superficial cartilage and a strong decrease toward the subchondral bone. In the present work, it is shown for the first time that LA‐ICP‐MS can be applied to validate the results from quantitative gadolinium‐enhanced MRI technique of articular cartilage. Copyright © 2012 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.     

Nano assembly and encapsulation; a versatile platform for slowing the rotation of polyanionic Gd3+‐based MRI contrast agents

Encapsulating discrete Gd³⁺ chelates in nano‐assembled capsules (NACs) is a simple and effective method of preparing an MRI contrast agent capable of delivering a large payload of high relaxivity imaging agent. The preparation of contrast agent containing NACs had previously focussed on preparations incorporating GdDOTP^5‐ into the internal aggregate. In this report we demonstrate that other Gd³⁺ chelates bearing overall charges as low as 2‐ can also be used to prepare NACs. This discovery opens up the possibility of using Gd³⁺ chelates that have inner‐sphere water molecules that could further increase the relaxivity enhancement associated with the long τ_R that arises from encapsulation. However, encapsulation of the q = 1 chelate GdDTPA^2‐ did not give rise to a significant increase in relaxivity relative to encapsulation of the outer‐sphere chelate GdTTHA^3‐. This leads us to the conclusion that in the NAC interior proton transport is not mediated by movement of whole water molecules and the enhanced relaxivity of Gd³⁺ chelate encapsulated within NACs arises primarily from second sphere effects. Copyright © 2015 John Wiley & Sons, Ltd.     

Pharmacokinetics and magnetic resonance imaging of biodegradable macromolecular blood‐pool contrast agent PG–Gd in non‐human primates: a pilot study

The purpose of this study was to evaluate poly(L ‐glutamic acid)‐benzyl‐DTPA–Gd (PG–Gd), a new biodegradable macromolecular magnetic resonance imaging contrast agent, for its pharmacokinetics and MRI enhancement in nonhuman primates. Studies were performed in rhesus monkeys at intravenous doses of 0.01, 0.02 and 0.08 mmol Gd/kg. T₁‐weighted MR images were acquired at 1.5 T using fast spoiled gradient recalled echo and fast spin echo imaging protocols. The small‐molecule contrast agent Magnevist was used as a control. PG–Gd in the monkey showed a bi‐exponential disposition. The initial blood concentrations within 2 h of PG–Gd administration were much higher than those for Magnevist. The high blood concentration of PG–Gd was consistent with the MR imaging data, which showed prolonged circulation of PG–Gd in the blood pool. Enhancement of blood vessels and organs with a high blood perfusion (heart, liver, and kidney) was clearly visualized at 2 h after contrast injection at the three doses used. A greater than proportional increase of the area under the blood concentration–time curve was observed when the administered single dose was increased from 0.01 to 0.08 mmol/kg. By 2 days after PG–Gd injection, the contrast agent was mostly cleared from all major organs, including kidney. The mean residence time was 15 h at the 0.08 mmol/kg dose. A similar pharmacokinetic profile was observed in mice, with a mean residence time of 5.4 h and a volume of distribution at steady‐state of 85.5 ml/kg, indicating that the drug was mainly distributed in the blood compartment. Based on this pilot study, further investigations on the potential systemic toxicity of PG–Gd in both rodents and large animals are warranted before testing this agent in humans. Copyright © 2011 John Wiley & Sons, Ltd.     

Equilibrium‐phase MR angiography: Comparison of unspecific extracellular and protein‐binding gadolinium‐based contrast media with respect to image quality

The purpose of this study was to compare contrast and image quality of whole‐body equilibrium‐phase high‐spatial‐resolution MR angiography using a non‐protein‐binding unspecific extracellular gadolinium‐based contrast medium with that of two contrast media with different protein‐binding properties. 45 patients were examined using either 15 mL of gadobutrol (non‐protein‐binding, n = 15), 32 mL of gadobenate dimeglumine (weakly protein binding, n = 15) or 11 mL gadofosveset trisodium (protein binding, n = 15) followed by equilibrium‐phase high‐spatial‐resolution MR‐angiography of four consecutive anatomic regions. The time elapsed between the contrast injection and the beginning of the equilibrium‐phase image acquisition in the respective region was measured and was up to 21 min. Signal intensity was measured in two vessels per region and in muscle tissue. Relative contrast (RC) values were calculated. Vessel contrast, artifacts and image quality were rated by two radiologists in consensus on a five‐point scale. Compared with gadobutrol, gadofosveset trisodium revealed significantly higher RC values only when acquired later than 15 min after bolus injection. Otherwise, no significant differences between the three contrast media were found regarding vascular contrast and image quality. Equilibrium‐phase high‐spatial‐resolution MR‐angiography using a weakly protein‐binding or even non‐protein‐binding contrast medium is equivalent to using a stronger protein‐binding contrast medium when image acquisition is within the first 15 min after contrast injection, and allows depiction of the vasculature with high contrast and image quality. The protein‐binding contrast medium was superior for imaging only later than 15 min after contrast medium injection. Copyright © 2015 John Wiley & Sons, Ltd.     

MRI of cells and mice at 1 and 7 Tesla with Gd‐targeting agents: when the low field is better!

Tumor cells were targeted with Gd‐loaded/LDL (low density lipoproteins) adducts consisting of ca 300 Gd(III) amphiphilic complexes incorporated in the lipophilic LDL particles. The long reorientational time of the Gd(III) complex in the supramolecular adduct yielded a relaxivity peak at ca 1 T, whereas its relaxivity at 7 T was 5 times less. The field‐dependent relaxivity markedly affected the signal enhancement attainable at the two magnetic fields. As tumor cells showed up‐regulation of LDL transporters, B16 melanoma cells were labeled with the Gd‐loaded/LDL adduct. Each cell contained ca 2 × 10⁹ Gd atoms. Upon dispersion of 5000 labeled cells in 1 μl of agar, signal intensity (SI) enhancements of about 30 and 7% were observed at 1 and 7 T, respectively. The results obtained on cellular systems were confirmed in vivo upon the administration of Gd‐loaded/LDL particles to C57 mice bearing a transplanted melanoma (B16) tumor. From the herein reported results, one may conclude that, for slowly moving Gd complexes, it is possible to obtain in vivo sensitivity enhancements at 1 T several times higher than that attained at high fields. Copyright © 2011 John Wiley & Sons, Ltd.