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Due to their very small size, nanoparticles can interact with all cells in the central nervous system. One of the most promising nanoparticle subgroups are very small superparamagnetic iron oxide nanoparticles (VSOP) that are citrate coated for electrostatic stabilization. To determine their influence on murine blood-derived monocytes, which easily enter the injured central nervous system, we applied VSOP and carboxydextran-coated superparamagnetic iron oxide nanoparticles (Resovist). We assessed their impact on the viability, cytokine, and chemokine secretion, as well as iron uptake of murine blood-derived monocytes. We found that (1) the monocytes accumulated VSOP and Resovist, (2) this uptake seemed to be nanoparticle- and time-dependent, (3) the decrease of monocytes viability was treatment-related, (4) VSOP and Resovist incubation did not alter cytokine homeostasis, and (5) overall a 6-hour treatment with 0.75 mM VSOP-R1 was probably sufficient to effectively label monocytes for future experiments. Since homeostasis is not altered, it is safe to label blood-derived monocles with VSOP. VSOP labeled monocytes can be used to study injured central nervous system sites further, for example with drug-carrying VSOP.

Objective. The availability of magnetic nanoparticles (MNPs) with medical approval for human intervention is fundamental to the clinical translation of magnetic particle imaging (MPI). In this work, we thoroughly evaluate and compare the magnetic properties of an magnetic resonance imaging (MRI) approved tracer to validate its performance for MPI in future human trials. Approach. We analyze whether the recently approved MRI tracer Resotran is suitable for MPI. In addition, we compare Resotran with the previously approved and extensively studied tracer Resovist, with Ferrotran, which is currently in a clinical phase III study, and with the tailored MPI tracer Perimag. Main results. Initial magnetic particle spectroscopy (MPS) measurements indicate that Resotran exhibits performance characteristics akin to Resovist, but below Perimag. We provide data on four different tracers using dynamic light scattering, transmission electron microscopy, vibrating sample magnetometry measurements, MPS to derive hysteresis, point spread functions, and a serial dilution, as well as system matrix based MPI measurements on a preclinical scanner (Bruker 25/20 FF), including reconstructed images. Significance. Numerous approved MNPs used as tracers in MRI lack the necessary magnetic properties essential for robust signal generation in MPI. The process of obtaining medical approval for dedicated MPI tracers optimized for signal performance is an arduous and costly endeavor, often only justifiable for companies with a well-defined clinical business case. Resotran is an approved tracer that has become available in Europe for MRI. In this work, we study the eligibility of Resotran for MPI in an effort to pave the way for human MPI trials., (Creative Commons Attribution license.)

Angela Ariza de Schellenberger,1 Harald Kratz,1 Tracy D Farr,2,3 Norbert Löwa,4 Ralf Hauptmann,1 Susanne Wagner,1 Matthias Taupitz,1 Jörg Schnorr,1 Eyk A Schellenberger1 1Department of Radiology, 2Department of Experimental Neurology, Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Berlin, Germany; 3School of Life Sciences, University of Nottingham, Medical School, Nottingham, UK; 4Department of Biomagnetic Signals, Physikalisch-Technische Bundesanstalt Berlin, Berlin, Germany Abstract: Sensitive cell detection by magnetic resonance imaging (MRI) is an important tool for the development of cell therapies. However, clinically approved contrast agents that allow single-cell detection are currently not available. Therefore, we compared very small iron oxide nanoparticles (VSOP) and new multicore carboxymethyl dextran-coated iron oxide nanoparticles (multicore particles, MCP) designed by our department for magnetic particle imaging (MPI) with discontinued Resovist® regarding their suitability for detection of single mesenchymal stem cells (MSC) by MRI. We achieved an average intracellular nanoparticle (NP) load of >10 pg Fe per cell without the use of transfection agents. NP loading did not lead to significantly different results in proliferation, colony formation, and multilineage in vitro differentiation assays in comparison to controls. MRI allowed single-cell detection using VSOP, MCP, and Resovist® in conjunction with high-resolution T2*-weighted imaging at 7 T with postprocessing of phase images in agarose cell phantoms and in vivo after delivery of 2,000 NP-labeled MSC into mouse brains via the left carotid artery. With optimized labeling conditions, a detection rate of ~45% was achieved; however, the experiments were limited by nonhomogeneous NP loading of the MSC population. Attempts should be made to achieve better cell separation for homogeneous NP loading and to thus improve NP-uptake-dependent biocompatibility studies and cell detection by MRI and future MPI. Additionally, using a 7 T MR imager equipped with a cryocoil resulted in approximately two times higher detection. In conclusion, we established labeling conditions for new high-relaxivity MCP, VSOP, and Resovist® for improved MRI of MSC with single-cell sensitivity. Keywords: magnetic field microdistortions, single-cell imaging, mesenchymal stem cells, VSOP, MCP, Resovist®

