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Magnetic iron oxide containing MCM-41 silica (MM) with ~300 nm particle size was developed. The MM material before or after template removal was modified with NH 2 - or COOH-groups and then grafted with PEG chains. The anticancer drug tamoxifen was loaded into the organic groups' modified and PEGylated nanoparticles by an incipient wetness impregnation procedure. The amount of loaded drug and the release properties depend on whether modification of the nanoparticles was performed before or after the template removal step. The parent and drug-loaded samples were characterized by XRD, N 2 physisorption, thermal gravimetric analysis, and ATR FT-IR spectroscopy. ATR FT-IR spectroscopic data and density functional theory (DFT) calculations supported the interaction between the mesoporous silica surface and tamoxifen molecules and pointed out that the drug molecule interacts more strongly with the silicate surface terminated by silanol groups than with the surface modified with carboxyl groups. A sustained tamoxifen release profile was obtained by an in vitro experiment at pH = 7.0 for the PEGylated formulation modified by COOH groups after the template removal. Free drug and formulated tamoxifen samples were further investigated for antiproliferative activity against MCF-7 cells.

Recent evidence of gadolinium deposition in the brain has raised safety concerns. Iron oxide nanoparticles are re-emerging as promising alternative MR contrast agents, because the iron core can be metabolized. However, long-term follow up studies of the brain after intravenous iron oxide administration have not been reported thus far. In this study, we investigated, if intravenously administered ferumoxytol nanoparticles are deposited in porcine brains. Methods: In an animal care and use committee-approved prospective case-control study, ten Göttingen minipigs received either intravenous ferumoxytol injections at a dose of 5 mg Fe/kg (n=4) or remained untreated (n=6). Nine to twelve months later, pigs were sacrificed and the brains of all pigs underwent ex vivo MRI at 7T with T2 and T2*-weighted sequences. MRI scans were evaluated by measuring R2* values (R2*=1000/T2*) of the bilateral caudate nucleus, lentiform nucleus, thalamus, dentate nucleus, and choroid plexus. Pig brains were sectioned and stained with Prussian blue and evaluated for iron deposition using a semiquantitative scoring system. Data of ferumoxytol exposed and unexposed groups were compared with an unpaired t-test and a Mann-Whitney U test. Results: T2 and T2* signal of the different brain regions was not visually different between ferumoxytol exposed and unexposed controls. There were no significant differences in R2* values of the different brain regions in the ferumoxytol exposed group compared to controls (p>0.05). Prussian blue stains of the same brain regions, scored according to a semiquantitative score, were not significantly different either between the ferumoxytol exposed group and unexposed controls (p>0.05). Conclusions: Our study shows that intravenous ferumoxytol doses of 5-10 mg Fe/kg do not lead to iron deposition in the brain of pigs. We suggest iron oxide nanoparticles as a promising alternative for gadolinium-enhanced MRI., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Tumor response assessments on positron emission tomography (PET)/magnetic resonance imaging (MRI) scans require correct quantification of radiotracer uptake in tumors and normal organs. Historically, MRI scans have been enhanced with gadolinium (Gd)-based contrast agents, which are now controversial due to brain deposition. Recently, ferumoxytol nanoparticles have been identified as an alternative to Gd-based contrast agents because they provide strong tissue enhancement on MR images but are not deposited in the brain. However, it is not known if the strong T1- and T2-contrast obtained with iron oxide nanoparticles such as ferumoxytol could affect MR-based attenuation correction of PET data. The purpose of our study was to investigate if ferumoxytol administration prior to a 2-deoxy-2-[ 18 F]fluoro-D-glucose [ 18 F]FDG PET/MR scan would change standardized uptake values (SUV) of normal organs., Procedures: Thirty pediatric patients (6-18 years) with malignant tumors underwent [ 18 F]FDG-PET/MR scans (dose 3 MBq/kg). Fifteen patients received an intravenous ferumoxytol injection (5 mg Fe/kg) prior to the [ 18 F]FDG-PET/MR scans (group 1). Fifteen additional age- and sex-matched patients received unenhanced [ 18 F]FDG-PET/MR scans (group 2). For attenuation correction of PET data, we used a Dixon-based gradient echo sequence (TR 4.2 ms, TE 1.1, 2.3 ms, FA 5), which accounted for soft tissue, lung, fat, and background air. We used a mixed linear effects model to compare the tissue MRI enhancement, quantified as the signal-to-noise ratio (SNR), as well as tissue radiotracer signal, quantified as SUVmean and SUVmax, between group 1 and group 2. Alpha was assumed at 0.05., Results: The MRI enhancement of the blood and solid extra-cerebral organs, quantified as SNR, was significantly higher on ferumoxytol-enhanced MRI scans compared to unenhanced scans (p < 0.001). However, SUVmean and SUVmax values, corrected based on the patients' body weight or body surface area, were not significantly different between the two groups (p > 0.05)., Conclusion: Ferumoxytol administration prior to a [ 18 F]FDG PET/MR scan did not change standardized uptake values (SUV) of solid extra-cerebral organs. This is important, because it allows injection of ferumoxytol contrast prior to a PET/MRI procedure and, thereby, significantly accelerates image acquisition times.

