Superparamegnetic iron oxides for MRI

Pharmaceutical iron oxide preparations have been used as MRI contrast agents for a variety of purposes. These agents predominantly decrease T2 relaxation times and therefore cause a decrease in signal intensity of tissues that contain the agent. After intravenous adminstration, dextran-coated iron oxides typically accumulate in phagocytic cells in liver and spleen. Clinical trials have shown that iron oxide increases lesion/liver and lesion/spleen contrast, that more lesions can be depicted than on plain MRI or CT, and that the size threshold for lesion detection decreases. Decreased uptake of iron oxides in liver has been observed in hepatitis and cirrhosis, potentially allowing the assessment of organ function. More recently a variety of novel, target-specific monocrydtalline iron oxides compounds have been used for receptor and immunospecific images. Future development of targeted MRI contrast agents is critical for organ- or tissue-specific quantitative and functional MRI. Correspondence to: R. Weissleder     

Labeling efficacy of superparamagnetic iron oxide nanoparticles to human neural stem cells: comparison of ferumoxides, monocrystalline iron oxide, cross-linked iron oxide (CLIO)-NH2 and tat-CLIO.

OBJECTIVE: We wanted to compare the human neural stem cell (hNSC) labeling efficacy of different superparamagnetic iron oxide nanoparticles (SPIONs), namely, ferumoxides, monocrystalline iron oxide (MION), cross-linked iron oxide (CLIO)-NH(2) and tat-CLIO. MATERIALS AND METHODS: The hNSCs (5 x 10(5) HB1F3 cells/ml) were incubated for 24 hr in cell culture media that contained 25 microg/ml of ferumoxides, MION or CLIO-NH(2), and with or without poly-L-lysine (PLL) and tat-CLIO. The cellular iron uptake was analyzed qualitatively with using a light microscope and this was quantified via atomic absorption spectrophotometry. The visibility of the labeled cells was assessed with MR imaging. RESULTS: The incorporation of SPIONs into the hNSCs did not affect the cellular proliferations and viabilities. The hNSCs labeled with tat-CLIO showed the longest retention, up to 72 hr, and they contained 2.15+/-0.3 pg iron/cell, which are 59 fold, 430 fold and six fold more incorporated iron than that of the hNSCs labeled with ferumoxides, MION or CLIO-NH(2), respectively. However, when PLL was added, the incorporation of ferumoxides, MION or CLIO-NH(2) into the hNSCs was comparable to that of tat-CLIO. CONCLUSION: For MR imaging, hNSCs can be efficiently labeled with tat-CLIO alone or with a combination of ferumoxides, MION, CLIO-NH(2) and the transfection agent PLL.     

Evaluation of an ultrasmall superparamagnetic iron oxide in MRI in a bone tumor model in rabbits

Ultrasmall superparamagnetic iron oxides (USPIOs) are a class of MRI contrast agents having moderately selective affinity for the reticuloendothelial cells of lymph nodes and bone marrow. This study evaluated a USPIO preparation, Combidex (Code 7227), in MRI of a rabbit bone tumor model. VX2 carcinoma implanted into the tibial marrow of nine subject rabbits was studied. After tumor growth, the subjects underwent MRI of their lesions both before and after intravenous administration of Code 7227. Code 7227 was judged subjectively to conspicuously reduce the signal intensity of normal marrow on some pulse sequences. A hypointense zone outlined the tumor margins on postcontrast imaging, which allowed improved visualization of the soft tissue component of the larger lesions. Accumulation of the contrast agent in a zone of inflammation outside the tumor margin was demonstrated on histologic sections of the lesions. Code 7227 deserves additional study as a potential contrast agent for MRI of bone tumors.     

Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging

Superparamagnetic iron oxide MR imaging contrast agents have been the subjects of extensive research over the past decade. The iron oxide particle size of these contrast agents varies widely, and influences their physicochemical and pharmacokinetic properties, and thus clinical application. Superparamagnetic agents enhance both T1 and T2/T2* relaxation. In most situations it is their significant capacity to reduce the T2/T2* relaxation time to be utilized. The T1 relaxivity can be improved (and the T2/T2* effect can be reduced) using small particles and T1-weighted imaging sequences. Large iron oxide particles are used for bowel contrast [AMI-121 (i.e. Lumirem and Gastromark) and OMP (i.e. Abdoscan), mean diameter no less than 300 nm] and liver/spleen imaging [AMI-25 (i.e. Endorem and Feridex IV, diameter 80-150 nm); SHU 555A (i.e. Resovist, mean diameter 60 nm)]. Smaller iron oxide particles are selected for lymph node imaging [AMI-227 (i.e. Sinerem and Combidex, diameter 20-40 nm)], bone marrow imaging (AMI-227), perfusion imaging [NC100150 (i.e. Clariscan, mean diameter 20 nm)] and MR angiography (NC100150). Even smaller monocrystalline iron oxide nanoparticles are under research for receptor-directed MR imaging and magnetically labeled cell probe MR imaging. Iron oxide particles for bowel contrast are coated with insoluble material, and all iron oxide particles for intravenous injection are biodegradable. Superparamagnetic agents open up an important field for research in MR imaging.     

超小超顺磁性氧化铁微粒对神经干细胞生物学活性的影响

目的应用超小超顺磁性氧化铁微粒Sinerem标记大鼠骨髓源性神经干细胞（NSCs），探讨Sinerem的安全性及合适的标记浓度。方法分离、培养大鼠骨髓源性NSCs。制备Sinerem多聚赖氨酸复合物，以不同浓度Sinerem对细胞进行标记。普鲁士蓝染色和电镜观察细胞内铁，CCK-8法检测细胞生长增殖情况，AnnexinV—PI法检测细胞凋亡及死亡情况。结果普鲁士蓝染色显示细胞质内大量铁颗粒存在，标记率在99％以上。电镜观察见Sinerem标记干细胞内含纳米铁颗粒。CCK-8法检测结果表明，25～1500μg/ml不同浓度范围的Sinerem对细胞增殖的影响差异无统计学意义。AnnexinV—PI检测结果显示，Sinerem在25～200μg/ml范围内的不同浓度对细胞凋亡和死亡的影响差异无统计学意义。结论超小超顺磁性氧化铁微粒Sinerem可以有效标记大鼠骨髓源性NSCs，可以应用25～200μg／ml浓度范围的Sinerem标记细胞。     

Radiation dose rate affects the radiosensitization of MCF-7 and HeLa cell lines to X-rays induced by dextran-coated iron oxide nanoparticles

Background and purpose: The aim of radiotherapy is to deliver lethal damage to cancerous tissue while preserving adjacent normal tissues. Radiation absorbed dose of the tumoral cells can increase when high atomic nanoparticles are present in them during irradiation. Also, the dose rate is an important aspect in radiation effects that determines the biological results of a given dose. This in vitro study investigated the dose-rate effect on the induced radiosensitivity by dextran-coated iron oxide in cancer cells.

Materials and methods: HeLa and MCF-7 cells were cultured in vitro and incubated with different concentrations of dextran-coated iron oxide nanoparticles. They were then irradiated with 6?MV photons at dose rates of 43, 185 and 370 cGy/min. The MTT test was used to obtain the cells’ survival after 48?h of irradiations.

Results: Incubating the cells with the nanoparticles at concentrations of 10, 40 and 80?μg/ml showed no significant cytotoxicity effect. Dextran-coated iron oxide nanoparticles showed more radiosensitivity effect by increasing the dose rate and nanoparticles concentration. Radiosensitization enhancement factors of MCF-7 and HeLa cells at a dose-rate of 370 cGy/min and nanoparticles’ concentration of 80?μg/ml were 1.21?±?0.06 and 1.19?±?0.04, respectively.

Conclusion: Increasing the dose rate of 6?MV photons irradiation in MCF-7 and HeLa cells increases the radiosensitization induced by the dextran-coated iron nanoparticles in these cells.     

