Whole-heart coronary magnetic resonance angiography: contrast-enhanced high-resolution, time-resolved 3D imaging.

OBJECTIVES: To test the feasibility and performance of a 4D magnetic resonance coronary angiography sequence compared with conventional inversion recovery (IR) prepared gradient echo imaging. MATERIALS AND METHODS: A 4D sequence with 100 milliseconds temporal resolution was implemented on a 1.5 T system. Five minipigs were examined after administration of very small superparamagnetic iron oxide particles. Coronary angiographies with an isotropic resolution of 0.82 mm were performed in the pigs using 4D and IR sequences. RESULTS: The 4D sequence allowed visualization of the coronary arteries, the effect of their movement and that of the entire heart without prolonging scan time. The contrast-to-noise ratio of the IR images was on average 38% higher than that of the corresponding 4D phase. CONCLUSIONS: 4D magnetic resonance imaging is superior in that no trigger delay time needs to be determined and an additional whole-heart cine study can be obtained.

Iron oxide particles for molecular magnetic resonance imaging cause transient oxidative stress in rat macrophages.

Iron oxide particles are a promising marker in molecular magnetic resonance imaging. They are used to label distinct cell populations either in vitro or in vivo. We investigated for the first time whether small citrate-coated very small superparamagnetic iron oxide particles (VSOPs) can lead to an increase in cellular oxidative stress. We incubated rat macrophages (RAW) in vitro with iron oxide particles. We observed a massive uptake of VSOPs measured both with atomic absorption spectroscopy and with NMR, which could be visualized by confocal laser scanning microscopy. After incubation, cells were lysed and the levels of malonyldialdehyde (MDA) and protein carbonyls were determined. We found a significant increase in both MDA and protein carbonyl levels after incubation with the particles. Surprisingly, 24 h after incubation, a significant indication of oxidative stress could no longer be observed. The increase in oxidative stress seems to be transient and closely linked to the incubation procedure. The iron chelator desferal and the intracellular spin trap PBN caused a significant reduction in oxidative stress to almost control levels. This indicates that the augmentation of oxidative stress is closely linked to the free iron during incubation. Proliferation assays showed that incorporation of VSOPs did not lead to long-term cytotoxic effects even though the iron oxide particles remained in the cell. Magnetic labeling of cells with VSOPs seems to cause transient oxidative conditions not affecting cellular viability and seems to be a usable approach for molecular magnetic resonance imaging.

Monomer-coated very small superparamagnetic iron oxide particles as contrast medium for magnetic resonance imaging: preclinical in vivo characterization.

RATIONALE AND OBJECTIVES: Preclinical in-vivo characterization of a newly developed MR contrast medium consisting of very small superparamagnetic iron oxide particles (VSOP) coated with citrate (VSOP-C184). METHODS: VSOP-C184 (core diameter: 4 nm; total diameter: 8.6 nm; relaxivities in water at 0.94 T (T1) 20.1 and (T2) 37.1 l/[mmol*sec]) was investigated to determine its pharmacokinetics, efficacy, acute single dose toxicity, repeated dose toxicity, and genotoxicity. RESULTS: The plasma elimination half-life at 0.045 mmol Fe/kg was 21.3 +/- 5.5 minutes in rats and 36.1 +/- 4.2 minutes in pigs, resulting in a T1-relaxation time of plasma of < 100 milliseconds for 30 minutes in pigs. The particles are mainly cleared via the phagocytosing system of the liver. MR angiography at a dose of 0.045 mmol Fe/kg shows an excellent depiction of the thoracic and abdominal vasculature in rats and of the coronary arteries in pigs. The LD50 in mice is > 17.9 mmol Fe/kg. A good tolerance and safety profile was found. CONCLUSIONS: The experiments indicate, that VSOP-C184 may be a well tolerated and safe contrast medium for MR imaging that can be effectively used for MR angiography including visualization of the coronary arteries.

In vitro characterization of two different ultrasmall iron oxide particles for magnetic resonance cell tracking.

RATIONALE AND OBJECTIVES: Comparison of two different ultrasmall superparamagnetic iron oxide (USPIO) particles in terms of their intracellular cell-labeling properties of macrophages and subsequent visualization by MR imaging. MATERIALS AND METHODS: Cultures containing the macrophage cell line P-388D1 were incubated with a neutral carboxydextran-coated USPIO preparation (DDM 43/34/103) or an acidic citrate-coated USPIO (VSOP-C125). Experiments were performed in which incubation concentration and duration were varied and phagocytosis and pinocytosis suppressed by specific inhibitors. In cell culture specimens iron content was measured quantitatively and signal intensities determined by in vitro MR imaging. RESULTS: VSOP-C125 is incorporated by cells much faster than DDM 43/34/103 and produces significantly higher final intracellular iron concentrations per cell (3420 vs. 727 ng/million cells). Both preparations show similar signal-reducing effects at MR imaging relative to the Fe content per cell. Intracellular USPIO has a much lower detection threshold at MR imaging (50/80 micromol/L) than extracellular USPIO in free solution (300 micromol/L). CONCLUSIONS: Citrate-coated USPIO particles VSOP-C125 appear to have more favorable properties for magnetic labeling of macrophages than the carboxydextran-coated USPIO preparation DDM 43/34/103.

