Safety and technique of ferumoxytol administration for MRI

Ferumoxytol is an ultrasmall superparamagnetic iron oxide agent marketed for the treatment of anemia. There has been increasing interest in its properties as an MRI contrast agent as well as greater awareness of its adverse event profile. This mini‐review summarizes the current state of knowledge of the risks of ferumoxytol and methods of administration. Magn Reson Med 75:2107–2111, 2016. © 2016 Wiley Periodicals, Inc.     

Sensitivity of USPIO-enhanced R2 imaging to dynamic blood volume changes in the rat kidney

Purpose:

To determine whether MRI in combination with an intravascular contrast agent is sensitive to pharmacologically induced vasodilation and vasoconstriction in the rat kidney.

Materials and Methods:

R₂ imaging was performed in 25 Sprague Dawley rats at 3 Tesla in the presence of ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO) agent with a long plasma half‐life. R₂ changes were measured following manipulation of blood volume by intravenous administration of adenosine, a short‐acting vasodilator, or N^G‐nitro‐L‐arginine methyl ester (L‐NAME), a long‐acting nitric oxide synthase inhibitor with known vasoconstrictive effects. As a control, R₂ responses to adenosine and L‐NAME were also examined in the absence of ferumoxytol.

Results:

In the presence of ferumoxytol, adenosine induced a significant increase in R₂, while L‐NAME produced a reduction, although the latter was not statistically significant. Control experiments revealed small R₂ changes in the absence of ferumoxytol. An incidental finding was that the cross‐sectional area of the kidney also varied dynamically with adenosine and L‐NAME.

Conclusion:

Our results suggest that ferumoxytol‐enhanced R₂ imaging is sensitive to adenosine‐induced vasodilation. The responses to L‐NAME, however, were not statistically significant. The variations in kidney size and the R₂ changes in the absence of ferumoxytol may reflect alterations in the volume of the renal tubules. J. Magn. Reson. Imaging 2011;33:1091–1099. © 2011 Wiley‐Liss, Inc.     

Ferumoxytol in clinical practice: Implications for MRI

Ferumoxytol is an iron‐containing parenteral treatment for iron deficiency anemia that was recently approved by the Food and Drug Administration. The iron is in the form of a superparamagnetic iron oxide that causes T1, T2, and T2* shortening on magnetic resonance imaging (MRI). Furthermore, the drug has a long intravascular half‐life of 14–15 hours; a standard dose can affect MRI for days to months. We describe a case in which a patient underwent contrast‐enhanced MRI of the liver 2 days after receiving a dose of ferumoxytol, which was unknown to the radiology team. The blood pool and soft tissues were hyperintense on T1‐weighted images, concealing enhancement from the gadolinium‐based contrast agent that was administered during the exam and rendering the exam nondiagnostic. Radiologists must be aware of this potential effect in screening patients for MRI and interpreting exams. J. Magn. Reson. Imaging 2013;37:1476–1479. © 2012 Wiley Periodicals, Inc.     

Vascular Artifact Mimicking Thrombosis on MR Imaging Using Ferumoxytol as a Contrast Agent in Abdominal Vascular Assessment

PurposeTo describe an artifact that mimics thrombosis when assessing abdominal vasculature on magnetic resonance (MR) imaging using ferumoxytol in patients with contraindications to gadolinium-based contrast agents and to evaluate factors that may contribute to this artifact.Materials and MethodsThree radiologists in consensus retrospectively evaluated 61 abdominal MR imaging examinations using ferumoxytol as an intravenous contrast agent for the presence of an observed artifact that can mimic thrombosis. Patient demographics and contrast agent bolus concentrations were compared with an unpaired Wilcoxon signed rank test.ResultsAn artifact mimicking thrombosis was observed in 30 of 61 examinations, all on the arterial phase sequences. In examinations with this artifact, the average concentration of administered ferumoxytol was greater than in examinations where the artifact was not observed (P < .01). Several additional vascular findings were observed, including portal vein thrombosis (n = 2) and aneurysm (n = 1), renal vein thrombosis (n = 2), abdominal aortic aneurysm (n = 1), abdominal and iliac artery dissection (n = 3), and sequelae of portal hypertension (n = 8).ConclusionsAlthough MR imaging using ferumoxytol as an intravenous contrast agent can be useful in detecting abdominal vascular abnormalities, an artifact mimicking vascular thrombosis was observed in nearly half of the examinations.     