Extensive preoperative assessment of hepatic metastases is required in colon cancer patients. We report a case in whom the preoperative investigation by ultrasound scan and contrast-enhanced computed tomography revealed numerous cystic lesions of the liver, suspicious of von Meyenburg complex. Magnetic resonance and magnetic resonance cholangiographic images demonstrated typical features of von Meyenburg complex. Further Resovist-enhanced magnetic resonance imaging detected two hemangiomas in addition to the multiple cystic lesions. So-called Kupffer cell imaging strongly helped the detection of these hemangiomas, and a combination of various magnetic resonance pulse sequences was of great value for the differential diagnosis of cystic lesions and hemangiomas. In cases in whom conventional imaging studies fail to give a definite diagnosis, such as in the present case, superparamagnetic iron oxide-enhanced magnetic resonance imaging is meaningful for adequate preoperative staging.

Hyperthermia is a promising anti-cancer treatment in which the tissue temperature is increased to 42-45 °C, and which is often used in combination with chemotherapy or radiation therapy. Our aim in the present work was to examine the feasibility of combination therapy for oral cancer with cisplatin and hyperthermia generated with ferucarbotran (Resovist; superparamagnetic iron oxide) in an alternating magnetic field (AMF). First, we established that administration of ferucarbotran at the approved dosage for magnetic resonance imaging provides an iron concentration sufficient to increase the temperature to 42.5 °C upon exposure to AMF. Then, we examined the effect of cisplatin combined with ferucarbotran/AMF-induced hyperthermia on cultured human oral cancer cells (HSC-3 and OSC-19). Cisplatin alone induced apoptosis of cancer cells in a dose-dependent manner, as is well known. However, the combination of cisplatin with ferucarbotran/AMF was significantly more effective than cisplatin alone. This result suggests that it might be possible to reduce the clinically effective dosage of cisplatin by administering it in combination with ferucarbotran/AMF-induced hyperthermia, thereby potentially reducing the incidence of serious cisplatin-related side effects. Further work seems justified to evaluate simultaneous thermo-chemotherapy as a new approach to anticancer therapy. [ABSTRACT FROM AUTHOR]

Background: Molecular imaging using magnetic nanoparticles (MNPs)-magnetic particle imaging (MPI)-has attracted interest for the early diagnosis of cancer and cardiovascular disease. However, because a steep local magnetic field distribution is required to obtain a defined image, sophisticated hardware is required. Therefore, it is desirable to realize excellent image quality even with low-performance hardware. In this study, the spatial resolution of MPI was evaluated using an image reconstruction method based on the correlation information of the magnetization signal in a time domain and by applying MNP samples made from biocompatible ferucarbotran that have adjusted particle diameters. Methods: The magnetization characteristics and particle diameters of four types of MNP samples made from ferucarbotran were evaluated. A numerical analysis based on our proposed method that calculates the image intensity from correlation information between the magnetization signal generated from MNPs and the system function was attempted, and the obtained image quality was compared with that using the prototype in terms of image resolution and image artifacts. Results: MNP samples obtained by adjusting ferucarbotran showed superior properties to conventional ferucarbotran samples, and numerical analysis showed that the same image quality could be obtained using a gradient magnetic field generator with 0.6 times the performance. However, because image blurring was included theoretically by the proposed method, an algorithm will be required to improve performance. Conclusions: MNP samples obtained by adjusting ferucarbotran showed magnetizing properties superior to conventional ferucarbotran samples, and by using such samples, comparable image quality (spatial resolution) could be obtained with a lower gradient magnetic field intensity. [ABSTRACT FROM AUTHOR]