Phase I clinical evaluation of citrate-coated monocrystalline very small superparamagnetic iron oxide particles as a new contrast medium for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: To evaluate the safety and pharmacokinetics of a newly developed MR contrast medium consisting of very small superparamagnetic iron oxide particles (VSOP) coated with citrate (VSOP-C184) in a clinical phase I trial. METHODS: A total of 18 healthy subjects received either VSOP-C184 (core diameter: 4 nm; total diameter: 7 +/- 0.15 nm; relaxivities in water at 0.47 T (T1) 18.7 and (T2) 30 L/(mmol*seconds)) at doses of 0.015, 0.045, or 0.075 mmol Fe/kg (n = 5 per dose) or placebo (n = 1 per dose) as intravenous injections. Physical status and vital parameters were recorded, blood samples were collected for clinical chemistry and relaxometry (0.94 T), and urinalyses were performed before and for up to 2 weeks after administration. RESULTS: No serious adverse events occurred. The most pronounced adverse events occurred in 2 subjects of the highest dose group 45-50 minutes after injection. These were a drop in blood pressure and a drop in oxygen saturation, which were considered to be possibly drug-related and rapidly resolved without medication. Otherwise, no relevant changes in vital and laboratory parameters were observed. The parameters of iron metabolism exhibited short-term, dose-related changes. The injection of VSOP-C184 decreased T1 relaxation time of blood below 100 milliseconds for 18 minutes after a dose of 0.045 mmol [corrected] Fe/kg and for 60 minutes after 0.075 mmol [corrected] Fe/kg. CONCLUSIONS: The favorable data on the safety, tolerability, and efficacy of VSOP-C184 justify further clinical phase II and III trials as a contrast medium for MRI.

Comparison of the iron oxide-based blood-pool contrast medium VSOP-C184 with gadopentetate dimeglumine for first-pass magnetic resonance angiography of the aorta and renal arteries in pigs.

RATIONALE AND OBJECTIVES: VSOP-C184 at a dose of 0.045 mmol Fe/kg has been shown to be an efficient blood pool contrast medium for equilibrium magnetic resonance angiography (MRA) that can be administered as a bolus. The present study was performed to determine whether VSOP-C184 is also suitable for first-pass MRA. MATERIALS AND METHODS: Fifteen MRA examinations at 1.5 T were performed in minipigs using a fast 3D fast low-angle shot (FLASH) sequence (repetition time = 4.5 ms, echo time = 1.7 ms, excitation angle = 25 degrees, matrix 256, body phased-array coil). The citrate-stabilized iron oxide preparation VSOP-C184 was investigated (total particle diameter: 7.0 +/- 0.15 nm; core size: 4 nm) and compared with gadopentetate dimeglumine (Gd-DTPA). The following doses were tested: VSOP-C184: 0.015, 0.025, and 0.035 mmol Fe/kg; Gd-DTPA: 0.1 and 0.2 mmol Gd/kg; n = 3 examinations/dose. Data were analyzed quantitatively (signal enhancement (ENH) and vessel edge definition (VED)) and qualitatively. RESULTS: First-pass MRA using the 3 doses of VSOP-C184 yielded the following ENH: aorta: 9.4 +/- 2.6; 12.31 +/- 1.2; 16.53 +/- 1.7; renal arteries: 7.6 +/- 2.2; 9.9 +/- 1.0; 13.2 +/- 0.5. The values for the 2 doses of Gd-DTPA were aorta: 12.9 +/- 1.0; 16.8 +/- 2.2; renal arteries: 11.2 +/- 1.23; 11.3 +/- 1.7. VED for the 3 doses of VSOP-C184 was aorta: 106.3 +/- 31.0; 135.3 +/- 58.8; 141.3 +/- 71.0; renal arteries: 102.2 +/- 24.3; 146.8 +/- 63.0; 126.9 +/- 37.6 and for the 2 doses of Gd-DTPA, aorta: 157.2 +/- 47.8; 164.2 +/- 36.8; renal arteries: 165.9 +/- 30.4; 170.3 +/- 38.2 respectively. The differences between VSOP-C184 and Gd-DTPA are clinically not relevant and statistically not significant (p > or = .05). Qualitative evaluation of image quality, contrast, and delineation of vessels showed the results obtained with VSOP-C184 at doses of 0.025 and 0.035 mmol Fe/kg to be similar to those of Gd-DTPA at 0.1 and 0.2 mmol Gd/kg. CONCLUSION: VSOP-C184 is suitable for first-pass MRA at doses of 0.025 and 0.035 mmol Fe/kg and thus, in addition to its blood pool characteristics, allows for selective visualization of the arteries without interfering venous signal.

Focal liver lesions: SPIO-, gadolinium-, and ferucarbotran-enhanced dynamic T1-weighted and delayed T2-weighted MR imaging in rabbits.