Ultrasmall superparamagnetic iron oxide particles (AMI 227) as a blood pool contrast agent for MR angiography: Experimental study in rabbits

The purpose of this study was to evaluate the contribution of an ultrasmall superparamagnetic iron oxide particles (USPIOs) based contrast agent (AMI 227), in a transverse three-dimensional time-of-flight TONE MR angiography sequence of abdominal aorta in rabbits. The main goal was to assess improvement in the visualization of small arteries such as renal arteries, when using such a sequence. Imaging experiments were performed on a 1.5 T magnet, using a transverse 3D time-of-flight (TOF) tilted optimized nonsaturating excitation (TONE) sequence with magnetization transfer suppression. The contrast media used were composed of a USPIO core surrounded by a dextransurfactant (AMI 227). Different concentrations of AMI 227 were evaluated in 12 rabbits. Concentrations varied within the range 8.5–34 μmol Fe/kg-bw: 8.5 μmol Fe/kg (three rabbits); 17 μmol Fe/kg (three rabbits); 25.5 μmol Fe/kg (three rabbits); 34 μmol Fe/kg (three rabbits). A visual analysis based on the improvement of visualization of small arteries (renal arteries) on MIP images and a quantitative analysis based on the percentage of contrast enhancement of the aorta plotted against distance in the slab from the top edge of the acquisition volume were obtained. A signal-to-noise ratio enhancement of the distal part of the aorta and only improvement in the delineation of the renal arteries were noted when using low concentrations of the contrast media. A loss of signal-to-noise ratio of the aorta and a decrease in arterial visualization were respectively noted with higher concentration of contrast media. In this experimental study, using a transverse three-dimensional TOF TONE MR angiography sequence of renal arteries, in which sequence the saturation effect is minimized, the use of AMI 227 allows only improvement in the delineation.     

Evaluation of tumoral enhancement by superparamagnetic iron oxide particles: comparative studies with ferumoxtran and anionic iron oxide nanoparticles

This study was designed to compare tumor enhancement by superparamagnetic iron oxide particles, using anionic iron oxide nanoparticles (AP) and ferumoxtran. In vitro, relaxometry and media with increasing complexity were used to assess the changes in r2 relaxivity due to cellular internalization. In vivo, 26 mice with subcutaneously implanted tumors were imaged for 24 h after injection of particles to describe kinetics of enhancement using T1 spin echo, T2 spin echo, and T2 fast spin echo sequences. In vitro, the r2 relaxivity decreased over time (0–4 h) when AP were uptaken by cells. The loss of r2 relaxivity was less pronounced with long (Hahn Echo) than short (Carr–Purcell–Meiboom–Gill) echo time sequences. In vivo, our results with ferumoxtran showed an early T2 peak (1 h), suggesting intravascular particles and a second peak in T1 (12 h), suggesting intrainterstitial accumulation of particles. With AP, the late peak (24 h) suggested an intracellular accumulation of particles. In vitro, anionic iron oxide nanoparticles are suitable for cellular labeling due to a high cellular uptake. Conversely, in vivo, ferumoxtran is suitable for passive targeting of tumors due to a favorable biodistribution.     

磁性纳米氧化铁粒子在肿瘤影像及治疗中的应用及进展

磁性纳米氧化铁粒子是指直径在纳米范围的氧化铁粒子,具有化学性质稳定、血液滞留时间长、低毒性、顺磁性、生物可降解性等特点,可通过静电作用或化学作用耦联多肽、单克隆抗体、化疗药物、基因片段等靶肿瘤功能分子,因而在肿瘤影像、治疗、研究中有着广泛的应用.该文对近年来磁性纳米氧化铁粒子在肿瘤影像及治疗中的应用及进展进行了评述.     

MRI detection of macrophages labeled using micrometer-sized iron oxide particles

PURPOSE: To evaluate cellular labeling of immune cells using micron-sized iron oxide particles (MPIOs) and evaluate the MR relaxivity and MRI detection of the labeled cells. MATERIALS AND METHODS: Immune cells isolated from mice and rats were labeled with three different sizes of MPIO particles (0.35, 0.90, or 1.63 microm). These labeled cells were characterized using transmission electron microscopy (TEM), fluorescence microscopy, flow cytometry, MR relaxometry, and MRI. RESULTS: Macrophage uptake of MPIOs was found to be highest for the 1.63-microm size particles. MR relaxivity measurements indicated greater spin-spin relaxation for MPIO-labeled cells relative to cells labeled with nanometer-sized ultra-small superparamagnetic iron oxide (USPIO) particles with similar iron content. TEM and fluorescence microscopy indicated cellular uptake of multiple MPIO particles per cell. Macrophages labeled with 1.63-microm MPIOs had an average cellular iron uptake of 39.1 pg/cell, corresponding to approximately 35 particles per cell. CONCLUSION: Cells labeled with one or more MPIO particles could be readily detected ex vivo at 11.7 Tesla and after infusion of the MPIO-labeled macrophages into the kidney of a rat, hypointense regions of the outer cortex are observed, in vivo, by MRI at 4.7 Tesla.     