Monitoring of release of cargo from nanocarriers by MRI/MR spectroscopy (MRS): Significance of T2/T effect of iron particles

To monitor the release of cargo molecules from nanocarriers, a novel MRI/MRS technique was developed and tested. This novel approach uses a simultaneous encapsulation of superparamagnetic iron oxide (SPIO) nanoparticles and either a gadolinium (Gd)‐based paramagnetic contrast agent, Gd‐diethylenetriamine pentaacetic acid bismethylamide(GdDTPA‐BMA), for MRI, or an anticancer agent, 5‐fluorouracil (5‐FU), for MRS. These agents have significantly different diffusion properties due to their different molecular sizes. Strong negative signal enhancement due to the T₂ effects of SPIO dominates the positive T₁ contrast generated by GdDTPA‐BMA when SPIO and GdDTPA‐BMA are in close proximity (intact form). Positive T₁ contrast becomes evident upon release of GdDTPA‐BMA from the carrier once the distance between GdDTPA‐BMA and SPIO molecules is beyond the T₂ enhancement range. Similarly, intact nanocarriers loaded with 5‐FU and SPIO have a broad ¹⁹F resonance line because line‐width is inversely proportional to T^*₂, while free 5‐FU appears as a narrow resonance line once it is released from the liposomes. This technique allowed monitoring of the release of cargo molecules from liposomes encapsulating both SPIO and either GdDTPA‐BMA or 5‐FU by MRI/MRS in vitro using 2% agarose gel phantoms. Experimental results demonstrate successful demarcation of the released cargo molecules vs. encapsulated molecules. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

On the measurement of absolute cerebral blood volume (CBV) using vascular‐space‐occupancy (VASO) MRI

Recently, a vascular‐space‐occupancy (VASO) MRI technique was developed for quantitative assessment of cerebral blood volume (CBV). This method uses the T₁‐shortening effect of gadolinium diethylenetriamine pentaacetic acid (Gd‐DTPA) with imaging parameters chosen that null the precontrast blood magnetization but allow the postcontrast blood magnetization to recover to equilibrium. A key advantage of VASO CBV estimation is that it provides a straightforward procedure for converting MR signals to absolute physiologic values. However, as with other T₁‐based steady‐state approaches, several important factors need to be considered that influence the accuracy of CBV values obtained with VASO MRI. Here, the transverse relaxation (T₂/T) effect in VASO MRI was investigated using multiecho spin‐echo and gradient‐echo experiments, resulting in underestimation of CBV by 14.9% ± 1.1% and 16.0% ± 2.5% for spin echo (TE = 10 ms) and gradient echo (TE = 6 ms), respectively. In addition, the influence of contrast agent clearance was studied by acquiring multiple postcontrast VASO images at 2.2‐min intervals, which showed that the concentration of Gd‐DTPA in the first 14 min (single dose) was sufficient for the blood magnetization to fully recover to equilibrium. Finally, the effect of vascular Gd‐DTPA leakage was assessed for scalp tissue, and signal extrapolation as a function of postinjection time was demonstrated to be useful in minimizing the associated errors. Specific recommendations for VASO MRI acquisition and processing strategies are provided. Magn Reson Med, 2009. © 2008 Wiley‐Liss, Inc.     

Convertible manganese contrast for molecular and cellular MRI

We describe here the use of inorganic manganese based particles as convertible MRI agents. As has been demonstrated with iron oxide particles, manganese oxide and manganese carbonate particles can be internalized within phagocytotic cells, being subsequently shuttled to endosomes and/or lysosomes. As intact particles, only susceptibility‐induced MRI contrast is exhibited, most often seen as dark contrast in susceptibility‐weighted images. Modulation of MRI contrast is accomplished by the selective degradation of these particles within the endosomal and lysosomal compartments of cells. Upon particle deconstruction in the endosomes and lysosomes, the dissolved Mn²⁺ acts as a T₁ agent, eliciting bright contrast in T₁‐weighted images. This modulation of MRI contrast is demonstrated both in vitro in cells in culture, and also in vivo, in rat brain. These particles are the potential building blocks for an entire class of new environmentally responsive MRI contrast agents. Magn Reson Med 60:265–269, 2008. © 2008 Wiley‐Liss, Inc.     