The use of magnetic fluid hyperthermia (MFH) for cancer therapy has shown promise but lacks suitable methods for quantifying exogenous irons such as superparamagnetic iron oxide (SPIO) nanoparticles as a source of heat generation under an alternating magnetic field (AMF). Application of quantitative susceptibility mapping (QSM) technique to prediction of SPIO in preclinical models has been challenging due to a large variation of susceptibility values, chemical shift from tissue fat, and noisier data arising from the higher resolution required to visualize the anatomy of small animals. In this study, we developed a robust QSM for the SPIO ferumoxytol in live mice to examine its potential application in MFH for cancer therapy. We demonstrated that QSM was able to simultaneously detect high level ferumoxytol accumulation in the liver and low level localization near the periphery of tumors. Detection of ferumoxytol distribution in the body by QSM, however, required imaging prior to and post ferumoxytol injection to discriminate exogenous iron susceptibility from other endogenous sources. Intratumoral injection of ferumoxytol combined with AMF produced a ferumoxytol-dose dependent tumor killing. Histology of tumor sections corroborated QSM visualization of ferumoxytol distribution near the tumor periphery, and confirmed the spatial correlation of cell death with ferumoxytol distribution. Due to the dissipation of SPIOs from the injection site, quantitative mapping of SPIO distribution will aid in estimating a change in temperature in tissues, thereby maximizing MFH effects on tumors and minimizing side-effects by avoiding unwanted tissue heating.

Background The off-label use of ferumoxytol (FE), an intravenous iron preparation for iron deficiency anemia, as a contrast agent for MRI is increasing; therefore, it is critical to understand its pharmacokinetics. Purpose To evaluate the pharmacokinetics of FE in the abdomen and pelvis, as assessed with quantitative 1.5- and 3.0-T MRI relaxometry. Materials and Methods R2*, an MRI technique used to estimate tissue iron content in the abdomen and pelvis, was performed at 1.5 and 3.0 T in 12 healthy volunteers between April 2015 and January 2016. Volunteers were randomly assigned to receive an FE dose of 2 mg per kilogram of body weight (FE 2mg ) or 4 mg/kg (FE 4mg ). MRI was repeated at 1.5 and 3.0 T for each volunteer at five time points: days 1, 2, 4, 7, and 30. A radiologist experienced in MRI relaxometry measured R2* in organs of the mononuclear phagocyte system (MPS) (ie, liver, spleen, and bone marrow), non-MPS anatomy (kidney, pancreas, and muscle), inguinal lymph nodes (LNs), and blood pool. A paired Student t test was used to compare changes in tissue R2*. Results Volunteers (six female; mean age, 44.3 years ± 12.2 [standard deviation]) received either FE 2 mg ( n = 5) or FE 4 mg ( n = 6). Overall R2* trend analysis was temporally significant ( P < .001). Time to peak R2* in the MPS occurred on day 1 for FE 2mg and between days 1 and 4 for FE 4mg ( P < .001 to P < .002). Time to peak R2* in non-MPS anatomy, LNs, and blood pool occurred on day 1 for both doses ( P < .001 to P < .09). Except for the spleen (at 1.5 T) and liver, MPS R2* remained elevated through day 30 for both doses ( P = .02 to P = .03). Except for the kidney and pancreas, non-MPS, LN, and blood pool R2* returned to baseline levels between days 2 and 4 at FE 2mg ( P = .06 to P = .49) and between days 4 and 7 at FE 4mg ( P = .06 to P = .63). There was no difference in R2* change between non-MPS and LN R2* at any time (range, 1-71 sec -1 vs 0-50 sec -1 ; P = .06 to P = .97). Conclusion The pharmacokinetics of ferumoxytol in lymph nodes are distinct from those in mononuclear phagocyte system (MPS) organs, parallel non-MPS anatomy, and the blood pool. © RSNA, 2019 Online supplemental material is available for this article.