Influence of iron oxide nanoparticles (Fe3O4) on erythrocyte photohemolysis via photofrin and Rose Bengal sensitization

BackgroundIron oxide (Fe₃O₄) nanoparticles (IO-NP) were recently employed in medical applications as a diagnostic tool and drug carrier. Photofrin (PF) is a photosensitizer that clinically is used in Photodynamic therapy (PDT).Study designThe photosensitivity of PF and Rose Bengal (RB) mixed with (IO-NP) on red blood cells (RBCs) lysis was investigated. Second, Photohemolysis for post-irradiation (delayed) and during irradiation (continuous) with PF, RB and IO-NP combinations at different concentrations was investigated. Third, the photohemolysis rate, relative lysis steepness and power-concentration dependant parameter were evaluated by modeling and fitting the data using Gompertz function and power law.MethodsRBCs were isolated from healthy male human volunteer. Washed cells (7.86 × 10⁶ cells/mm³) were incubated with PF only or with IO-NP for 45 min at 37 °C then irradiated to a range of temperatures (4–41 °C). CPH results were recorded and evaluated using Gompertz function.ResultsThe relative steepness of the photohemolysis curves was approximately independent on light dose for delayed irradiation. The presence of IO-NP increases the rupturing time for 50% of the RBCs. Photohemolysis rate for delayed irradiation using the power law, led to 1.7 and 2.3 power dependence, respectively, for PF only and PF mixed with IO-NP. The power dependence of continuous irradiation measurements showed inverse proportionality for different concentrations of IO-NP combined with 2 μg/ml PF concentration and 1.5 μg/ml for RB concentration.ConclusionPhotosensitization of RBC with PF or RB mixed with IO-NP inhibited rupturing erythrocyte membrane and therefore a consideration should be taken against their combination in clinical applications.     

Study of competitive binding of gallium and iron by tumor cells

The influence of iron and gallium carriers on the in vitro and in vivo uptake of 67Ga and 59Fe by tumor cells has been studied. The results appear to indicate that ferritin might be involved in most of the systemic accumulation of 67Ga but that the mechanism of tumor uptake might be different.     

Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents

PURPOSE: To label mammalian and stem cells by combining commercially available transfection agents (TAs) with superparamagnetic iron oxide (SPIO) magnetic resonance (MR) imaging contrast agents. MATERIALS AND METHODS: Three TAs were incubated with ferumoxides and MION-46L in cell culture medium at various concentrations. Human mesenchymal stem cells, mouse lymphocytes, rat oligodendrocyte progenitor CG-4 cells, and human cervical carcinoma cells were incubated 2-48 hours with 25 microg of iron per milliliter of combined TAs and SPIO. Cellular labeling was evaluated with T2 relaxometry, MR imaging of labeled cell suspensions, and Prussian blue staining for iron assessment. Proliferation and viability of mesenchymal stem cells and human cervical carcinoma cells labeled with a combination of TAs and ferumoxides were evaluated. RESULTS: When ferumoxides-TA or MION-46L-TA was used, intracytoplasmic particles stained with Prussian blue stain were detected for all cell lines with a labeling efficiency of nearly 100%. Limited or no uptake was observed for cells incubated with ferumoxides or MION-46L alone. For TA-SPIO-labeled cells, MR images and relaxometry findings showed a 50%-90% decrease in signal intensity and a more than 40-fold increase in T2s. Cell viability varied from 103.7% +/- 9 to 123.0% +/- 9 compared with control cell viability at 9 days, and cell proliferation was not affected by endosomal incorporation of SPIO nanoparticles. Iron concentrations varied with ferumoxides-TA combinations and cells with a maximum of 30.1 pg +/- 3.7 of iron per cell for labeled mesenchymal stem cells. CONCLUSION: Magnetic labeling of mammalian cells with use of ferumoxides and TAs is possible and may enable cellular MR imaging and tracking in experimental and clinical settings.     