Magnetic resonance imaging of experimental atherosclerotic plaque: comparison of two ultrasmall superparamagnetic particles of iron oxide

PURPOSE: To evaluate a new ultrasmall superparamagnetic particles of iron oxide (USPIO) compound, ferumoxytol, as a marker of macrophage activity in atherosclerotic plaques and to compare it to ferumoxtran-10. MATERIALS AND METHODS: Ten mature heritable hyperlipidemic (WHHL) female Watanabe rabbits served as the animal model for atherosclerosis, four coeval female New Zealand White (NZW) rabbits were the control group. Five WHHL and two NZW received a single intravenous injection (250 micromol/kg) of either ferumoxtran-10 or ferumoxytol and were subjected to daily MR examinations on a 1.5T whole body scanner for the next five days. Development of signal intensity changes and susceptibility effects was assessed. Statistical analysis was based on a nonparametric Wilcoxon-Mann-Whitney-U test by using a P value at the 0.05 significance level. On day 5, the rabbits were sacrificed and the aorta was referred to histopathology, distribution of iron particles in the vessel wall was analyzed. RESULTS: MRI was feasible in all animals. Three days after injection of ferumoxytol the highest luminal signal intensity measurements were observed in the ferumoxytol group; the highest measurements were five days after injection in the ferumoxtran-10 group (P < 0.05). In the WHHL, susceptibility effects presented as homogeneous dark lines parallel to the aortic wall after ferumoxytol and spotted areas void of signal after ferumoxtran-10. None of these findings were observed in the NZW control groups. CONCLUSION: Ferumoxtran-10 and ferumoxytol at a respective dose of 250 mumol/kg appear well suited for atherosclerotic plaque detection with MRI in experimental atherosclerosis. Ferumoxytol warrants further analysis in humans.     

Ferumoxytol-enhanced magnetic resonance angiography for the assessment of potential kidney transplant recipients

Objectives

Traditional contrast-enhanced methods for scanning blood vessels using magnetic resonance imaging (MRI) or CT carry potential risks for patients with advanced kidney disease. Ferumoxytol is a superparamagnetic iron oxide nanoparticle preparation that has potential as an MRI contrast agent in assessing the vasculature.

Methods

Twenty patients with advanced kidney disease requiring aorto-iliac vascular imaging as part of pre-operative kidney transplant candidacy assessment underwent ferumoxytol-enhanced magnetic resonance angiography (FeMRA) between December 2015 and August 2016. All scans were performed for clinical indications where standard imaging techniques were deemed potentially harmful or inconclusive. Image quality was evaluated for both arterial and venous compartments.

Results

First-pass and steady-state FeMRA using incremental doses of up to 4 mg/kg body weight of ferumoxytol as intravenous contrast agent for vascular enhancement was performed. Good arterial and venous enhancements were achieved, and FeMRA was not limited by calcification in assessing the arterial lumen. The scans were diagnostic and all patients completed their studies without adverse events.

Conclusions

Our preliminary experience supports the feasibility and utility of FeMRA for vascular imaging in patients with advanced kidney disease due for transplant listing, which has the advantages of obtaining both arteriography and venography using a single test without nephrotoxicity.

Key Points

? Evaluation of vascular disease is important in planning kidney transplantation. ? Standard vascular imaging methods are often problematic in kidney disease patients. ? FeMRA has the advantage of arteriography and venography in a single test. ? FeMRA is safe and non-nephrotoxic. ? FeMRA is not limited by arterial calcification.