Magnetic resonance imaging (MRI) is widely applied in medical research and diagnosis, and a MRI contrast medium plays a crucial role in improving the sensitivity of detection. Ultrasmall superparamagnetic iron oxides (USPIOs) exhibit the potential as a T 2 enhancement contrast medium for MRI due to their excellent magnetic response performance; however, to endow them with specific tumor targetability, long-term circulation performance has always been a hot topic in this field. In this study, a well-designed procedure of chemical coprecipitation, surface modification, and peptide grafting was applied to prepare the active tumor-targeting USPIOs@F127-WSG, in which Pluronic F127 (F127) and the peptide WSGPGVWGASVK (peptide-WSG) were selected as the template agent and the ovarian tumor-targeting ligand, respectively. The results showed that single USPIOs@F127-WSG particles were Fe 3 O 4 nanoparticles regulated by the confinement effect of F127 micelles with a uniform globular morphology and size (∼9 nm), and peptide-WSG was grafted for their tumor targetability. USPIOs@F127-WSG particles presented superparamagnetic behavior with high T 2 relaxivity ( r 2 = 278.15 mM -1 s -1 ) and in vitro targetability for SKOV-3 cells due to the special binding between peptide-WSG and specific receptors of SKOV-3. The test results in vivo verified the targetability of USPIOs@F127-WSG by their specific aggregation in the tumor regions, leading to the T 2 -weighted MRI contrast enhancement. These outstanding properties indicate that USPIOs@F127-WSG have great potential to be applied as the active tumor-targeting contrast agent for MRI.

Developing nanocarriers that accumulate in targeted organs and are harmlessly eliminated still remains a big challenge. Nanoparticles (NP) biodistribution is governed by their size, composition, surface charge and coverage. The current thinking in bionanotechnology is that renal clearance is limited by glomerular basement membrane pore size (≈6 nm), although there is a growing evidence that NP exceeding the threshold can also be excreted with urine. Here we compare biodistribution of PEGylated 140 nm iron oxide cubes and clusters with a special focus on renal accumulation and excretion. Atomic emission spectroscopy, fluorescent microscopy and magnetic resonance imaging revealed rapid and transient accumulation of magnetic NP in kidney. Using intravital microscopy we tracked in real time NP translocation from peritubular capillaries to basal compartment of tubular cells and subsequent excretion to the lumen within 60 min after systemic administration. Transmission electron microscopy revealed persistence of intact full-sized NP in urine 2 h post injection. The results suggest that translocation through peritubular endothelium to tubular epithelial cells is an alternative mechanism of renal clearance enabling excretion of NP above glomerular cut-off size., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Acute myeloid leukaemia is a fatal disease for most patients. We have found that ferumoxytol (Feraheme), an FDA-approved iron oxide nanoparticle for iron deficiency treatment, demonstrates an anti-leukaemia effect in vitro and in vivo. Using leukaemia cell lines and primary acute myeloid leukaemia patient samples, we show that low expression of the iron exporter ferroportin results in a susceptibility of these cells via an increase in intracellular iron from ferumoxytol. The reactive oxygen species produced by free ferrous iron lead to increased oxidative stress and cell death. Ferumoxytol treatment results in a significant reduction of disease burden in a murine leukaemia model and patient-derived xenotransplants bearing leukaemia cells with low ferroportin expression. Our findings show how a clinical nanoparticle previously considered largely biologically inert could be rapidly incorporated into clinical trials for patients with leukaemia with low ferroportin levels.

