Atle Bjørnerud

NC100150 injection, a preparation of optimized iron oxide nanoparticles for positive-contrast MR angiography

A preparation of monocrystalline iron oxide nanoparticles with an oxidized starch coating, currently in clinical trials (NC100150 Injection; CLARISCAN™), was characterized by magnetization measurements, relaxometry, and photon correlation spectroscopy. By combining the results with a measure of iron content, one can obtain the size and magnetic attributes of the iron cores, including the relevant correlation times for outer sphere relaxation (τSO and τD), and information about the interaction of the organic coating with both core and solvent. The results are 6.43 nm for the iron oxide core diameter, a magnetic moment of 4.38 × 10−17 erg/G, and a water‐penetrable coating region of oxidized oligomeric starch fragments and entrained water molecules. The latter extends the hydrodynamic diameter to 11.9 nm and lowers the average diffusivity of solvent about 64% (which increases τD accordingly). The nanoparticles show little size‐polydispersity, evidenced by the lowest value of r2/r1 at 20 MHz reported to date, an asset for magnetic resonance angiography. J. Magn. Reson. Imaging 2000;11:488–494.

A targeted contrast agent for magnetic resonance imaging of thrombus: Implications of spatial resolution

A preparation of ultra‐small superparamagnetic iron oxide (USPIO) particles coupled to an RGD peptide (RGD‐USPIO) was investigated as an MR contrast agent, targeted to activated platelets, in both ex vivo and in vivo thrombus models. Thrombus visualization ex vivo was compared using RGD‐USPIO and a non‐targeted UPSIO. The influence of thrombus visualization on thrombus exposure time to RGD‐USPIO (ex vivo) and on the spatial resolution of the MR image (ex vivo and in vivo) was assessed. RGD‐USPIO resulted in better thrombus visualization than non‐targeted USPIO ex vivo, and maximum enhancement was achieved after approximately one hour exposure time of the thrombus to RGD‐USPIO. The ability to visualize the clots was highly dependent on the spatial resolution of the image. In vivo, an in‐plane resolution of less than 0.2 × 0.2 mm2 was required for good clot visualization after contrast enhancement. It is concluded that the achievable resolution and sensitivity is a potential limitation to the usefulness of active vascular targeting in MRI. J. Magn. Reson. Imaging 2001;13:615–618.

Assessment of T1 and T2* effects in vivo and ex vivo using iron oxide nanoparticles in steady state : dependence on blood volume and water exchange

Accurate knowledge of the relationship between contrast agent concentration and tissue relaxation is a critical requirement for quantitative assessment of tissue perfusion using contrast‐enhanced MRI. In the present study, using a pig model, the relationship between steady‐state blood concentration levels of an iron oxide nanoparticle with a hydrated diameter of 12 nm (NC100150 Injection) and changes in the transverse and longitudinal relaxation rates (1/T u2009*2 and 1/T1, respectively) in blood, muscle, and renal cortex was investigated at 1.5 T. Ex vivo measurements of 1/T u2009*2 and 1/T1 were additionally performed in whole pig blood spiked with different concentrations of the iron oxide nanoparticle. In renal cortex and muscle, 1/T u2009*2 increased linearly with contrast agent concentration with slopes of 101 ± 22 s−1mM−1 and 6.5 ± 0.9 s−1mM−1 (mean ± SD), respectively. In blood, 1/T u2009*2 increased as a quadratic function of contrast agent concentration, with different quadratic terms in the ex vivo vs. the in vivo experiments. In vivo, 1/T1 in blood increased linearly with contrast agent concentration, with a slope (T1‐relaxivity) of 13.9 ± 0.9 s−1mM−1. The achievable increase in 1/T1 in renal cortex and muscle was limited by the rate of water exchange between the intra‐ and extravascular compartments and the 1/T1‐curves were well described by a two‐compartment water exchange limited relaxation model. Magn Reson Med 47:461–471, 2002.

Thermosensitive paramagnetic liposomes for temperature control during MR imaging-guided hyperthermia: In vitro feasibility studies