     

Fat‐water separated delayed hyperenhanced myocardial infarct imaging

Fat deposition associated with myocardial infarction (MI) has been reported as a commonly occurring phenomenon. Magnetic resonance imaging (MRI) has the ability to efficiently detect MI using T₁‐sensitive contrast‐enhanced sequences and fat via its resonant frequency shift. In this work, the feasibility of fat‐water separation applied to the conventional delayed hyperenhanced (DHE) MI imaging technique is demonstrated. A three‐point Dixon acquisition and reconstruction was combined with an inversion recovery gradient‐echo pulse sequence. This allowed fat‐water separation along with T₁ sensitive imaging after injection of a gadolinium contrast agent. The technique is demonstrated in phantom experiments and three subjects with chronic MI. Areas of infarction were well defined as conventional hyperenhancement in water images. In two cases, fatty deposition was detected in fat images and confirmed by precontrast opposed‐phase imaging. Magn Reson Med 60:503–509, 2008. © 2008 Wiley‐Liss, Inc.     

Correlative dynamic contrast MRI and microscopic assessments of tumor vascularity in RIP‐tag2 transgenic mice

The purpose of this study was to define the feasibility of dynamic contrast‐enhanced magnetic resonance imaging (MRI) to estimate the vascular density and leakiness of spontaneous islet cell tumors in RIP‐Tag2 transgenic mice. Dynamic T₁‐weighted spoiled gradient echo (SPGR) imaging at 2.0 T was performed in 17 RIP‐Tag2 mice using a prototype blood pool macromolecular contrast medium (MMCM), albumin‐(Gd‐DTPA)₃₅. Kinetic analysis of the dynamic enhancement responses based on a two‐compartment model was used to estimate fractional plasma volume (fPV) and the coefficient of endothelial permeability (K^PS) for each tumor. The MRI estimate of fPV was correlated on a tumor‐by‐tumor basis with corresponding microscopic measurements of vascular density. The fPV assays by MMCM‐enhanced imaging ranged from 2.4%–14.1% of tissue volume. Individual tumor fPV values correlated significantly (r = 0.79, P < 0.001) with the corresponding microscopic estimates of vascularity consisting of the combined area densities of lectin‐perfused microvessels plus erythrocyte‐stained blood lakes. A biotinylated derivative of the albumin‐based MMCM confirmed extravasation of the contrast agent from some tumor blood vessels and accumulation in 25% of blood lakes. The K^PS values ranged from 0 (no detectable leak) to 0.356 mL/min/100 cm³. Dynamic MMCM‐enhanced MRI is feasible in RIP‐Tag2 pancreatic tumors, yielding estimates of vascular permeability and microscopically validated measurements of vascular richness. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Estimation of liver T*2 in transfusion‐related iron overload in patients with weighted least squares T*2 IDEAL

MRI imaging of hepatic iron overload can be achieved by estimating T₂* values using multiple‐echo sequences. The purpose of this work is to develop and clinically evaluate a weighted least squares algorithm based on T₂* Iterative Decomposition of water and fat with Echo Asymmetry and Least‐squares estimation (IDEAL) technique for volumetric estimation of hepatic T₂* in the setting of iron overload. The weighted least squares T₂* IDEAL technique improves T₂* estimation by automatically decreasing the impact of later, noise‐dominated echoes. The technique was evaluated in 37 patients with iron overload. Each patient underwent (i) a standard 2D multiple‐echo gradient echo sequence for T₂* assessment with nonlinear exponential fitting, and (ii) a 3D T₂* IDEAL technique, with and without a weighted least squares fit. Regression and Bland–Altman analysis demonstrated strong correlation between conventional 2D and T₂* IDEAL estimation. In cases of severe iron overload, T₂* IDEAL without weighted least squares reconstruction resulted in a relative overestimation of T₂* compared with weighted least squares. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Combined off-resonance imaging and T2 relaxation in the rotating frame for positive contrast MR imaging of infection in a murine burn model

Purpose

To develop novel magnetic resonance (MR) imaging methods to monitor accumulation of macrophages in inflammation and infection. Positive‐contrast MR imaging provides an alternative to negative‐contrast MRI, exploiting the chemical shift induced by ultra‐small superparamagnetic iron‐oxide (USPIO) nanoparticles to nearby water molecules. We introduce a novel combination of off‐resonance (ORI) positive‐contrast MRI and T_2ρ relaxation in the rotating frame (ORI‐T_2ρ) for positive‐contrast MR imaging of USPIO.