Fe3O4-magnetic liposome (MLP) can deliver drugs to target tissues and can increase drug efficacy. The present study aimed to investigate the effects of solamargine (SM) and Fe3O4-SM in pancreatic cancer (PC). Cell viability was detected using a Cell Counting kit‑8 assay. Apoptosis and cell cycle progression was tested using a flow cytometry assay. A scratch assay was used to examine cell metastasis. Quantitative polymerase chain reaction, western blot analysis or immunohistochemical analysis were performed to determine the expression of target factors. Magnetic resonance imagining (MRI) and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling were conducted to detect tumor growth and apoptosis in vivo, respectively. It was demonstrated that Fe3O4-SM inhibited cancer cell growth via a slow release of SM over an extended period of time. SM was revealed to induce apoptosis and cell cycle arrest. Furthermore, SM decreased the expression of X-linked inhibitor of apoptosis, Survivin, Ki‑67, proliferating cell nuclear antigen and cyclin D1, but increased the activity of caspase-3. It was also observed that SM inhibited tumor cell metastasis by modulating the expression of matrix metalloproteinase (MMP)-2 and TIMP metallopeptidase inhibitor-2. Furthermore, the phosphorylation of protein kinase B and mechanistic target of rapamycin was suppressed by SM. Notably, the effect of SM was enhanced by Fe3O4-SM. The malignant growth of PC was decreased by SM in vivo. Furthermore, the expression of Ki‑67 was decreased by SM and Fe3O4-SM. Additionally, cell apoptosis was increased in the Fe3O4-SM group, compared with the SM group. The present study illustrated the antitumor effect and action mec-hanism produced by SM. Additionally, it was demonstrated that Fe3O4-SM was more effective than SM in protecting against PC.

In this study, Fe 3 O 4 /hyperbranched polyester-(2-dodecen-1-yl)succinic anhydride2-Dodecen-1-/isoniazid magnetic nanoparticles (Fe 3 O 4 /HBPE-DDSA/INH MNPs) with controlled drug release characteristics were synthesized successfully by a simple one-step method. Orthogonal experiments were performed to optimize the loading capacity and encapsulation efficiency of the MNPs. The structure of the Fe 3 O 4 /HBPE-DDSA/INH MNPs was characterized by 1 H nuclear magnetic resonance spectroscopy, matrix-assisted laser desorption/ionization mass spectrometry, Fourier transform infrared spectroscopy, X-ray diffraction analysis, transmission electron microscopy, and superconducting quantum interference device measurements, while their properties were characterized based on swelling behavior observations, in-vitro release experiments, and cytotoxicity analysis. The results indicated that the fabricated Fe 3 O 4 /HBPE-DDSA/INH MNPs had a high drug-loading capacity and encapsulation efficiency. Further, the drug-release rate of the MNPs was higher in an acidic buffer, indicating that the MNPs were pH-responsive. Swelling studies revealed that the MNPs exhibited diffusion-controlled drug release, while in-vitro release studies revealed that the drug-release properties could be controlled readily, owing to the high encapsulation efficiency of the MNPs and the uniform dispersion of the drug in them. These results collectively suggest that this multifunctional nontoxic drug delivery system, which exhibits good magnetic properties and pH-triggered drug-release characteristics, should be suitable for the treatment of tuberculosis., (Copyright © 2018. Published by Elsevier B.V.)