RATIONALE AND OBJECTIVESnMagnetic resonance (MR) imaging-based temperature monitoring has gained interest for use in general hyperthermia treatment of tumors. Such therapy requires an accurate control of the temperature, which should range from 41 degrees to 45 degrees C. A novel type of thermosensitive MR agent is proposed: liposome-encapsulated gadolinium chelates whose temperature response is linked to the phase-transition properties of the liposome carrier. In vitro relaxometry and MR imaging were used to evaluate the thermosensitivity of the contrast properties of liposomal gadolinium diethylenetriaminepentaacetic acid bis(methylamide) (Gd-DTPA-BMA).nnnMATERIALS AND METHODSnT1 relaxivity (rl) measurements of liposomal Gd-DTPA-BMA were undertaken at 0.47 T and at temperatures of 20 degrees-48 degrees C. MR imaging was performed at 2.0 T with a gel phantom containing inserts of liposomes. Diffusion-weighted and T1-weighted gradient-recalled echo images were acquired as the phantom was heated from 22 degrees to about 65 degrees C.nnnRESULTSnAt ambient temperature, the r1 of liposomal Gd-DTPA-BMA was exchange limited due to slow water exchange between the liposome interior and exterior. A sharp, marked increase in r1 occurred as the temperature reached and exceeded the gel-to-liquid crystalline phase-transition temperature (Tm) of the liposomes (42 degrees C). The relaxation enhancement was mainly attributable to the marked increase in transmembrane water permeability, yielding fast exchange conditions. There was good correlation between the relaxometric and imaging results; the signal intensity on T1-weighted gradient-recalled echo images increased markedly as the temperature approached Tm. The temperature sensitivity of the diffusion-weighted technique differed from that of the liposome-based T1-weighted approach, with an apparent water diffusion coefficient increasing linearly with temperature.nnnCONCLUSIONnSince the transition from low to high signal intensity occurred in the temperature range of 38 degrees - 42 degrees C, the investigated paramagnetic liposomes have a potential role as off-on switches for temperature control during hyperthermia treatment.

CBF and CBV measurements by USPIO bolus tracking: Reproducibility and comparison with Gd-based values

The authors measured cerebral blood flow (CBF) and cerebral blood volume (CBV) by bolus tracking of a novel ultrasmall superparamagnetic iron oxide (USPIO) contrast agent (NC100150) and compared absolute and relative perfusion measurements with those obtained by a standard gadolinium‐based contrast agent. They found a linear correlation between the two methods. A dose of 0.4 mg Fe/kg body weight was found to produce a signal drop similar to that of a standard 0.2 mmol/kg gadodiamide injection using spin‐echo echoplanar imaging (SE‐EPI) at 1.0 T. The measurements showed a high degree of reproducibility of repeated absolute as well as relative CBF and CBV values, lending further hope to the possibility of using magnetic resonance bolus tracking for routine CBF and CBV measurements. Finally, the authors present their initial experience with high‐resolution, non‐EPI CBV maps obtained from steady‐state levels of an intravascular superparamagnetic contrast agent.J. Magn. Reson. Imaging 1999;9:342–347.

pH-sensitive paramagnetic liposomes as MRI contrast agents: in vitro feasibility studies

A novel type of pH-sensitive paramagnetic contrast agent is introduced; a low molecular weight gadolinium (Gd) chelate (GdDTPA-BMA) encapsulated within pH-sensitive liposomes. The in vitro relaxometric properties of the liposomal Gd chelate were shown to be a function of the pH in the liposomal dispersion and the membrane composition. Only a minor pH-dependency of the T1 relaxivity (r1) was observed for liposomal GdDTPA-BMA composed of the unsaturated lipids dioleoyl phosphatidyl ethanolamine (DOPE) and oleic acid (OA). On the other hand, the r1 of GdDTPA-BMA encapsulated within saturated dipalmitoyl phosphatidyl ethanolamine/palmitic acid (DPPE/PA) liposomes demonstrated a strong pH-dependency. At physiological pH and above, the r1 of this system was significantly lowered compared to that of non-liposomal Gd chelate, which was explained by an exchange limited relaxation process. Lowering the pH below physiological value, however, gave a sharp and 6-7 fold increase in r1, due to liposome destabilisation and subsequent leakage of entrapped GdDTPA-BMA. The pH-sensitivity of the DPPE/PA liposome system was confirmed in an in vitro magnetic resonance imaging (MRI) phantom study.

Renal T(*)(2) perfusion using an iron oxide nanoparticle contrast agent : influence of T(1) relaxation on the first-pass response

Quantitative perfusion measurements require accurate knowledge of the correlation between first‐pass signal changes and the corresponding tracer concentration in tissue. In the present study, a detailed analysis of first‐pass renal cortical changes in T1 and T u2009*2 following bolus injection of the iron oxide nanoparticle NC100150 Injection was investigated in a pig model using a double‐echo gradient‐echo sequence. The estimated change in 1/T u2009*2 during first pass calculated from single‐echo sequences was compared to the true double‐echo‐derived 1/T u2009*2 curves. Using a single‐echo (TE = 6 ms) spoiled gradient‐echo sequence, the first‐pass 1/T u2009*2 response following a bolus injection of 1 mg Fe/kg of NC100150 Injection was significantly underestimated due to counteracting T1 effects. Signal response simulations showed that the relative error in the first‐pass response decreased with increasing TE and contrast agent dose. However, both the maximum TE and the maximum dose are limited by excessive cortical signal loss, and the maximum TE is further limited by high temporal resolution requirements. The problem of T1 contamination can effectively be overcome by using a double‐echo gradient‐echo sequence. This yields a first‐pass response that truly reflects the tissue tracer concentration, which is a critical requirement for quantitative renal perfusion assessment. Magn Reson Med 47:298–304, 2002.