Materials and Methods

We tested ORI‐T_2ρ in phantoms and imaged in vivo the accumulation of USPIO‐labeled macrophages at the infection site in a mouse model of burn trauma and infection with Pseudomonas aeruginosa (PA). PA infection is clinically important. The USPIO nanoparticles were injected directly in the animals in solution, and macrophage labeling occurred in vivo in the animal model.

Results

We observed a significant difference between ORI‐T_2ρ and ORI, which leads us to suggest that ORI‐T_2ρ is more sensitive in detecting USPIO signal. To this end, the ORI‐T_2ρ positive contrast method may prove to be of higher utility in future research.

Conclusion

Our results may have direct implications in the longitudinal monitoring of infection, and open perspectives for testing novel anti‐infective compounds. J. Magn. Reson. Imaging 2010;32:1172–1183. © 2010 Wiley‐Liss, Inc.     

Chronic hepatitis B:Enlarged perihepatic lymph nodes correlated with hepatic histopathology

AIM:To assess the value of enlarged perihepatic lymph nodes in determining hepatic histopathology for chronic hepatitis B(CHB) by magnetic resonance imaging(MRI).METHODS:Sixty-seven patients who were clinically and histologically diagnosed with CHB and 18 healthy subjects without history of liver disease underwent abdominal MRI.Histological diagnosis and hepatic inflammation(grade 0-4) and fibrosis(stage 0-4) were assessed by a simplified system for scoring in chronic viral hepatitis.The major imaging protocol included an axial breath-hold fat suppressed fast spoiled gradient echo T2-weighted imaging(T2WI),axial breath-trigger fat suppressed fast recovery fast spin echo T2WI,and axial and coronal fast imaging employing steady-state acquisition.Perihepatic lymph nodes larger than 5 mm in shortest diameter were noted.RESULTS:The numbers and size indexes of lymphnodes greater than 5 mm in shortest diameter in hepatic hilum suggested inflammatory activity for subjects with grade 2 or higher,with a high accuracy of diagnosis(the area under the curves > 0.9,P < 0.001).The numbers of lymph nodes were 2 or more with a sensitivity of 87.27%,a specificity of 90.00%,an accuracy of 88.24%,a positive predictive value of 94.12%,and a negative predictive value of 79.41% in patients with grade 2 or higher,and the size indexes were no less than 180 mm 2 with a sensitivity of 83.64%,a specificity of 100%,an accuracy of 89.41%,a positive predictive value of 100%,and a negative predictive value of 76.92%.The numbers and size indexes of lymph nodes were not correlated with hepatic fibrosis.The signal intensity indexes of lymph nodes were no significant correlation with histological grading or staging of liver.CONCLUSION:The numbers and size indexes of enlarged perihepatic lymph nodes for patients with CHB suggest inflammatory activity for subjects with grade 2 or higher.     

Differential uptake of ferumoxtran-10 and ferumoxytol, ultrasmall superparamagnetic iron oxide contrast agents in rabbit: critical determinants of atherosclerotic plaque labeling

PURPOSE: To compare atherosclerotic plaque uptake of a first (ferumoxtran-10) and second generation (ferumoxytol) ultrasmall superparamagnetic iron oxide (USPIO) contrast agent with different pharmacokinetic/pharmacodynamic properties. MATERIALS AND METHODS: New Zealand White rabbits maintained on a high cholesterol/fat diet were subjected to balloon injury to the abdominal aorta. Ferumoxtran-10 or ferumoxytol (500 micromol/kg) was administered at 2, 4, and 8 weeks following injury. In vivo magnetic resonance imaging (MRI) was performed immediately prior to, immediately after, and 6 days post-contrast administration. Ex vivo MRI, histologic, and inductively coupled plasma-mass spectrometry (ICP-MS) iron analyses were performed on the excised vessels. RESULTS: The blood pool clearance of ferumoxytol (t(1/2) < or = 6 hours) was more rapid than that of ferumoxtran-10 (t(1/2) < or = 48 hours). Decreased in vivo MRI signal intensity in the abdominal aorta was observed at 2, 4, and 8 weeks following injury with ferumoxtran-10, but not with ferumoxytol. Consistent with these observations, ex vivo MRI signal intensity was decreased in the ferumoxtran-10 vessels, and to a lesser degree in the ferumoxytol vs. control vessels (- contrast agent). In contrast, in vitro macrophage phagocytosis of USPIO was four to six fold greater with ferumoxytol than with ferumoxtran-10. Additionally, the absolute iron content correlated with ex vivo MRI signal intensity in all vessels (r = -0.86, P < 0.0001). CONCLUSIONS: These data suggest that the exposure period of atherosclerotic plaque to USPIO rather than the kinetics of the USPIO uptake by plaque alone is a critical criterion for experimental design of in vivo studies.     