Objective:: Radiation therapy for cancer can lead to atherosclerosis by inducing inflammatory changes in the vascular wall. It is difficult to quantitatively measure inflammation on CT and MRI studies. The purpose of this study was to assess the use of ferumoxytol, an ultrasmall superparamagnetic iron oxide nanoparticle, as a noninvasive marker of vessel wall inflammation secondary to radiation therapy in pancreatic cancer patients in comparison with healthy volunteers., Methods:: MRI of upper abdomen (T 1 , T 2 , multi echo T 2 * weighted imaging) was performed on 3 T magnet before and 48 h after intravenous administration of ferumoxytol in pancreatic cancer patients who underwent radiation therapy (n = 8) and in healthy volunteers (n = 8). R 2 * value was obtained by drawing regions of interest outlining the aortic wall directly on the T 2 * medic image and subsequently transposed to the R 2 * image using Amira software (v. 5.3.2, FEI, Bordeaux, France). The change in R 2 * values was analyzed by student's t-test., Results:: The average change in R 2 * value of the pancreatic cancer patients was determined to be 216.1 ms -1 . The average change R 2 * value of the control patients was determined to be 54.6 ms -1 . Thus, pancreatic cancer patients following radiation therapy had a greater uptake of ferumoxytol (p = 0.0082) in their aortic wall as compared to healthy controls., Conclusion:: This proof of concept study suggests that greater uptake of ferumoxytol in the aortic wall in cancer patients without visible atherosclerosis may be the expression of increased inflammation., Advances in Knowledge:: Ultrasmall superparamagnetic iron oxide enhanced MRI can offer an imaging biomarker for quantitative estimation of aortic inflammation preceding atherosclerosis.

Reduction-responsive biodegradable micelles were prepared by linking of poly(ethylene glycol) and poly(ε‑caprolactone) with disulfide bond (PEG-SS-PCL) for co-delivery of superparamagnetic iron oxide (SPIO) nanoparticles (NPs) and an anticancer agent, doxorubicin (DOX). This amphiphilic diblock copolymer shows redox-responsive properties, which is arising from disulfide bonds throughout the main chain. The ability of these copolymers for self-assembly with oleic acid modified SPIONs can help to organize nanomicelles in aqueous solution. Doxorubicin (DOX) was loaded in the magnetic nanomicelles with a loading of 32%. Coarse-Grained Molecular Dynamics (CG-MD) simulation approach was exploited to reassure the construction of self-assembled PEG-PCL micelles in presence of oleic acid and water solvent while the hydrophobic and hydrophilic ratios of each block copolymer were equally chosen and each oleic acid was connected to Fe 3 O 4 nanoparticles. Our results confirmed the stability, cytocompatibility, magnetic and redox-responsive properties for these self-assembled nanomicelles and revealed that the DOX-SPION-loaded reduction-sensitive nanomicelles could be used in drug targeting to the cancer cells., (Copyright © 2018 Elsevier B.V. All rights reserved.)

OBJECTIVE Patients with brain arteriovenous malformations (AVMs) often require repeat imaging with MRI or MR angiography (MRA), CT angiography (CTA), and digital subtraction angiography (DSA). The ideal imaging modality provides excellent vascular visualization without incurring added risks, such as radiation exposure. The purpose of this study is to evaluate the performance of ferumoxytol-enhanced MRA using a high-resolution 3D volumetric sequence (fe-SPGR) for visualizing and grading pediatric brain AVMs in comparison with CTA and DSA, which is the current imaging gold standard. METHODS In this retrospective cohort study, 21 patients with AVMs evaluated by fe-SPGR, CTA, and DSA between April 2014 and August 2017 were included. Two experienced raters graded AVMs using Spetzler-Martin criteria on all imaging studies. Lesion conspicuity (LC) and diagnostic confidence (DC) were assessed using a 5-point Likert scale, and interrater agreement was determined. The Kruskal-Wallis test was performed to assess the raters' grades and scores of LC and DC, with subsequent post hoc pairwise comparisons to assess for statistically significant differences between pairs of groups at p < 0.05. RESULTS Assigned Spetzler-Martin grades for AVMs on DSA, fe-SPGR, and CTA were not significantly different (p = 0.991). LC and DC scores were higher with fe-SPGR than with CTA (p < 0.05). A significant difference in LC scores was found between CTA and fe-SPGR (p < 0.001) and CTA and DSA (p < 0.001) but not between fe-SPGR and DSA (p = 0.146). A significant difference in DC scores was found among DSA, fe-SPGR, and CTA (p < 0.001) and between all pairs of the groups (p < 0.05). Interrater agreement was good to very good for all image groups (κ = 0.77-1.0, p < 0.001). CONCLUSIONS Fe-SPGR performed robustly in the diagnostic evaluation of brain AVMs, with improved visual depiction of AVMs compared with CTA and comparable Spetzler-Martin grading relative to CTA and DSA.