High resolution MRI of MCF7 human breast tumors: Complemented use of iron oxide microspheres and Gd-DTPA

The differential capacity of iron oxide microspheres and of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) to serve as contrast agents that can map the microcirculation of MCF7 human breast cancer implanted in nude mice has been examined by high resolution MRI. Modulation of signal intensity in T2*-weighted, gradient-echo images after iron oxide administration and the temporal signal enhancement after Gd-DTPA administration were monitored and analyzed at a spatial resolution of 98 × 98 × 500 μm and 195 × 390 × 1,000 μm, respectively. The pathophysiologic features revealed in the contrast-enhanced images were analyzed in reference to those obtained from the corresponding high resolution T2-weighted, spin-echo images and from histologic sections stained with hematoxylin and eosin and with an endothelial cell marker. The results showed that iron oxide microspheres can aid in the characterization of gross histopathologic features and in the assessment of the distribution of the microvasculature, whereas Gd-DTPA estimates the permeability of the microvessels to this agent and determines the cellularity (cell volume fraction) in the vicinity of the vessels.     

神经退行性疾病脑铁负荷的MRI测量研究

铁是人体内含量最多的金属元素,在正常功能的神经元中起关键作用。铁缺乏与铁过载均可导致神经退行性疾病。神经退行性疾病中的不宁腿综合征可发现脑铁含量的减低,而阿尔茨海默病、帕金森病、亨廷顿病、多发性硬化、肌萎缩脊髓侧索硬化症等疾病发病过程都伴有铁过载。了解神经退行性疾病脑铁含量的变化对于早期疾病的诊断及临床治疗具有重要的指导意义。综述不同神经退行性疾病的脑铁含量的空间变化特点。     

Uptake of FDG (2-fluoro-2-deoxy-D-glucose) as a tumor imaging agent into erythrocytes and accumulation of FDG in tumor cells

Fluorine-18-2-fluoro-2-deoxy-D-glucose (18F-FDG) injectable was developed as a tumor imaging agent reflecting glucose metabolism. In membrane transportation studies, the uptake of 14C-FDG into erythrocytes decreased with an increase in glucose concentration, and Cytochalasin B, inhibitor of glucose transporter (GLUT), blocked the uptake about 75%. The results means FDG is transported into tumor cells mainly by GLUT as glucose analogues. 18F-FDG is recognized to be phosphorylated to 18F-FDG-6-phosphate with hexokinase. We found that FDG-6-phosphate was further isomerized to 18F-FDM-6-phosphate by phosphoglucose isomerase (PGI) in vitro. About 27% 18F-FDM-6-phosphate was generated at the reaction with 70 U PGI for 90 min. These results show that the 18F-FDG injectable manufactured by the commercial supply system has equivalent properties; membrane transportation characteristic and enzyme affinity, to FDG synthesized at each PET institution.     

MRI assessment of changes in liver iron deposition post-venesection

Objective

The aim of this study was to determine if changes in hepatic iron content in patients with hemochromatosis pre- and post-venesection could be detected by changes in liver signal intensity with MRI.

Materials and methods

The study was performed with institutional ethics approval and with informed consent. Gradient echo images were performed on 20 patients with hemochromatosis pre- and post-venesection and 10 control subjects: gradient echo T1-weighted in- and out-phases (4.54 (in)/2.27 (out), 167 [TE/TR], Flip 70°) and gradient echo T2* (5/18 [TE/TR], Flip 10°). The liver to muscle signal ratio was compared pre- and post-venesection.

Results

All MRI sequences showed significant correlation between the liver to muscle signal intensity ratio and the serum ferritin pre-venesection [r = −0.70, −0.65, −0.74, −0.72, in/out/T2*r/T2*, respectively]. There was a significant increase on all sequences in the liver to muscle signal intensity ratio post-venesection (p < 0.001). The control group and patients post-venesection had almost identical liver to muscle signal intensity ratios.

Conclusion

The reduction in liver signal intensity caused by iron excess in hemochromatosis returns to normal post-venesection. Measurement of liver to muscle signal intensity ratios may be a useful tool in assessing treatment response in iron overload states.