The effectiveness of Resovist-labeled bone marrow stem cells (BMSCs) was evaluated in vivo following their cerebral transplantation in a model of Parkinson's disease (PD) in rats using MRI, and the MRI findings were further compared with the behavior and histopathological manifestations of these rats. Forty PD rats were randomly assigned into five groups according to the cell doses injected into the rat brain site: control group (normal saline injection) and groups injected with 1 × 10, 1.5 × 10, 2 × 10, and 2.5 × 10 BMSCs. Gradient echo T2-weighted images were obtained immediately after cell transplantation and repeatedly taken 1, 4, 8, and 12 week(s) after cell transplantation. The rotational behavior of the animals was observed before and 1, 4, and 8 week(s) after transplantation. The rats were killed after the last MRI scanning, the brain tissues were analyzed by histopathology techniques, and RNAs were extracted for the expression analysis of selected genes using RT-PCR. One week following cell transplantation, all injected sites showed well-defined hypointense areas on MR images, with the most significant effect observed in rats injected with 2 × 10 BMSCs. These MR findings in PD rats lasted up to 12 weeks. The effectiveness of BMSC transplantation revealed by MRI was well confirmed by the behavioral and histopathological observations as well as indirectly supported by gene expression analyses. With the use of SPIO labeling, MRI techniques provided a dynamic evaluation of the spatial and temporal changes following cell transplantation and allowed the association analysis among the imaging, functions, and gene expression analysis in rats. These data also suggest the therapeutic potential of transplanted BMSCs. It is reasonable to speculate that the use of MRI in in vivo evaluation of the effect and fate of transplanted cells in various disease models will be beneficial to developing new strategies of cell-based gene therapy. [ABSTRACT FROM AUTHOR]

Superparamagnetic iron oxide (SPIO) nanoparticles are emerging as ideal probes for noninvasive cell tracking. In this study, poly-L-lysine (PLL) was mixed with Resovist to form the PLL-Resovist complexes and the control of the complexes formed by PLL and Resovist and their subsequent properties was easily achievable. MSCs could be safely and efficiently labeled for MR imaging using PLL-Resovist complexes (w/w 0.01:1) and the labeled MSCs could be detected to have definite decreased signal intensity on T2-weight imaging until 20 days with standard 1.5 T MR equipment. This study describes a simple protocol to label MSCs using PLL-Resovist complexes and the results presented in our study can provide a basis for the application of PLL-Resovist complexes cell labeling. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: The cell trafficking in vivo is a crucial element in the development of successful cell-based therapies and it is important to develop methods that can assess the fate and distribution of cells non-invasively. Because of its high spatial resolution, magnetic resonance (MR) imaging appears ideally suited for imaging the biodistribution of magnetically labeled cells. Superparamagnetic iron oxide (SPIO) nanoparticles have been used to label these cells to provide future possibilities to monitor the cell migration and proliferation by MRI non-invasively. In this study, we investigate the cell labeling efficiencies of two different SPIO nanoparticles using adipose tissue derived stem cells (ADSCs). Cellular labeling was evaluated with Prussian blue staining for iron assessment. The iron content of the labeled cells was assessed by using MR relaxometry and ICP atomic emission spectrometer. Proliferation and viability of ADSCs labeled with a combination of TA and two different SPIO nanoparticles were evaluated. The results showed that when Feridex–Lipofectamine or Resovist–Lipofectamine was used, intracytoplasmic particles stained with Prussian blue stain were detected for all cell lines with a labeling efficiency of nearly 100%. However, iron concentrations varied with SPIO nanoparticle–TA combinations for labeled ADSCs. In addition, while cell proliferation was not affected by incorporation of two SPIO nanoparticles, cell viability varied depending on the type of SPIO nanoparticle used. [Copyright &y& Elsevier]

The purpose of this study was to evaluate the diagnostic efficacy of iron-oxide-enhanced MRI vs CT during arterial portography (CTAP) and intraoperative ultrasound (IOUS) in detection of liver neoplasms. Seventeen patients with malignant focal liver lesions (liver metastases, n=7), hepatocellular carcinomas (HCC, n=9), and cholangiocellular carcinoma (CCC, n=1) underwent presurgical Resovist-enhanced MRI and CTAP. Two independent observers (A and B) assessed the blinded images of unenhanced and iron-oxide-enhanced MRI vs CTAP for the presence, number, and location of the liver lesions. These results were compared lesion by lesion and segment by segment with the results of intraoperative ultrasound ( n=17) serving as the reference standard. Eighty lesions were detected by intraoperative ultrasound in 17 patients. In comparison with IOUS (lesion-by-lesion analysis) the sensitivity was 86.8% for CTAP, 65% for combined unenhanced MR imaging, and 86.8% for combined Resovist-enhanced MRI as well as 86.8% for the combination of unenhanced and Resovist-enhanced MRI. Compared with the sensitivity of combined unenhanced MRI the sensitivity of CTAP as well as the sensitivity of combined Resovist-enhanced MRI was significantly higher (p<0.05). False-positive results were much higher in CTAP as compared with combined unenhanced and SPIO-enhanced MRI. Using the segment-by-segment analysis the specificity of combined unenhanced MRI with 100% (96.7-100%) as well as combined Resovist-enhanced MRI with 100% (96.7-100%) was significantly higher (p<0.05) in comparison with the specificity of CTAP with 91.1% (83.2-96.1%). The accuracy of combined unenhanced MRI was 100% (93.2-100%), combined Resovist-enhanced MRI 100% (93.6-100%) and of CTAP 85.2% (72.9-93.4%). In the detection of focal liver lesions iron-oxide-enhanced MR imaging is superior to unenhanced MRI and similar to CTAP. [ABSTRACT FROM AUTHOR]

