Comparison of ultrasmall superparamagnetic iron oxide particles and low molecular weight contrast agents to detect rejecting transplanted hearts with magnetic resonance imaging

PURPOSE: This study compared 3 different contrast agents for magnetic resonance imaging (MRI) to determine whether their rate of permeability could discriminate between acutely rejecting and nonrejecting transplanted hearts. MATERIALS AND METHODS: Heterotopic heart transplantation in rats was performed and animals were divided into allogeneic and syngeneic groups. At the sixth postoperative day, MRI was performed with 2 ultrasmall superparamagnetic iron oxide particles of different sizes, unformulated NC 100150 and AMI-227, besides gadodiamide. RESULTS: For unformulated NC100150, the signal intensity between the groups differed at all times (P < 0.0001); for AMI-227, all times but 3 (P < 0.05). With low molecular weight gadolinium chelate, no discrimination between rejecting and nonrejecting groups could be made. CONCLUSION: Acutely rejecting and nonrejecting transplanted hearts can be discriminated from each other using the difference in permeability assessed by blood pool agents and MRI. With first pass of gadolinium chelate no discrimination could be made between rejecting and nonrejecting grafts.     

The magnetic properties of some materials affecting MR images.

We have compared the magnetic properties of various types of materials known to affect MR images. The materials compared were: (i) MR contrast agents based on chelates of paramagnetic metals (Gd-DTPA, Dy-DTPA); (ii) biological forms of iron (horse spleen ferritin and deoxyhemoglobin); and (iii) a superparamagnetic iron oxide (AMI-25). The properties compared were the magnetic susceptibility and the magnetization. The magnetization and susceptibility of superparamagnetic AMI-25 are far larger than that of ferritin or low molecular weight, paramagnetic chelates. Superparamagnetic iron oxide colloids, like AMI-25, are a uniquely powerful class of magnetic materials.     

Long-term imaging effects in rat liver after a single injection of an iron oxide nanoparticle based MR contrast agent

PURPOSE: To investigate the duration of liver R2* enhancement and pharmacokinetics following administration of an iron oxide nanoparticle in a rat model. MATERIALS AND METHODS: Rats were injected with 0, 1, 2, or 5 mg Fe/kg of NC100150 Injection, and quantitative in vivo 1/T2* liver measurements were obtained between 1 and 133 days after injection. The concentration of NC100150 Injection was determined by relaxometry methods in ex vivo rat liver homogenate. RESULTS: At all dose levels, 1/T2* remained greater than control values up to 63 days after injection. In the highest dose group, 1/T2* was above control levels during the entire 133 day time-course investigated. There were no quantifiable amounts of NC100150 Injection present 63 days after injection in any of the dose groups. The half-life of NC100150 Injection in rat liver was dose dependent. For the lowest dose group, the degradation of the particles could be defined by a mono-exponential function with a half-life of eight days. For the 2 and 5 mg Fe/kg dose groups, the degradation was bi-exponential with a fast initial decay of seven to eight days followed by a slow terminal decay of 43-46 days. CONCLUSION: NC100150 Injection exhibits prolonged 1/T2* enhancement in rat liver. The liver enhancement persisted at time points when the concentration of iron oxide particles present in the liver was below method detection limits. The prolonged 1/T2* enhancement is likely a result of the particle breakdown products and the induction of ferritin and hemosiderin with increasing iron cores/loading factors.     

Signal loss induced by superparamagnetic iron oxide particles in NMR spin-echo images: the role of diffusion

MR contrast agents are used to improve the detectability of pathologic conditions. In this study we clarify the mechanism of action of a newly developed superparamagnetic agent (AMI-25, Advanced Magnetics Inc., Cambridge, MA). Transverse relaxation rates were measured from segments of rat brain, heart, and liver using a CPMG pulse sequence. Relaxation rates varied with the time interval between the refocusing pulses in the sequence (tau). The diffusion effect on signal intensity was quantitated from the variation of T2 with tau. We find that diffusion in the presence of microscopic field gradients reduces T2, and that this effect differs in magnitude among tissues. Superparamagnetic iron oxide particles enhance this T2 reduction. The dependence of T2 upon tau suggests a model of restricted diffusion. Tissue image contrast induced by superparamagnetic iron oxide in spin-echo NMR studies is the result of a combination of diffusion-dependent and diffusion-independent differences in transverse relaxation.     

