Diffusion-weighted imaging versus superparamagnetic iron oxide (SPIO)-enhanced MRI: exclusive and combined values in the assessment of hepatic metastases

Purpose

The purpose was to validate diffusion-weighted imaging (DWI) in the assessment of hepatic metastases compared with superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging.

Materials and Methods

For 21 consecutive patients with 160 metastases from extrahepatic malignancy and 25 benign focal lesions, two radiologists evaluated four separate review sessions (I, SPIO-enhanced T2?-weighted images; II, precontrast DWI; III, SPIO-enhanced T2?-weighted images and precontrast DWI; IV, SPIO-enhanced T2?-weighted images plus precontrast and SPIO-enhanced DWI) and assigned confidence levels using a five-grade scale for each hepatic lesion.

Results

The A_z values after receiver operating characteristic curve analysis for Reader 1 and Reader 2 were 0.80 and 0.75 on session I, 0.91 and 0.91 on session II, 0.97 and 0.96 on session III and 0.96 and 0.96 on session IV, respectively. The A_z value of session II was significantly higher than that of session I (Reader 1, P=.004; Reader 2, P<.001), and that of session III was significantly higher than that of session I (P<.001 for each reader) or session II (Reader 1, P=.004; Reader 2, P=.003). Although there was no significant difference of A_z value between session III and session IV (Reader 1, P=.231; Reader 2, P=.878), the sensitivity improved for session IV compared with that for session III (Reader 1, P=.031; Reader 2, P=.039).

Conclusion

In the assessment of hepatic metastases, DWI can provide more accurate information than can SPIO-enhanced images. Diagnostic accuracy can be increased even more through the combination of both techniques.     

Synthesis and characterization of superparamagnetic iron oxide nanoparticles for biomedical applications

Monodisperse iron oxide nanoparticles (NPs) of 4 nm were obtained through high-temperature solution phase reaction of iron (III) acetylacetonate with 1, 2-hexadecanediol in the presence of oleic acid and oleylamine. The as-synthesized iron oxide nanoparticles have been characterized by X-ray diffraction, transmission electron microscopy, Mössbauer spectroscopy and magnetic measurements. The species obtained were Fe₃O₄ and/or $\upgamma$ -Fe₂O₃. These NPs are superparamagnetic at room temperature and even though the reduced particle size they show a high saturation magnetization (MS ≈ 90 emu/g).     

Magnetic resonance imaging with superparamagnetic iron oxide particles for the detection of myocardial reperfusion

The effect of superparamagnetic iron oxide particles on magnetic resonance myocardial signal intensity was examined in order to define the ability of this agent to identify normal, ischemic, and reperfused myocardium. Data were obtained from 6 normal rats (group 1) and from 6 heterotopic isogenic rat heart transplants (group 2) at 4.7 T with a multislice spin-echo sequence. Images were acquired in (a) normal rats before and after the infusion of 36 μmol Fe/kg of AMI-25 (group 1) and (b) rat heart transplants during control, global myocardial ischemia (before and after the injection of 72 μmol Fe/kg of AMI-25), and following reperfusion (group 2). Myocardial signal intensity decreased by 36 ± 4%, p < 0.001, following contrast infusion in normal hearts (group 1). The intensity remained constant in the rat heart transplants (group 2) during coronary occlusion, both before and after the infusion of AMI-25 and decreased by 61 ± 7%, p < 0.001, upon reperfusion. The larger effect of AMI-25 in reperfused as compared to normal myocardium suggests the presence of ischemia-induced hyperemia. There was no significant difference (analysis of variance) among intensities from different myocardial regions in either group at any stage of the experiment. We conclude that the use of AMI-25 permits identification of normal, ischemic, and reperfused myocardium and may therefore be helpful for the early detection of reperfusion following thrombolytic therapy for acute myocardial infarction.     