Single‐shot T1 mapping using simultaneous acquisitions of spin‐ and stimulated‐echo‐planar imaging (2D ss‐SESTEPI)

The conventional stimulated‐echo NMR sequence only measures the longitudinal component while discarding the transverse component, after tipping up the prepared magnetization. This transverse magnetization can be used to measure a spin echo, in addition to the stimulated echo. Two‐dimensional single‐shot spin‐ and stimulated‐echo‐planar imaging (ss‐SESTEPI) is an echo‐planar‐imaging‐based single‐shot imaging technique that simultaneously acquires a spin‐echo‐planar image and a stimulated‐echo‐planar image after a single radiofrequency excitation. The magnitudes of the spin‐echo‐planar image and stimulated‐echo‐planar image differ by T₁ decay and diffusion weighting for perfect 90° radiofrequency and thus can be used to rapidly measure T₁. However, the spatial variation of amplitude of radiofrequency field induces uneven splitting of the transverse magnetization for the spin‐echo‐planar image and stimulated‐echo‐planar image within the imaging field of view. Correction for amplitude of radiofrequency field inhomogeneity is therefore critical for two‐dimensional ss‐SESTEPI to be used for T₁ measurement. We developed a method for amplitude of radiofrequency field inhomogeneity correction by acquiring an additional stimulated‐echo‐planar image with minimal mixing time, calculating the difference between the spin echo and the stimulated echo and multiplying the stimulated‐echo‐planar image by the inverse functional map. Diffusion‐induced decay is corrected by measuring the average diffusivity during the prescanning. Rapid single‐shot T₁ mapping may be useful for various applications, such as dynamic T₁ mapping for real‐time estimation of the concentration of contrast agent in dynamic contrast enhancement MRI. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

A pilot investigation of new superparamagnetic iron oxide (ferumoxytol) as a contrast agent for cardiovascular MRI

Purpose: To evaluate the imaging potential of ferumoxytol, a new superparamagnetic iron oxide colloidal blood pool contrast agent.Materials and Methods: Magnetic resonance (MR) imaging at 1.5 Tesla was performed before and after intravenous injection of ferumoxytol using escalating doses of 0.4, 0.8, 1.2 and 1.6 mg Fe/kg for a total of 4 mg Fe/kg in five subjects imaged with 3D MR Angiography (MRA) of the trifurcation after each dose. In five subjects cardiac cine MRI was performed pre and post 4.0 mg Fe/kg. Image quality was assessed by measuring signal to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in the vascular structures. Pre- and post-dose urine and blood tests as well as EKG/vital sign monitoring were performed to evaluate safety and blood samples were collected for T1 relaxivity measurements.Results: Cumulative doses of 0, 0.4, 1.2, 2.4 and 4 mg Fe/kg yielded mean SNR in the arteries of 10, 16, 39, 57 and 69 respectively indicating that the higher doses produced higher SNR on 3D vascular images. Similarly aorta SNR on 2D time-of-flight increased from 11.8 without Fe to 15.4 post Fe (p = 0.004) indicating improved image quality on MRA sequences optimized for use without contrast. At 4 mg Fe/kg there was a substantial T1 shortening measured in the blood from 1990 ± 573 ms to 80 ± 42 ms (p < 0.0001), corresponding to the increased SNR. Images of large vascular structures including cardiac chambers, aorta, and pulmonary arteries were excellent post ferumoxytol but images of smaller arteries of the trifurcation were difficult to evaluate due to enhancement of the overlapping veins. No serious adverse events occurred.Conclusion: The new superparamagnetic iron oxide colloid ferumoxytol is a promising blood pool agent especially for cardiac, aorta and pulmonary imaging.     