Application of superparamagnetic iron oxide to imaging of hepatocellular carcinoma

Superparamagnetic iron oxide (SPIO) particles are as MR contrast media composed of iron oxide crystals coated with dextran or carboxydextran. These particles are sequestered by phagocytic Kupffer cells in normal reticuloendothelial system (RES), but are not retained in tumor tissue. Consequently, there are significant differences in T2/T2* relaxation between normal RES tissue and tumors, which result in increased lesion conspicuity and detectability. The introduction of SPIO has been expected to substantially increase the detectability of hepatic metastases. For focal hepatocellular lesions, it has been documented that SPIO-enhanced MR imaging exhibits slightly better diagnostic performance than dynamic helical CT in the detection of hypervascular hepatocellular carcinoma (HCC). A combination of dynamic and static MR imaging technique using T1- and T2 imaging criteria appears to provide clinically more useful patterns of enhancement. SPIO-enhanced MR imaging also provides information useful for differential diagnosis, via enhancement of RES-containing tumors. With the exploitation of rapid T2*-sensitive sequences, SPIO-enhanced dynamic MR imaging may become comparable to gadolinium-enhanced dynamic MR imaging and dynamic studies with multidetector-row CT. SPIO-enhanced MR imaging plays an important role in therapeutic decision-making for patients with HCC.     

Safety and preliminary findings with the intravascular contrast agent NC100150 injection for MR coronary angiography

In this Phase I clinical study, a novel ultrasmall superparamagnetic iron oxide contrast agent, NC100150 Injection (Nycomed Imaging, Oslo, Norway, a part of Nycomed Amersham), was used in two-dimensional magnetic resonance coronary angiography (MRCA). Safety and imaging data were acquired from 18 healthy male volunteers at both 0.5 and 1.5 T, before and after the administration of NC100150 Injection. Through-plane and in-plane images of the right coronary artery were analyzed. The postcontrast imaging sequences used prepulses and a high flip angle, to introduce T1 weighting. At 1.5 T (TE 2.6 msec), the through-plane coronary artery signal-to-noise ratio (SNR) (P = 0.04), coronary artery-to-fat signal difference-to-noise ratio (SDNR) (P = 0.001), coronary artery-to-myocardium SDNR (P<0.001), and coronary artery delineation (P<0.001) were improved by the administration of NC100150 Injection. For in-plane imaging, coronary artery delineation improved, but there were no significant changes in the SNR and SDNR. At 0.5 T, with the longer TE (6.7 msec) imaging sequence used, there was a reduction in the SNR (P = 0.01), the fat SDNR (through-plane P = 0.02; in-plane P = 0.25), and the coronary artery diameter (P<0.01 in both imaging planes). There was a trend toward improvement in the myocardial SDNR and coronary artery delineation. In conclusion, NC 100150 Injection was given safely to 18 healthy subjects, with no major adverse reactions. Coronary artery delineation was improved in both imaging planes at 1.5 T, with a trend toward improvement at 0.5 T. At 1.5 T, with a short TE imaging sequence, the marked T1 shortening effects of NC100150 Injection were dominant, leading to an improvement in the quantitative parameters for the through-plane images. At 0.5 T, with a longer TE imaging sequence, the T2* effects of the contrast agent played a role in reducing the quantitative image parameters. With further optimization of imaging sequences, to take advantage of the long-lived intravascular T1 shortening effect of NC100150 Injection, further improvements in MRCA will be possible.     