Pre-clinical results with Clariscan™ (NC100150 Injection); experience from different disease models

A superparamagnetic nanoparticle (NC100150 Injection) was investigated in two different animal models; renal perfusion in pigs and tumour imaging in mice. In the pig model, qualitative first-pass perfusion maps following a bolus injection of NC100150 Injection enabled good visualisation of hypoperfused regions of the renal cortex following partial ligation of the renal artery. High temporal resolution was found to be essential to accurately capture the first passage of the contrast agent through the kidney due to the very rapid blood flow in normal renal cortex. In the tumour model (LS174T cells implanted in nude mice), NC100150 Injection was found to cause a gradual (over 60 min) signal increase on Tl-w images in part of the tumours which was attributed to contrast agent leakage from the vascular space to the extravascular space in areas of increased capillary permeability. This observation is consistent with previous reports on the molecular cut-off size for vascular extraction for this tumour cell line. The specific enhancement of tumour tissue suggest potential utility of NC100150 Injection as an angiogenesis marker.

Macromolecular contrast medium (feruglose) versus small molecular contrast medium (gadopentetate) enhanced magnetic resonance imaging

RATIONALE AND OBJECTIVESnTo compare the diagnostic performance of the blood pool agent feruglose and the standard extracellular contrast agent gadopentetate in their abilities to differentiate benign and malignant breast tumors.nnnPATIENTS AND METHODSnFourteen women, aged 35-77 years (mean, 55 years), with 19 breast lesions underwent dynamic fast field echo 14/1/30 degrees (TR/TE/alpha) magnetic resonance imaging of the breast after bolus injection of feruglose (Clariscan; Amersham Health, Amersham, UK: dose, 2 mg Fe/kg) and an additional, comparative gadopentetate (dose, 0.2 mmol gadolinium/kg)-enhanced fast field echo 10/4/30 degrees (TR/TE/alpha) magnetic resonance study within 1-11 days (mean, 4.8 days) before or after the feruglose study. All breast tumors were surgically excised within 1-6 days (mean, 2.5 days) after completion of the magnetic resonance studies. Data were analyzed by measuring quantitative enhancement data and qualitatively by categorizations of the shape of the tumor enhancement curves. Group differences between quantitative data of the two contrast agents and between benign and malignant tumors were evaluated using a two-tailed paired-sample t test. Differences in curve type distribution between benign and malignant tumors were tested with the chi2 test.nnnRESULTSnHistopathology showed a spectrum of 10 benign and nine malignant breast lesions: five mastopathies, two fibroadenomas, two chronic inflammations, and one papillomatosis, as well as five invasive ductal carcinomas and four invasive lobular carcinomas. Substantial differences were observed between feruglose- and gadopentetate-enhanced images: the mean tumor deltaSI(%) peak enhancement and wash-in rate were significantly higher for gadopentetate- as compared with feruglose-enhanced images (P < .05). Using either contrast agent, morphologic enhancement characteristics showed a considerable overlap between benign and malignant breast lesions. However, the kinetic enhancement profiles of benign and malignant lesions were significantly different based on feruglose-enhanced data (chi2 = 9.017; P = .0027) but not gadopentetate-enhanced data (chi2 = 2.239; P = .3264).nnnCONCLUSIONnCompared with gadopentetate, the new blood pool agent feruglose provided an improved characterization of the evaluated breast lesions; however, at the cost of weaker overall tumor enhancement.

Effect of NC100150 injection on the 1H NMR linewidth of human whole blood ex vivo: Dependency on blood oxygen tension

The linewidth of the 1H NMR signal (7.05 T) of human whole blood titrated with a superparamagnetic contrast agent (NC100150 injection) was evaluated at different blood oxygen tensions. In deoxygenated blood and low contrast agent concentrations, NC100150 injection caused a decrease in linewidth. After reaching a minimum, the linewidth increased as the concentration of NC100150 injection increased. At the concentration corresponding to the minimum linewidth, the magnetization of the extracellular space containing the NC100150 injection was equal to that of the paramagnetic (deoxygenated hemoglobin) intracellular space. The minimum linewidth is therefore consistent with a complete elimination of the local microscopic susceptibility effect, the major cause of linebroadening. Additionally, phantom studies were performed at 1.5 T, confirming that the contrast enhancement of NC100150 injection in blood is dependent on oxygen tension. The data suggest that NC100150 injection may be useful in differentiating vessels with varying relative oxygen tensions. Magn Reson Med 44:803–807, 2000.