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A new system for the quantification of super paramagnetic iron oxide nanoparticles (SPIONs) is presented. The proposed system relies on the particle electron paramagnetic resonance (pEPR) technique and utilises the linear response of the SPIONs to generate a pEPR signal under a static field. By extracting the pEPR signals, whose intensity is proportional to the SPIONs concentration, the quantitative information of the SPIONs is derived. To evaluate the system performance, sensitivity measurements have been conducted with two commercial SPIONs, FeraSpin M and Resovist, and reveal a measurement sensitivity of 300 ng. [ABSTRACT FROM AUTHOR]

Platelets are the smallest blood cells and important for hemostasis. Platelet concentrates (PC) are medicinal products transfused to prevent or treat bleeding. Typically, platelets in PCs are assessed by in vitro tests for their function. However, in vivo testing of these platelets is highly desirable. To distinguish transfused platelets from patients or probands own cells after PC transfusions within the scope of clinical studies, platelets need to be efficiently labeled with minimal preactivation prior to transfusion. Here we report on a method for improved cell uptake of ferucarbotran magnetic nanoparticles contained in Resovist, an FDA-approved MRI contrast agent, by modifying the nanoparticle shell with human serum albumin (HSA). Both HSA-ferucarbotran nanoparticles and magnetically labeled platelets were produced according to EU-GMP guidelines. Platelet function after labeling was evaluated by light transmission aggregometry and by determination of expression of CD62P as platelet activation marker. Magnetic labeling does not impair platelet function and platelets showed reasonable activation response to agonists. Platelet survival studies in NOD/SCID-mice resulted in comparable survival behavior of magnetically labeled and nonlabeled platelets. Additionally, labeled platelets can be recovered from whole blood by magnetic separation.

An abstract of the article "Migration of Resovist-labeled Neural Stem Cells Towards Focal Rat Cerebral Ischemic Regions As Determined by in Vivo Tracking and Magnetic Resonance Imaging," by Shuang Wang and colleagues is presented.

In this study, we sought to label mouse bone marrow-derived endothelial progenitor cells (EPCs) with Resovist(®) in vitro and to image them using 7.0 Tesla (T) magnetic resonance imaging (MRI). Mouse bone marrow-derived EPCs were cultured in endothelial basal medium with endothelial growth supplement. They were then characterized by immunocytochemistry, flow cytometry, and fluorescence quantitative polymerase chain reaction. Their functions were evaluated by measuring their uptake of 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine-labeled acetylated low-density lipoprotein (Dil-Ac-LDL), binding of fluorine isothiocyanate (FITC)-labeled Ulex europaeus agglutinin (UEA), and formation of capillary-like networks. EPCs were labeled with superparamagnetic iron oxide (SPIO) and their proliferation was then assessed in a water-soluble tetrazolium (WST-8)-based cell proliferation assay. Spin echo sequence (multislice, multiecho [MSME]) and gradient echo sequence (2D-FLASH) were used to detect differences in the numbers of labeled cells by 7.0 T MRI. The results showed that the cultured cells were of "cobblestone"-like shape and positive for CD133, CD34, CD31, von Willebrand factor, kinase domain receptor, and CD45, but negative for F4/80. They could take up Dil-Ac-LDL, bind FITC-UEA, and form capillary-like networks on Matrigel in vitro. Prussian-blue staining demonstrated that the cells were efficiently labeled with SPIO. The single-cell T2* effect was more obvious in the 2D-FLASH sequence than in the MSME sequence. Further, there were almost no adverse effects on cell vitality and proliferation. In conclusion, mouse bone marrow-derived EPCs can be efficiently labeled with SPIO and imaged with 7.0-T MRI. They may thus be traced by MRI following transplantation for blood vessel disorders and cancer treatment.