Inflammatory imaging with ultrasmall superparamagnetic iron oxide

The purpose of this study was to investigate the usefulness and feasibility of magnetic resonance imaging (MRI) with ultrasmall superparamagnetic iron oxide (USPIO) (USPIO-enhanced MRI) for imaging inflammatory tissues. First, we investigated the relationship between the apparent transverse relaxation rate (R2*) and the concentration of USPIO by phantom studies and measured the apparent transverse relaxivity (r2*) of USPIO. Second, we performed animal experiments using a total of 30 mice. The mice were divided into five groups [A (n=6), B (n=6), C (n=6), sham control (n=6), and control (n=6)]. The mice in Groups A, B, C and control were subcutaneously injected with 0.1 ml of turpentine oil on Day 0, while those in the sham control group were subcutaneously injected with 0.1 ml of saline. The mice in Groups A, B, C and sham control were intraperitoneally injected with 200 μmol Fe per kilogram body weight of USPIO (28 nm in diameter) immediately after the first MRI study on Days 3, 5, 7 and 7, respectively, and those in the control group were not injected with USPIO. The second and third MRI studies were performed at 24 and 48 h after USPIO administration, respectively. The maps of R2* were generated from the apparent transverse relaxation time (T2*)-weighted images with six different echo times. The phantom studies showed that there was a linear relationship between R2* and the concentration of USPIO (r=0.99) and the r2* value of USPIO was 105.7 mM⁻¹ s⁻¹. There was a significant increase of R2* in inflammatory tissues in Group C at 24 h after USPIO administration compared with the precontrast R2* value. Our results suggest that USPIO-enhanced MRI combined with R2* measurement is useful for detecting inflammatory tissues.     

Investigation of atherosclerotic plaques with MRI at 3 T using ultrasmall superparamagnetic particles of iron oxide

This study aims to investigate the uptake of the experimental ultrasmall superparamagnetic particles of iron oxide (USPIO) contrast agent DDM43/34 (Schering AG, Berlin, Germany) by aortic atherosclerotic plaques using magnetic resonance imaging (MRI) at 3 T. Six Watanabe heritable hyperlipidemic rabbits were injected with USPIO at doses of 0.1–1.0 mmol/kg Fe. Parasagittal magnetic resonance angiography (MRA) scans were acquired using 3D gradient-echo sequences before and after USPIO administration, then again after 6 h, 1 day, 2 days and 5 days. At later time points, when the USPIO concentration was too low to enhance blood signal, additional MRA scans were acquired during the infusion of gadopentate dimeglumine (Magnevist; Schering AG). In the images, widespread susceptibility artifacts demonstrated readily detectable USPIO uptake in the liver, bone marrow and lymphatic vessels. Surprisingly, however, no such effects could be associated specifically with the aortic vessel wall, in contrast to previous studies that showed strong uptake with similar pulse sequences. Histological analysis was performed on aortic slices from two animals, demonstrating that aortic plaques were active but showed very little USPIO uptake, consistent with MRI findings. We conclude that, despite the exciting potential of plaque detection using USPIO, some caution is advised since the absence of susceptibility effects does not necessarily imply the absence of plaque, even at 3 T, which offers increased sensitivity to susceptibility. Future work will investigate the dependence of such results on stage of plaque development, magnetic field strength and choice of contrast agent.     

Nitric acid-stabilized superparamagnetic iron oxide nanoparticles studied with X-rays

Using density functional theory, we systematically investigate the adsorption geometries and electrical properties of (3,3) carbon nanotube (CNT) integrated on hydrogen-terminated Si(001):1?×?1 surface. Prior to adsorption of the CNT, the surface is patterned in two different ways by desorbing selective hydrogen atoms from the surface. The (3,3) CNT which is metallic in nature becomes semiconducting with a band gap around the fermi level when it is supported on patterned hydrogen-terminated Si(001):1?×?1 surface. However, the band gap is reduced when a transverse electric field is applied, allowing the (3,3) CNT on the patterned hydrogen-terminated Si(001):1?×?1 to become metallic at a critical field strength. The tuning of electrical properties of the (3,3) CNT integrated with Si surface may have potential technological applications.     

MRI of blood volume with superparamagnetic iron in choroidal melanoma treated with thermotherapy

Functional magnetic resonance imaging (MRI) with a new intravascular contrast agent, monocrystalline iron oxide nanoparticles (MION), was applied to assess the effect of transpupillary thermotherapy in a rabbit model of choroidal melanoma. 3D-spoiled gradient recalled sequences were used for quantitative assessment of blood volume. The MRI-parameters were 5/22/35 degrees (time of repetition (TR)/echo delay (TE)/flip angle (FA)) for T(1)- and 50/61/10 degrees for T(2)-weighted sequences. Images were collected before and at different times after MION injection. In all untreated tissues studied, MION reduced the T(2)-weighted signal intensity within 0.5 h and at 24 h (all p <== 0.012), whereas no significant changes were detected in treated tumors. T(1)-weighted images also revealed differences of MION-related signal changes between treated tumors and other tissues, yet at lower sensitivity and specificity than T(2). The change of T(2)-weighted MRI signal caused by intravascular MION allows early distinction of laser-treated experimental melanomas from untreated tissues. Further study is necessary to determine whether MRI can localize areas of tumor regrowth within tumors treated incompletely.     

Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles

Stable 30–50 nm polymeric polyethylene glycol–phosphatidylethanolamine (PEG–PE)-based micelles entrapping superparamagnetic iron oxide nanoparticles (SPION) have been prepared. At similar concentrations of SPION, the SPION-micelles had significantly better magnetic resonance imaging (MRI) T2 relaxation signal compared to ‘plain’ SPION. Freeze-fracture electron microscopy confirmed SPION entrapment in the lipid core of the PEG–PE micelles. To enhance the targeting capability of these micelles, their surface was modified with the cancer cell-specific anti-nucleosome monoclonal antibody 2C5 (mAb 2C5). Such mAb 2C5-SPION immunomicelles demonstrated specific binding with cancer cells in vitro and were able to bring more SPION to the cancer cells thus demonstrating the potential to be used as targeted MRI contrast agents for tumor imaging.     

Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles

We prepared five folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles (F₅-Liposuperparamagnetic iron oxide nanoparticles(SPIONs), 5.5 and 11 nm) and investigated their cellular uptake with KB cells, which is one of the representative folate-receptor over-expressing human epidermoid carcinoma cells, using MRI. The cellular uptake tests with the respective 5.5 and 11 nm F₅-LipoSPIONs at a fixed particle concentration showed appreciable amount of receptor-mediated uptakes and the specificity was higher in 5.5 nm SPIONs, due to its higher folic acid (FA) density, without inhibition. However, the numbers of the particles taken up under FA inhibition were similar, irrespective of their sizes.     

Temperature dependence of superparamagnetic resonance of iron oxide nanoparticles

Nanoparticles of maghemite (γ-Fe₂O₃) are formed in a sol–gel silicate glass with a molar ratio Fe/Si of 2% by a treatment at 1000°C for 6 h. Electron paramagnetic resonance spectrum at 300 K shows a relatively narrow sharp line at g_eff≈2. As the temperature lowers to 5 K, the apparent resonance field decreases and the linewidth considerably increases. We develop a theoretical formalism based on a distribution of diameters or volumes of the nanoparticles following a lognormal. The nanoparticles are considered as single magnetic domains with random orientations of magnetic moments and thermal fluctuations of anisotropic axes. The individual line shape function is derived from the damped precession equation of Landau–Lifshitz. An appropriate linewidth expression is put forward, which account for the averaging of the fluctuations of orientations of the magnetic moments with respect to the magnetic field and to the magnetic anisotropy axes. A single set of parameters provides good fits to the spectra recorded at the different temperatures. The low-temperature blocking of the nanoparticle magnetic moments has been clearly evidenced in the resonance absorption intensity and the blocking temperature of the assembly of nanoparticles (averaged over the distribution in the nanoparticle volume) has been evaluated as 90 K.     

How size evaluation of lymph node is protocol dependent in MRI when using ultrasmall superparamagnetic iron oxide nanoparticles

In this study, the volume of susceptibility artifact was evaluated in T1 and T2-weighted spin echo (SE) and gradient echo (GRE) images at various parameters using registration and subtraction methods. In order to state an important misinterpretation problem in lymphography, it was demonstrated that a lymph node size may be enlarged approximately 10 times when a T2*-weighted GRE protocol is used. To overcome this problem a technical consideration using multisequence (GRE and SE) paradigm was suggested to ensure both lymph node detection and metastasis identification in lymphatic system. The paradigm was also extended by post-processing manipulation of the SE images using a registration and subtraction approach for detection of lymphatic lesions.     

Synthesis,characterization, and in vitro biological evaluation of highly stable diversely functionalized superparamagnetic iron oxide nanoparticles

In this article, we report the design and synthesis of a series of well-dispersed superparamagnetic iron oxide nanoparticles (SPIONs) using chitosan as a surface modifying agent to develop a potential T ₂ contrast probe for magnetic resonance imaging (MRI). The amine, carboxyl, hydroxyl, and thiol functionalities were introduced on chitosan-coated magnetic probe via simple reactions with small reactive organic molecules to afford a series of biofunctionalized nanoparticles. Physico-chemical characterizations of these functionalized nanoparticles were performed by TEM, XRD, DLS, FTIR, and VSM. The colloidal stability of these functionalized iron oxide nanoparticles was investigated in presence of phosphate buffer saline, high salt concentrations and different cell media for 1 week. MRI analysis of human cervical carcinoma (HeLa) cell lines treated with nanoparticles elucidated that the amine-functionalized nanoparticles exhibited higher amount of signal darkening and lower T ₂ relaxation in comparison to the others. The cellular internalization efficacy of these functionalized SPIONs was also investigated with HeLa cancer cell line by magnetically activated cell sorting (MACS) and fluorescence microscopy and results established selectively higher internalization efficacy of amine-functionalized nanoparticles to cancer cells. These positive attributes demonstrated that these nanoconjugates can be used as a promising platform for further in vitro and in vivo biological evaluations.     