Receptor imaging: application to MR imaging of liver cancer

A new contrast agent for magnetic resonance (MR) imaging, directed to asialoglycoprotein (ASG) receptors on hepatocytes, was used for detection of liver cancer in rats. Ultrasmall superparamagnetic (mean size, 12 nm) particles of iron oxide (USPIOs) were targeted to ASG receptors by coating particles with arabinogalactan (AG). Liver T2 relaxation times decreased more effectively after a single intravenous administration of AG-USPIO than after an equal dose of a conventional superparamagnetic liver MR contrast agent (AMI-25; mean size, 72 nm). Receptor affinity studies demonstrated that receptor-mediated attachment and subsequent cellular endocytosis do not occur in primary malignant (hepatocellular carcinoma) or metastatic (adenocarcinoma) tumors, because the surface ASG receptors are lost during malignant dedifferentiation. In vitro relaxation and in vivo MR imaging experiments of liver tumors show that targeting USPIO to hepatocytes rather than to the mononuclear phagocytic system allows a considerable dose reduction, increases tumor-liver contrast, and potentially allows distinction of ASG-positive (benign hepatocellular) and ASG-negative (malignant hepatocellular) tumors.     

Enhancement of phase-contrast MR angiography with superparamagnetic iron oxide

The effect of superparamagnetic iron oxide particles (AMI-227) was assessed in three-dimensional (3D) phase-contrast (PC) MR angiography (MRA), with various scanning parameters for rats at 1.5 T. The blood T1 and T2 before and after 20 μmol Fe/kg of AMI-227 injection were measured sequentially at .47 T. The visualization of abdominal aorta, renal artery, inferior vena cava, and portal vein was respectively evaluated before and after AMI-227 injection qualitatively by the four confidence levels and quantitatively by analysis of signal-to-noise ratio (SNR) of vessels. The blood T1 and T2 were sufficiently shortened for at least 1 hour after AMI-227 injection. The visualization of each vessel was improved by AMI-227 at various velocity encoding (VENC) value, suggesting the extended application of PC-MRA in various conditions. The optimal flip angle was increased from 20° to 30° in higher VENC after AMI-227 injection, resulting in higher signal from blood flow. Quantitative analyses showed that the optimal flip angle to achieve the maximum SNR seemed to be 20° in unenhanced images, but the optimal flip angle of the high speed flow was increased by contrast enhancement. The postcontrast PC-MRA provides the increased sensitivity of slow flow components, even with a high VENC gradient. AMI-227 can significantly improve SNR to blood vessels during 3D-PC-MRA with various scanning parameters.     

Superparamagnetic iron oxide: enhanced detection of focal splenic tumors with MR imaging

Superparamagnetic iron oxide (AMI-25), a reticuloendothelial cell-specific contrast agent for magnetic resonance (MR) imaging, was evaluated for its ability to permit detection of splenic metastases in 18 patients. Superparamagnetic iron oxide, at a dose of 30 mumol of iron per kilogram, decreased the signal intensity of spleen from 19.5 +/- 4.8 to 3.1 +/- 2.2 (spin-echo sequence, repetition time msec/echo time msec = 1,500/42; P less than .05), without changing the signal intensity of tumor. As a result, the tumor-spleen contrast-to-noise ratio increased from 0.2 (tumor isointense relative to spleen) to 18.0 (tumor hyperintense relative to spleen). As a consequence of increased contrast, splenic tumors were detected in four of 18 patients (45 individual lesions; P less than .05), whereas nonenhanced MR imaging permitted detection of splenic lesions in only two of 18 patients (four individual lesions). Maximum tumor-spleen contrast was achieved within 60 minutes after intravenous administration. These initial clinical results indicate that MR imaging with superparamagnetic iron oxide may offer improved accuracy in the diagnosis of splenic tumors.     

Clearance of iron oxide particles in rat liver: effect of hydrated particle size and coating material on liver metabolism

OBJECTIVES: We sought to evaluate the effect of the particle size and coating material of various iron oxide preparations on the rate of rat liver clearance. MATERIALS AND METHODS: The following iron oxide formulations were used in this study: dextran-coated ferumoxide (size = 97 nm) and ferumoxtran-10 (size = 21 nm), carboxydextran-coated SHU555A (size = 69 nm) and fractionated SHU555A (size = 12 nm), and oxidized-starch coated materials either unformulated NC100150 (size = 15 nm) or formulated NC100150 injection (size = 12 nm). All formulations were administered to 165 rats at 2 dose levels. Quantitative liver R2* values were obtained during a 63-day time period. The concentration of iron oxide particles in the liver was determined by relaxometry, and these values were used to calculate the particle half-lives in the liver. RESULTS: After the administration of a high dose of iron oxide, the half-life of iron oxide particles in rat liver was 8 days for dextran-coated materials, 10 days for carboxydextran materials, 14 days for unformulated oxidized-starch, and 29 days for formulated oxidized-starch. CONCLUSIONS: The results of the study indicate that materials with similar coating but different sizes exhibited similar rates of liver clearance. It was, therefore, concluded that the coating material significantly influences the rate of iron oxide clearance in rat liver.     