Magnetic Particle Imaging (MPI) is a rapidly developing imaging modality that directly measures and maps the concentration of injected superparamagnetic iron oxide nanoparticles (SPIOs). Since the agent does not cross the blood-brain barrier, cerebral SPIO concentration provides a direct probe of Cerebral Blood Volume (CBV). Here we provide an initial demonstration of the ability of MPI to detect functional CBV changes (fCBV) by monitoring SPIO concentration during hypercapnic manipulation in a rat model. As a tracer detection method, MPI offers a more direct probe of agent concentration and therefore fCBV than MRI measurements in which the agent is indirectly detected through perturbation of water relaxation time constants such as T 2 ∗ . We found that MPI detection could measure CBV changes during hypercapnia with high CNR (CNR = 50) and potentially with high temporal resolution. Although the detection process more closely resembles a tracer method, we also identify evidence of physiological noise in the MPI time-series, with higher time-series variance at higher concentration levels. Our findings suggest that CBV-based MPI can provide a detection modality for hemodynamic changes. Further investigation with tomographic imaging is needed to assess tomographic ability of the method and further study the presence of time-series fluctuations which scale with signal level similar to physiological noise in resting fMRI time-courses., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine the relaxation properties of ferumoxytol, an off-label alternative to gadolinium-based contrast agents, under physiological conditions at 1.5 T and 3.0 T., Materials and Methods: Ferumoxytol was diluted in gradually increasing concentrations (0.26-4.2 mM) in saline, human plasma, and human whole blood. Magnetic resonance relaxometry was performed at 37°C at 1.5 T and 3.0 T. Longitudinal and transverse relaxation rate constants (R1, R2, R2*) were measured as a function of ferumoxytol concentration, and relaxivities (r1, r2, r2*) were calculated., Results: A linear dependence of R1, R2, and R2* on ferumoxytol concentration was found in saline and plasma with lower R1 values at 3.0 T and similar R2 and R2* values at 1.5 T and 3.0 T (1.5 T: r1saline = 19.9 ± 2.3 smM; r1plasma = 19.0 ± 1.7 smM; r2saline = 60.8 ± 3.8 smM; r2plasma = 64.9 ± 1.8 smM; r2*saline = 60.4 ± 4.7 smM; r2*plasma = 64.4 ± 2.5 smM; 3.0 T: r1saline = 10.0 ± 0.3 smM; r1plasma = 9.5 ± 0.2 smM; r2saline = 62.3 ± 3.7 smM; r2plasma = 65.2 ± 1.8 smM; r2*saline = 57.0 ± 4.7 smM; r2*plasma = 55.7 ± 4.4 smM). The dependence of relaxation rates on concentration in blood was nonlinear. Formulas from second-order polynomial fittings of the relaxation rates were calculated to characterize the relationship between R1blood and R2 blood with ferumoxytol., Conclusions: Ferumoxytol demonstrates strong longitudinal and transverse relaxivities. Awareness of the nonlinear relaxation behavior of ferumoxytol in blood is important for ferumoxytol-enhanced magnetic resonance imaging applications and for protocol optimization.