Toxicity of superparamagnetic iron oxide nanoparticles: Research strategies and implications for nanomedicine

Superparamagnetic iron oxide nanoparticles （SPIONs） are one of the most versatile and safe nanoparticles in a wide variety of biomedical applications. In the past decades, considerable efforts have been made to investigate the potential adverse biological effects and safety issues associated with SPIONs, which is essential for the development of next-generation SPIONs and for continued progress in translational research. In this mini review, we summarize recent developments in toxicity studies on SPIONs, focusing on the relationship between the physicochemical properties of SPIONs and their induced toxic biological responses for a better toxicological understanding of SPIONs.     

Hypervascular hepatocellular carcinoma in the cirrhotic liver: diffusion-weighted imaging versus superparamagnetic iron oxide-enhanced MRI

Purpose

The purpose of the study was to validate diffusion-weighted imaging (DWI) in the assessment of hypervascular hepatocellular carcinoma (HCC) compared with superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) in the cirrhotic liver.

Material and Methods

Forty-six consecutive patients with 106 hypervascular focal lesions in the cirrhotic liver who underwent DWI using three b factors and gadopentetate dimeglumine-enhanced dynamic MRI followed by SPIO-enhanced MRI were enrolled. Two independent radiologists evaluated two separated image sets (SPIO set, dynamic MRI and SPIO-enhanced T2*-weighted images; DWI set, DWI and dynamic MRI) and assigned confidence levels for diagnosis of HCC using a five-point scale for each lesion. Area under the receiver operating characteristic curve (A_z) was calculated for each image set.

Results

The A_z value of the DWI set was larger than the SPIO set by both readers (reader 1, 0.936 vs. 0.900, P=.050; reader 2, 0.938 vs. 0.905, P=.110). For the sensitivity (reader 1, 93.1% vs. 86.2%, P=.146; reader 2, 95.4% vs. 88.5%, P=.070) and specificity (reader 1, 89.5% vs. 73.7%, P=.250; reader 2, 79.0% vs. 73.7%, P=1.000) of HCC diagnosis, DWI sets were superior to SPIO sets without statistically significant differences.

Conclusion

For assessment of hypervascular HCC, DWI in combination with dynamic MRI provides comparable or slightly better information compared with the combination of dynamic and SPIO-enhanced MRI.     

A prospective assessment of breath-hold fast spin echo and inversion recovery fast spin echo techniques for detection and characterization of focal hepatic lesions

The purpose of this study was to prospectively assess two breath-hold T(2)-weighted fast spin-echo sequences and two breath-hold inversion recovery fast spin-echo sequences to determine their relative ability to detect and characterize focal hepatic lesions. Fourteen patients with a total of nineteen proven focal hepatic lesions were imaged with two breath-hold T(2)-weighted (T2W) fast spin echo sequences (HASTE TE = 66 and HASTE TE = 120), two breath-hold inversion recovery fast spin echo sequences (IRFSE TE = 64 and IRFSE TE = 95), and a nonbreath-hold T(2)-weighted fast-spin echo sequence (FSE TE = 96-120). Contrast-to-noise ratios (CNRs) were measured for all proven lesions on all sequences. Both IRFSE sequences and the HASTE sequence with TE = 66 showed an improvement in lesion-liver and liver-spleen CNRs compared to the nonbreath-hold T2W sequence. The mean difference in CNR between benign and malignant lesions was largest for the HASTE TE = 120 sequence. These preliminary results suggest that a breath-hold IRFSE sequence (TE = 64 or 95) has an equal ability to detect focal hepatic lesions as a nonbreath-hold T2W FSE sequence (TE = 96-120). The HASTE TE = 120 showed the greatest ability to discriminate between benign and malignant lesions.     

Incorporation and release of drug into/from superparamagnetic iron oxide nanoparticles

The aim of this study was to attach a model drug (naproxen) onto superparamagnetic iron oxide nanoparticles (SPION). First, SPION were coated with thin layer of silica that contained micropores. We demonstrated that such surface functionalization could be optimized by the use of citric acid which prevented SPION agglomeration during the procedure. HRTEM investigation showed a uniform 1-2-nm-thick silica coating around SPION. This coating did not affect significantly the magnetic properties of the SPION. Into the coated SPION we successfully incorporated about 30 wt% of naproxen. The latter was readily released after immersion into a testing solution. The composites could be interesting for potential use in diagnostics.     

