Jörg Schnorr

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 μmol Fe/kg and for 60 minutes after 0.075 μmol 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.

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

Wagner S, Schnorr J, Pilgrimm H, et al. Monomer-coated very small superparamagnetic iron oxide particles as contrast medium for magnetic resonance imaging: preclinical in vivo characterization. Invest Radiol 2002;37:167–177. 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.

New generation of monomer‐stabilized very small superparamagnetic iron oxide particles (VSOP) as contrast medium for MR angiography: Preclinical results in rats and rabbits

The purpose of this study was to evalute the signal enhancement characteristics of very small superparamagnetic iron oxide particles (VSOP)‐C63, a new monomer‐coated, iron oxide‐based magnetic resonance (MR) blood pool contrast medium with a very small particle size and optimized physical properties. Equilibrium MR angiography (MRA) of rats (thoracic and abdominal vessels) was performed at 1.5 T with a three‐dimensional gradient‐recalled echo (3D GRE) technique (TR/TE 6.6/2.3 msec, flip angle 25°) before and after (every 3–5 minutes up to 50 minutes) i.v. injection of VSOP‐C63 [dosages: 15, 30, 45, 60, 75, and 90 μmol Fe/kg; diameter: 8 nm; relaxivities at 0.47 T: R1 = 30 l/(mmol • s); R2 = 39 l/(mmol • s)]. First‐pass MRA images (3D‐GRE, TR/TE 4.5/1.7 msec, flip angle 25°) were obtained with 45 μmol Fe/kg VSOP‐C63 in comparison with 0.2 mmol Gd/kg of gadolinium diethylene triamine pentaacetic acid (Gd DTPA; before and every 5 seconds p.i.). MRA (3D GRE, TR/TE 4.5/1.7 msec, flip angle 25°) of coronary vessels in rabbits was performed after i.v. injection of 45 μmol Fe/kg of VSOP‐C63. In rats maximal S/N ratio in thoracic and abdominal arteries directly after i.v. injection of VSOP‐C63 was 25 ± 1, 43 ± 2, 49 ± 4, 57 ± 3, 64 ± 3, and 63 ± 3 for the different dosages. Blood half‐life was dose dependent (15 ± 2, 20 ± 3, 29 ± 6, 37 ± 5, 61 ± 16, and 86 ± 21 minutes). At a dose of 30 μmol Fe/kg even small intrarenal arteries were sharply delineated. First‐pass MRA showed no significant difference in the S/N ratio between Gd‐DTPA (71.5 ± 11.5) and VSOP‐C63 (65.1 ± 18.3). The proximal segments of the coronary arteries in rabbits were clearly depicted at a dose of 45 μmol Fe/kg. The monomer‐coated, iron oxide‐based contrast medium VSOP‐C63 exhibits favorable properties as a blood pool agent for both equilibrium and first‐pass MRA. J. Magn. Reson. Imaging 2000;12:905–911.

Cardiac MR Elastography: Comparison with left ventricular pressure measurement

Purpose of studyTo compare magnetic resonance elastography (MRE) with ventricular pressure changes in an animal model.MethodsThree pigs of different cardiac physiology (weight, 25 to 53 kg; heart rate, 61 to 93 bpm; left ventricular [LV] end-diastolic volume, 35 to 70 ml) were subjected to invasive LV pressure measurement by catheter and noninvasive cardiac MRE. Cardiac MRE was performed in a short-axis view of the heart and applying a 48.3-Hz shear-wave stimulus. Relative changes in LV-shear wave amplitudes during the cardiac cycle were analyzed. Correlation coefficients between wave amplitudes and LV pressure as well as between wave amplitudes and LV diameter were determined.ResultsA relationship between MRE and LV pressure was observed in all three animals (R2 ≥ 0.76). No correlation was observed between MRE and LV diameter (R2 ≤ 0.15). Instead, shear wave amplitudes decreased 102 ± 58 ms earlier than LV diameters at systole and amplitudes increased 175 ± 40 ms before LV dilatation at diastole. Amplitude ratios between diastole and systole ranged from 2.0 to 2.8, corresponding to LV pressure differences of 60 to 73 mmHg.ConclusionExternally induced shear waves provide information reflecting intraventricular pressure changes which, if substantiated in further experiments, has potential to make cardiac MRE a unique noninvasive imaging modality for measuring pressure-volume function of the heart.