A chemical template strategy was put forward to synthesize monodisperse rattle-type magnetic carbon (Fe 3 O 4 @C) hollow microspheres. During the synthesis procedure, monodisperse Fe 2 O 3 microspheres were used as chemical template, which released Fe 3+ ions in acidic solution and initiated the in-situ polymerization of pyrrole into polypyrrole (PPy) shell. With the continual acidic etching of Fe 2 O 3 microspheres, rattle-type Fe 2 O 3 @PPy microspheres were generated with the cavity appearing between the PPy shell and left Fe 2 O 3 core, which were then transformed into Fe 3 O 4 @C hollow microspheres through calcination in nitrogen atmosphere. Compared with traditional physical template, the shell and cavity of rattle-type hollow microspheres were generated in one step using the chemical template method, which obviously saved the complex procedures including the coating and removal of middle shells. The experimental results exhibited that the rattle-type Fe 3 O 4 @C hollow microspheres with different parameters could be regulated through controlled synthesis of the intermediate Fe 2 O 3 @PPy product. Moreover, when the rattle-type Fe 3 O 4 @C hollow microspheres were investigated as drug carrier, they manifested sustained-release behaviour of doxorubicin, justifying their promising applications as carriers in drug delivery., Statement of Significance: The aim of the present study was first to synthesize rattle-type Fe 3 O 4 @C hollow microspheres through a simple synthesis method as a drug carrier. Here a chemical template synthesis of rattle-type hollow microspheres was developed, which saved the complex procedures including the coating and removal of middle shells in traditional physical template. Second, all the influence factors in the reaction processes were systematically investigated to obtain rattle-type Fe 3 O 4 @C hollow microspheres with controlled parameters. Third, the rattle-type Fe 3 O 4 @C hollow microspheres were studied as drug carriers and the influences of their structural parameters on drug loading and releasing performance were investigated., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Contrast-enhanced magnetic resonance imaging is a commonly used diagnostic tool. Compared with standard gadolinium-based contrast agents, ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA), used as an alternative contrast medium, is feasible in patients with impaired renal function. Other attractive imaging features of i.v. ferumoxytol include a prolonged blood pool phase and delayed intracellular uptake. With its unique pharmacologic, metabolic, and imaging properties, ferumoxytol may play a crucial role in future magnetic resonance imaging of the central nervous system, various organs outside the central nervous system, and the cardiovascular system. Preclinical and clinical studies have demonstrated the overall safety and effectiveness of this novel contrast agent, with rarely occurring anaphylactoid reactions. The purpose of this review is to describe the general and organ-specific properties of ferumoxytol, as well as the advantages and potential pitfalls associated with its use in magnetic resonance imaging. To more fully demonstrate the applications of ferumoxytol throughout the body, an imaging atlas was created and is available online as supplementary material., (Published by Elsevier Inc.)