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/T2* and 1/T1, respectively) in blood, muscle, and renal cortex was investigated at 1.5 T. Ex vivo measurements of 1/T2* 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/T2* increased linearly with contrast agent concentration with slopes of 101 +/-22 s(-1)mM(-1) and 6.5 +/-0.9 s(-1)mM(-1) (mean +/- SD), respectively. In blood, 1/T2* 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(-1)mM(-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.     

MR contrast agents in acute experimental cerebral ischemia: potential adverse impacts on neurologic outcome and infarction size

The purpose of the study was to investigate the effects of magnetic resonance (MR) contrast agents on neurologic outcome and infarction size in a rat stroke model. Focal cerebral ischemia was induced in 80 rats using an endovascular occlusion technique of the middle cerebral artery. Four hours after occlusion, 64 animals (4 groups of 16 each) received gadodiamide (Gd-DTPA-BMA) in a single (0.1 mmol/kg) or triple (0.3 mmol/kg) clinical dose or the ultrasmall superparamagnetic iron oxide particles contrast agent NC 100150 in a single (0.03 mmol/kg, 1.5 mg Fe(2+)/kg) or double (0.06 mmol/kg, 3.0 mg Fe(2+)/kg) clinical dose, respectively. Sixteen animals received equivolumetric saline (control group). Neurologic score and body weight were recorded every 8 hours. Twenty-four hours after vessel occlusion, infarction size was measured by 2,3, 5-triphenyl-tetrazolium-chloride (TTC) staining. Neither the normal nor the triple clinical dose of gadodiamide or NC 100150 in the single or double dose had any statistically significant effects on infarction volume, mortality, body weight, or neurologic outcome (P > 0.05). Our results suggest that bolus injection of gadodiamide and the ultrasmall superparamagnetic iron oxide particles NC 100150 in clinically relevant doses does not significantly affect infarction volume and clinical outcome of acute cerebral ischemia.     

Ferrite particles for bowel contrast in MR imaging: design issues and feasibility studies

Diverse materials with varying physical and magnetic properties have been evaluated as gastrointestinal contrast agents for magnetic resonance (MR) imaging. Uniform marking of the small bowel remains the greatest challenge. Ferrites are magnetically active iron oxide particles that are miscible with water and cause loss of signal on MR images. The decrease in MR signal intensity produced by ferrites occurs with a wide range of iron concentrations (0.1-10 mM) and with both T1- and T2-weighted pulse sequences. These effects of ferrites are explained by predominant T2 shortening with negligible T1 effects. The ferrite preparation used in this study was stable in vitro, with little iron solubilized by acid. Intragastric administration of ferrite (5 mg of iron per kg in 6 ml) routinely marked the small bowel of rats. The authors conclude that ferrites represent a promising new class of contrast agents for gastrointestinal MR imaging.     

Assessment of peritoneal tolerance of a new MR blood pool contrast agent in rabbits.

OBJECTIVE: Fast 3D MR angiography in conjunction with a new blood pool contrast agent (iron oxide crystals) is a recently described method for detection and localization of intra-abdominal bleeding sites with high sensitivity and specificity. However, peritoneal reactions to the contrast agent have not yet been investigated. The purpose of this study was to assess the peritoneal tolerance of the contrast agent in an animal experiment. METHODS: Eleven rabbits were intraperitoneally injected with 5 mL diluted NC100150 Injection; two rabbits were used as the control group. Rabbits injected with NC100150 Injection were imaged in pairs at 12, 24, and 48 hours and 3 weeks, and a single rabbit was imaged at 72 hours and 1 and 2 weeks after the intraperitoneal administration of the agent. Immediately after imaging, the rabbits were killed and an autopsy was performed. Samples of peritoneal surfaces and intra-abdominal organs were harvested for histology. MR imaging, gross pathology, and histology were evaluated. RESULTS: MR imaging and gross pathology demonstrated the presence of intraperitoneal contrast agent up to 24 hours after administration. Histology revealed a considerable amount of iron in the peritoneum, mesenteric fat, and lymph nodes within the first 24 hours. In most cases, iron was rapidly cleared from these sites within 2 days; in one animal, however, iron was detectable up to 1 week. No signs of inflammation or fibrosis were detected. CONCLUSIONS: This study shows no evidence of inflammatory reactions or signs of fibrosis after the intraperitoneal application of NC100150 Injection.     