Covalent immobilization of invertase on PAMAM-dendrimer modified superparamagnetic iron oxide nanoparticles

In this study, polyamidoamine (PAMAM) dendrimer was synthesized on the surface of superparamagnetite nanoparticles to enhance invertase immobilization. The amount of immobilized enzyme on the surface-hyperbranched magnetite nanoparticle was up to 2.5 times (i.e., 250%) as much as that of magnetite nanoparticle modified with only amino silane. Maximum reaction rate (V _max) and Michaelis–Menten constant (K _m) were determined for the free and immobilized enzymes. Various characteristics of immobilized invertase such as; the temperature activity, thermal stability, operational stability, and storage stability were evaluated and results revealed that stability of the enzyme is improved upon immobilization.     

PEGylation of superparamagnetic iron oxide nanoparticle for drug delivery applications with decreased toxicity: an in vivo study

Journal of Nanoparticle Research - Superparamagnetic iron oxide nanoparticles (SPIONs) are evolving as a mainstay across various applications in the field of Science and Technology. SPIONs have...     

Quantification of superparamagnetic iron oxide using inversion recovery balanced steady-state free precession

Cellular and molecular MRI trafficking studies using superparamagnetic iron oxide (SPIO) have greatly improved non-invasive investigations of disease progression and drug efficacy, but thus far, these studies have largely been restricted to qualitative assessment of hypo- or hyperintense areas near SPIO. In this work, SPIO quantification using inversion recovery balanced steady-state free precession (IR-bSSFP) was demonstrated at 3 T by extracting R₂ values from a monoexponential model (P. Schmitt et al., 2004). A low flip angle was shown to reduce the apparent recovery rate of the IR-bSSFP time course, thus extending the dynamic range of quantification. However, low flip angle acquisitions preclude the use of traditional methods for combining RF phase-cycled images to reduce banding artifacts arising from off-resonance due to B₀ inhomogeneity. To achieve R₂ quantification of SPIO, we present a new algorithm applicable to low flip angle IR-bSSFP acquisitions that is specifically designed to identify on-resonance acquisitions. We demonstrate in this work, using both theoretical and empirical methods, that the smallest estimated R₂ from multiple RF phase-cycled acquisitions correspond well to the on-resonance time course. Using this novel minimum R₂ algorithm, homogeneous R₂ maps and linear R₂ calibration curves were created up to 100 μg(Fe)/mL with 20° flip angles, despite substantial B₀ inhomogeneity. In addition, we have shown this technique to be feasible for pre-clinical research: the minimum R₂ algorithm was resistant to off-resonance in a single slice mouse R₂ map, whereas maximum intensity projection resulted in banding artifacts and overestimated R₂ values. With the application of recent advances in accelerated acquisitions, IR-bSSFP has the potential to quantify SPIO in vivo, thus providing important information for oncology, immunology, and regenerative medicine MRI studies.     

Control of the interparticle spacing in superparamagnetic iron oxide nanoparticle clusters by surface ligand engineering

Polymer-mediated self-assembly of superparamagnetic iron oxide(SPIO) nanoparticles allows modulation of the structure of SPIO nanocrystal cluster and their magnetic properties. In this study, dopamine-functionalized polyesters(DApolyester) were used to directly control the magnetic nanoparticle spacing and its effect on magnetic resonance relaxation properties of these clusters was investigated. Monodisperse SPIO nanocrystals with different surface coating materials(poly(ε-caprolactone), poly(lactic acid)) of different molecular weights containing dopamine(DA) structure(DA-PCL2k,DA-PCL1k, DA-PLA1k)) were prepared via ligand exchange reaction, and these nanocrystals were encapsulated inside amphiphilic polymer micelles to modulate the SPIO nanocrystal interparticle spacing. Small-angle x-ray scattering(SAXS)was applied to quantify the interparticle spacing of SPIO clusters. The results demonstrated that the tailored magnetic nanoparticle clusters featured controllable interparticle spacing providing directly by the different surface coating of SPIO nanocrystals. Systematic modulation of SPIO nanocrystal interparticle spacing can regulate the saturation magnetization(Ms) and T_2 relaxation of the aggregation, and lead to increased magnetic resonance(MR) relaxation properties with decreased interparticle spacing.