PURPOSE: To compare a superparamagnetic iron oxide (SPIO), VSOP-C184, with a gadopentetate dimeglumine with regard to signal-enhancing effects on T1-weighted dynamic magnetic resonance (MR) images and with another SPIO contrast medium with regard to signal-reducing effects on delayed T2-weighted MR images. MATERIALS AND METHODS: All experiments were approved by the responsible Animal Care Committee. Twenty rabbits (five for each contrast agent and dose) implanted with VX-2 carcinoma were imaged at 1.5 T. VSOP-C184 at 0.015 and 0.025 mmol Fe/kg was compared with gadopentetate dimeglumine at 0.15 mmol Gd/kg and ferucarbotran at 0.015 mmol Fe/kg. The imaging protocol comprised a T1-weighted dynamic gradient-echo (GRE) MR before injection and at 6-second intervals for up to 42 seconds after injection and a T2-weighted turbo spin-echo MR before and 5 minutes after injection. Images were evaluated quantitatively, and contrast media were compared by using nonparametric analysis of variance. RESULTS: At dynamic T1-weighted GRE MR imaging with 0.015-mmol Fe/kg VSOP-C184, 0.025-mmol Fe/kg VSOP-C184, gadopentetate dimeglumine, and ferucarbotran, the median peak contrast-to-noise ratio (CNR) was 20.7 (25th percentile, 16.3; 75th percentile, 22.6), 24.2 (25th percentile, 19.3; 75th percentile, 28.5), 16.4 (25th percentile, 13.7; 75th percentile, 20.3), and 14.0 (25th percentile, 11.4; 75th percentile, 16.8), respectively. Both doses of VSOP-C184 yielded significantly higher CNR (P < .05) than the other two agents. At T2-weighted turbo spin-echo imaging with 0.015-mmol Fe/kg VSOP-C184, 0.025-mmol Fe/kg VSOP-C184, gadopentetate dimeglumine, and ferucarbotran, the median CNR was 15.0 (25th percentile, 13.4; 75th percentile, 21.3), 15.7 (25th percentile, 14.5; 75th percentile, 19.8), 11.3 (25th percentile, 8.2; 75th percentile, 12.2), and 15.7 (25th percentile, 12.5; 75th percentile, 22.4), respectively. There was no significant difference between VSOP-C184 and ferucarbotran; both had a significantly higher CNR than did gadopentetate dimeglumine. CONCLUSION: VSOP-C184 produces higher liver-to-tumor contrast at dynamic T1-weighted imaging than does gadopentetate dimeglumine; at delayed T2-weighted imaging, the contrast is comparable to that achieved with ferucarbotran.

In vivo detection limits of magnetically labeled embryonic stem cells in the rat brain using high-field (17.6 T) magnetic resonance imaging.

Stem cell transplantation is a promising therapeutic approach for several neurological disorders. However, it has yet to fulfill its high expectations, partially due to the lack of a reliable noninvasive method for monitoring the biodistribution of the grafted stem cells in vivo. We have used high-resolution magnetic resonance imaging (MRI) at 17.6 T, combined with efficient magnetic labeling of the stem cells with iron oxide nanoparticles, in order to assess the in vivo detection limit in small animal models. Injection of different concentrations of magnetically labeled stem cells in gel phantoms led to significant reductions in image intensity from small cellular clusters of less than 10 cells. To determine the detection limit in vivo, various numbers of both labeled and unlabeled cells were injected stereotactically into the striatum of rats. Significant hypointense signal changes were observed for 100 labeled cells. After injection of approximately 20 labeled cells, signal reduction at the injection site was observed but could not be assigned unambiguously to the cells. Our results show that high-field MRI allows tracking of a minimal number of cells in vivo, well below the number used in previous studies, opening the possibility of gaining new insights into cell migration and differentiation.

Coronary MR angiography: experimental results with a monomer-stabilized blood pool contrast medium.

PURPOSE: To evaluate the signal-enhancing characteristics of monomer-coated very small superparamagnetic iron oxide (SPIO) particles used as a blood pool contrast medium for magnetic resonance (MR) angiography in the coronary arteries. MATERIALS AND METHODS: The particles used in this study were coated with citrate as the monomer (VSOP-C91). The particles have a total diameter of 7 nm and show the following relaxivities at 0.47 T: T1, 19 L/mmol. sec(-1); T2, 29 L/mmol. sec(-1). Fifteen cardiac MR examinations were performed at 1.5 T in five pigs. Images were acquired from immediately to 35 minutes (equilibrium phase) after intravenous injection of gadopentetate dimeglumine, gadobenate dimeglumine, and the very small SPIO particles (n = 5 for each substance). RESULTS: Immediately after administration of gadopentetate dimeglumine, gadobenate dimeglumine, and the very small SPIO particles, respectively, increases in the signal-to-noise ratio in blood were 94%, 103%, and 102% and in myocardium were 83%, 83%, and 29% (P <.05, very small SPIO particles versus the low-molecular-weight gadolinium-based compounds). Differences in the blood-to-myocardium contrast-to-noise ratio and visualization of the coronary arteries and their branches were also significant. CONCLUSION: VSOP-C91 significantly improves visualization of the coronary arteries at MR angiography from immediately to 35 minutes after injection.