Macrophage uptake of ultra-small iron oxide particles for magnetic resonance imaging in experimental acute cardiac transplant rejection

Purpose: To discriminate between acutely rejecting and non-rejecting transplanted hearts using a blood pool contrast agent and T2* magnetic resonance imaging (MRI) in a clinical 1.5T scanner.

Material and Methods: Allogeneic and syngeneic heterotopic heart transplantations were performed in rats. One allogeneic and one syngeneic group each received either the ultra-small iron oxide particle (USPIO), at two different doses, or no contrast agent at all. MRI was performed on postoperative day 6. Immediately after the MR scanning, contrast agent was injected and a further MRI was done 24 h later. Change in T2* was calculated.

Results: No significant difference in change in T2* could be seen between rejecting and non-rejecting grafts in either of the doses, or in the control groups. There was a difference between the allogeneic group that received the higher contrast agent dose and the allogeneic group that did not receive any contrast agent at all.

Conclusion: In our rat model, measurements of T2* after myocardial macrophage uptake of AMI-227 in a clinical 1.5T scanner were not useful for the diagnosis of acute rejection.     

Iron oxide-enhanced MR lymphography: initial experience

The detection of nodal metastases is of utmost importance in oncologic imaging. Ultrasmall superparamagnetic iron oxide particles (USPIO) are novel contrast agents specifically developed for MR lymphography. After intravenous administration, they are taken up by the macrophages of the lymph nodes, where they accumulate. They reduce the signal intensity (SI) of normally functioning nodes on postcontrast T2-and T2*-weighted images through the magnetic susceptibility effects on iron oxide. Metastatic nodes, in which macrophages are replaced by tumor cells, show no significant change in SI on postcontrast T2-and T2*-weighted images. Early clinical experience suggests that USPIO-enhanced MR lymphography improves the sensitivity and specificity for the detection of nodal metastases. It also suggests that micrometastases could be detected in normal-sized nodes. This article reviews the physiochemical properties of USPIO contrast agents, their enhancement patterns, and early clinical experience.     

Distribution of iron oxide nanoparticles in rat lymph nodes studied using electron energy loss spectroscopy (EELS) and electron spectroscopic imaging (ESI)

Superparamagnetic iron nanoparticles have been developed as contrast agents for magnetic resonance lymphography. The kinetics of uptake of these particles has not yet been accurately determined. We have therefore monitored the distribution of individual iron particles (ferumoxtran, AMI-227, Sinerem) in rat lymph nodes 1.5, 3, 6, 12, and 24 hours after i.v. injection (two rats per time point). The ultrastructural distribution of the iron was determined by energy-filtered transmission electron microscopy (EFTEM). This method allows the identification of elements using element-specific energy-loss electrons. Iron was identified by the Fe-L(2,3) edge (EELS), and iron maps were obtained using iron-specific electrons for imaging (ESI). The background was calculated by simplex optimization (EELS) and by the two-window method (ESI). Ferumoxtran particles were regularly observed at the periphery of the lymph nodes but not in their centers. Isolated iron particles were seen extracellularly within lymph vessels and, 3 hours after injection, as small dots in phagocytic cells. Numerous dense clusters appeared within the cells at later times (6 and 12 hours after injection). These results suggest that the contrast agent moves rapidly across the capillary wall to the lymph and is then taken up by phagocytic cells. J. Magn. Reson. Imaging 2000;12:505-509.     

First-pass myocardial perfusion imaging and equilibrium signal changes using the intravascular contrast agent NC100150 injection.