Manganese‐guided cellular MRI of human embryonic stem cell and human bone marrow stromal cell viability

This study investigated the ability of MnCl₂ as a cellular MRI contrast agent to determine the in vitro viability of human embryonic stem cells (hESC) and human bone marrow stromal cells (hBMSC). Basic MRI parameters including T₁ and T₂ values of MnCl₂‐labeled hESC and hBMSC were measured and viability signal of manganese (Mn²⁺)‐labeled cells was validated. Furthermore, the biological activity of Ca²⁺‐channels was modulated utilizing both Ca²⁺‐channel agonist and antagonist to evaluate concomitant signal changes. Metabolic effects of MnCl₂‐labeling were also assessed using assays for cell viability, proliferation, and apoptosis. Finally, in vivo Mn²⁺‐guided MRI of the transplanted hESC was successfully achieved and validated by bioluminescence imaging. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Tyrosine polyethylene glycol (PEG)‐micelle magnetic resonance contrast agent for the detection of lipid rich areas in atherosclerotic plaque

Vulnerable or high‐risk atherosclerotic plaques often exhibit large lipid cores and thin fibrous caps that can lead to deadly vascular events when they rupture. In this study, polyethylene glycol (PEG)‐micelles that incorporate a gadolinium diethylenetriamine pentaacetic acid (Gd‐DTPA) amphiphile were used as an MR contrast agent. In an approach inspired by lipoproteins, the micelles were functionalized with tyrosine residues, an aromatic, lipophilic amino acid, to reach the lipid‐rich areas of atherosclerotic plaque in a highly efficient manner. These micelles were applied to apolipoprotein E^?/? (ApoE^?/?) mice as a model of atherosclerosis. The abdominal aortas of the animals were imaged using T₁‐weighted (T₁W) high‐resolution MRI at 9.4T before and up to 48 h after the administration of the micelles. PEG‐micelles modified with 15% tyrosine residues yielded a significant enhancement of the abdominal aortic wall at 6 and 24 h postinjection (pi) as compared to unmodified micelles. Fluorescence microscopy on histological sections of the abdominal aorta showed a correlation between lipid‐rich areas and the distribution of the functionalized contrast agent in plaque. Using a simple approach, we demonstrated that lipid‐rich areas in atherosclerotic plaque of ApoE^?/? mice can be detected by MRI using Gd‐DTPA micelles. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Relaxation effects of ferucarbotran‐labeled mesenchymal stem cells at 1.5T and 3T: Discrimination of viable from lysed cells

Human mesenchymal stem cells (hMSCs) were labeled with Ferucarbotran by simple incubation and cultured for up to 14 d. Iron content was determined by spectrometry and the intracellular localization of the contrast agent uptake was studied by electron and confocal microscopy. At various time points after labeling, ranging from 1 to 14 d, samples with viable or lysed labeled hMSCs, as well as nonlabeled controls, underwent MRI. Spin‐echo (SE) and gradient‐echo (GE) sequences with multiple TRs and TEs were used at 1.5T and 3T on a clinical scanner. Spectrometry showed an initial iron oxide uptake of 7.08 pg per cell. Microscopy studies revealed lysosomal compartmentalization. Contrast agent effects of hMSCs were persistent for up to 14 d after labeling. A marked difference in the T₂ effect of compartmentalized iron oxides compared to free iron oxides was found on T₂‐weighted sequences, but not on T‐weighted sequences. The observed differences may be explained by the loss of compartmentalization of iron oxide particles, the uniformity of distribution, and the subsequent increase in dephasing of protons on SE images. These results show that viable cells with compartmentalized iron oxides may—in principle—be distinguished from lysed cells or released iron oxides. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.