Linking Proteins with Anionic Nanoparticles via Protamine: Ultrasmall Protein‐Coupled Probes for Magnetic Resonance Imaging of Apoptosis

Magnetic resonance imaging (MRI) of a target in vivo depends on the surface, size, and particle relaxivity of the target-specific nanoparticles for MRI. Here a new method for decorating very small iron oxide particles (VSOPs) with target-specific ligands is described. The method is based on the electrostatic attraction of the strongly positively charged peptide protamine to the anionic citrate shell of the electrostatically stabilized VSOPs. The protamine coat allows linkage chemistry and chimera technology to functionalize VSOPs or other negative charged surfaces with biologics. Annexin A5 (anxA5)-VSOP utilizing thiol chemistry was generated to couple biologically active anxA5 to VSOPs for in vivo MRI of apoptosis. Annexin A5-VSOP comprises five anxA5 molecules per iron oxide nanoparticle with a high R2 particle relaxivity of 180 000 mM(-1) s(-1) yet small hydrodynamic diameter of only 14.7+/-2.9 nm beneficial for in vivo MRI of extravascular targets.

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°, 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 ≥ .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.

Coronary MR angiography using citrate-coated very small superparamagnetic iron oxide particles as blood-pool contrast agent: Initial experience in humans

To evaluate very small superparamagnetic iron oxide particles (VSOP‐C184) as blood‐pool contrast agent for coronary MR angiography (CMRA) in humans.

Coronary magnetic resonance angiography: Experimental evaluation of the new rapid clearance blood pool contrast medium P792

The signal‐enhancing characteristics of a new monodisperse monogadolinated macromolecular MR contrast medium (P792) were evaluated for magnetic resonance angiography (MRA) of the coronary arteries. A total of 15 cardiac examinations were performed in pigs at 1.5 T using a 3D gradient‐echo sequence. Images were acquired during breath‐hold before and up to 35 min after IV injection of Gd‐DTPA (0.3 mmol Gd/kg), Gd‐BOPTA (0.2 mmol Gd/kg), and P792 (13 μmol Gd/kg). An increase in the signal‐to‐noise ratio (SNR) of 97% ± 17%, 108% ± 37%, and 109% ± 31% in coronary arteries and of 82% ± 19%, 82% ± 24%, and 28% ± 18% in myocardium, respectively, was measured during the first postcontrast acquisition. The blood‐to‐myocardium signal‐difference‐to‐noise ratio (SDNR) was significantly higher for P792 than for the other Gd compounds (P < .05) for up to 15 min after injection. Qualitative assessment showed that visualization of the coronary arteries and their branches was significantly better for P792 compared to the low‐molecular Gd compounds (P < .05). The blood pool contrast medium P792 is well suited for MRA of the coronary arteries. Magn Reson Med 46:932–938, 2001.

Fundamentals and applications of magnetic particle imaging

Magnetic particle imaging (MPI) is a new medical imaging technique which performs a direct measurement of magnetic nanoparticles, also known as superparamagnetic iron oxide. MPI can acquire quantitative images of the local distribution of the magnetic material with high spatial and temporal resolution. Its sensitivity is well above that of other methods used for the detection and quantification of magnetic materials, for example, magnetic resonance imaging. On the basis of an intravenous injection of magnetic particles, MPI has the potential to play an important role in medical application areas such as cardiovascular, oncology, and also in exploratory fields such as cell labeling and tracking. Here, we present an introduction to the basic function principle of MPI, together with an estimation of the spatial resolution and the detection limit. Furthermore, the above-mentioned medical applications are discussed with respect to an applicability of MPI.

Contrast-enhanced MR imaging of atherosclerosis using citrate-coated superparamagnetic iron oxide nanoparticles: calcifying microvesicles as imaging target for plaque characterization.

Objective To evaluate the suitability of citrate-coated very small superparamagnetic iron oxide particles (VSOP) as a contrast agent for identifying inflammation in atherosclerotic lesions using magnetic resonance imaging (MRI). Methods and results VSOP, which have already been evaluated as a blood pool contrast agent for MR angiography in human clinical trials, were investigated in Watanabe heritable hyper-lipidemic rabbits to determine to what extent their accumulation in atherosclerotic lesions is a function of macrophage density and other characteristics of progressive atherosclerotic plaques. In advanced atherosclerotic lesions, a significant MRI signal loss was found within 1 hour after intravenous administration of VSOP at the intended clinical dose of 0.05 mmol Fe/kg. Histological examinations confirmed correlations between the loss of MRI signal in the vessel wall and the presence of Prussian blue-stained iron colocalized with macrophages in the plaque cap, but surprisingly also with calcifying microvesicles at the intimomedial interface. Critical electrolyte magnesium chloride concentration in combination with Alcian blue stain indicates that highly sulfated glycosaminoglycans are a major constituent of these calcifying microvesicles, which may serve as the key molecules for binding VSOP due to their highly complexing properties. Conclusion Calcifying microvesicles and macrophages are the targets for intravenously injected VSOP in atherosclerotic plaques, suggesting that VSOP-enhanced MRI may render clinically relevant information on the composition and inflammatory activity of progressive atherosclerotic lesions at risk of destabilization.