In this phase I clinical study, the new ultrasmall superparamagnetic iron oxide contrast agent, NC100150 Injection (Nycomed AS, Oslo, Norway, a part of Nycomed Amersham), was assessed for first-pass magnetic resonance myocardial perfusion studies and its ability to produce equilibrium signal changes, as a possible indicator of myocardial blood volume. Data were acquired in 18 healthy male volunteers at 0.5 T and 1.5 T. At both field strengths, first-pass studies using T1-weighted sequences were acquired. Long TE spin-echo echoplanar imaging (EPI) was used at 0.5 T and short TE fast low-angle shot (FLASH) imaging at 1.5 T. With both sequences, T1 effects dominated the images for low doses, and time intensity curves potentially suitable for perfusion analysis were generated. At higher doses, T2 and T2* effects were observed. At 1.5 T, these predominantly affected the blood pool signal; however, at 0.5 T the myocardial signal was also involved, reflecting the relative T2 and T2* sensitivity of the spin-echo EPI sequence as a result of the long TE and long readout window, respectively. Equilibrium changes were assessed at both field strengths using T1-weighted FLASH sequences and in addition at 1.5 T using T2*-weighted gradient-echo EPI. With the T1-weighted images at both field strengths, signal changes were observed in all subjects; however, no dose-response relationship could be shown. With the T2*-weighted EPI there was significantly lower signal (P < 0.05) with the 3 and 4 mg/kg doses than with the 2 mg/kg dose. In conclusion, NC100150 Injection is useful for first-pass myocardial perfusion using T1-weighted sequences; however, low doses in combination with short TE sequences are required to minimize sensitivity to T2* effects. Equilibrium signal changes can also be induced in the myocardium. More work is required to optimize the imaging sequences and dose of NC100150 Injection for first-pass studies and also to determine whether the equilibrium signal changes can be used to measure myocardial blood volume changes in ischemic heart disease.     

Liver-specific MR contrast agents: current status and prospects]

Liver-specific MR contrast agents include superparamagnetic iron oxide (SPIO) particles and hepatobiliary paramagnetic agents. SPIO particles are phagocytosed by reticuloendothelial cells in the liver, resulting in negative enhancement of the liver parenchyma on T2- or T2*-weighted images. Ferumoxides and related iron oxide formulations have been tested clinically throughout the world, and have been demonstrated to improve the detection and characterization of hepatic neoplasms. Hepatobiliary paramagnetic agents are partially taken up by hepatocytes, yielding positive, sustained enhancement of the liver parenchyma on T1-weighted images. These agents are referred to as "value-added" versions of extracellular gadolinium compounds because they increase tumor-liver contrast in both the perfusion phase and hepatobiliary phase. Although only ferumoxides are currently available for clinical use, many agents are in the pipeline. The possibility of "one-stop shopping" diagnosis by liver-specific MR contrast agents is an attractive alternative to the existing multistep diagnosis in liver imaging. Further studies to analyze the cost-benefit ratio will follow, to determine whether liver-specific MR contrast agents lead to change in patient treatment and whether such a decision would be reliable.     

Characterization of ultrasmall magnetite [correction of paramagnetic magnetite] particles as superparamagnetic contrast agents in MRI

RATIONALE AND OBJECTIVES: Very small dextran-coated magnetite particles were developed. These particles can be used either as immunospecific contrast agents for MRI by coupling to antibodies or as an interstitial contrast agent. METHODS: The particles were synthesized from iron chloride/dextran solutions. Size was evaluated by electron microscopy and photon correlation spectroscopy. The iron concentration was determined by x-ray spectroscopy. T1 and T2 values as well as relaxivities RI and R2 were evaluated with a clinical MR scanner at 1.5 T. Biocompatibility assays were performed with the cell line U937 in methylcellulose cultures. RESULTS: Superparamagnetic, dextran-coated magnetite particles with a hydrodynamic diameter of 10 nm were developed. The iron core size was 7 nm; R1,7 L/mmol x s; and R2, 19 L/mmol x s. These particles are smaller than those currently available commercially and therefore show a smaller R1 to R2 ratio. Biocompatibility tests have shown no toxic side effects so far. CONCLUSIONS: Ultrasmall magnetite particles with a dextran coating were developed; the physical properties of these particles evaluated in vitro are described in this study.