Background Aims: Tracking cells during regenerative cytotherapy is crucial for monitoring their safety and efficacy. Macrophages are an emerging cell-based regenerative therapy for liver disease and can be readily labeled for medical imaging. A reliable, clinically applicable cell-tracking agent would be a powerful tool to study cell biodistribution., Methods: Using a recently described chemical design, we set out to functionalize, optimize and characterize a new set of superparamagnetic iron oxide nanoparticles (SPIONs) to efficiently label macrophages for magnetic resonance imaging-based cell tracking in vivo., Results: A series of cell health and iron uptake assays determined that positively charged SPIONs (+16.8 mV) could safely label macrophages more efficiently than the formerly approved ferumoxide (-6.7 mV; Endorem) and at least 10 times more efficiently than the clinically approved SPION ferumoxytol (-24.2 mV; Rienso). An optimal labeling time of 4 h at 25 µg/mL was demonstrated to label macrophages of mouse and human origin without any adverse effects on cell viability whilst providing substantial iron uptake (>5 pg Fe/cell) that was retained for 7 days in vitro. SPION labeling caused no significant reduction in phagocytic activity and a shift toward a reversible M1-like phenotype in bone marrow-derived macrophages (BMDMs). Finally, we show that SPION-labeled BMDMs delivered via the hepatic portal vein to mice are localized in the hepatic parenchyma resulting in a 50% drop in T2* in the liver. Engraftment of exogenous cells was confirmed via immunohistochemistry up to 3 weeks posttransplantation., Discussion: A positively charged dextran-coated SPION is a promising tool to noninvasively track hepatic macrophage localization for therapeutic monitoring., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Medical imaging is routine in the diagnosis and staging of a wide range of medical conditions. In particular, magnetic resonance imaging (MRI) is critical for visualizing soft tissue and organs, with over 60 million MRI procedures performed each year worldwide. About one-third of these procedures are contrast-enhanced MRI, and gadolinium-based contrast agents (GBCAs) are the mainstream MRI contrast agents used in the clinic. GBCAs have shown efficacy and are safe to use with most patients; however, some GBCAs have a small risk of adverse effects, including nephrogenic systemic fibrosis (NSF), the untreatable condition recently linked to gadolinium (Gd) exposure during MRI with contrast. In addition, Gd deposition in the human brain has been reported following contrast, and this is now under investigation by the US Food and Drug Administration (FDA). To address a perceived need for a Gd-free contrast agent with pharmacokinetic and imaging properties comparable to GBCAs, we have designed and developed zwitterion-coated exceedingly small superparamagnetic iron oxide nanoparticles (ZES-SPIONs) consisting of ∼3-nm inorganic cores and ∼1-nm ultrathin hydrophilic shell. These ZES-SPIONs are free of Gd and show a high T 1 contrast power. We demonstrate the potential of ZES-SPIONs in preclinical MRI and magnetic resonance angiography.

Chitosan and its derivatives can be used to modify magnetic materials to promote the adsorption properties of the magnetic materials and avoid the weakness of chitosan and its derivatives. In the present study, chitosan grafted poly(trimethyl allyl ammonium chloride) (CTS-g-PTMAAC) was prepared by graft copolymerization; then it was coated on the surfaces of the sodium citrate coated Fe3O4 nanoparticles (SC-Fe3O4) to prepare a novel composite CTS-g-PTMAAC/SC-Fe3O4 magnetic nanoparticles, with which possesses abundant surface positive charges. The structure and properties of the CTS-g-PTMAAC/SC-Fe3O4 composite magnetic nanoparticles were characterized by FTIR, TEM, VSM, and zeta potential. The dye adsorption characteristics of the CTS-g-PTMAAC/SC-Fe3O4 nanoparticles were determined using the food yellow 3 aqueous solutions as a model food effluent. Effect of pH of the dye solution on the adsorption of food yellow 3 was determined and compared with N-2-hydroxylpropyl trimethyl ammonium chloride chitosan coated sodium citrate-Fe3O4 (CTS-g-HTCC/SC-Fe3O4) composite magnetic nanoparticles. The adsorption kinetics, adsorption isotherms, adsorption thermodynamics, and desorption and reusability of the magnetic nanoparticles were investigated., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Magnetic iron oxide nanoparticles have been well known for their applications in magnetic resonance imaging (MRI), hyperthermia, targeted drug delivery, etc. The surface modification of these magnetic nanoparticles has been explored extensively to achieve functionalized materials with potential application in biomedical, environmental and catalysis field. Herein, we report a novel and versatile single step methodology for developing curcumin functionalized magnetic Fe3O4 nanoparticles without any additional linkers, using a simple coprecipitation technique. The magnetic nanoparticles (MNPs) were characterized using transmission electron microscopy, X-ray diffraction, fourier transform infrared spectroscopy and thermogravimetric analysis. The developed MNPs were employed in a cellular application for protection against an inflammatory agent, a polychlorinated biphenyl (PCB) molecule., (Copyright © 2016. Published by Elsevier B.V.)

Malignant dural neoplasms are not reliably distinguished from benign dural neoplasms with contrast-enhanced magnetic resonance imaging (MRI). MRI enhancement in central nervous system (CNS) diseases imaged with ferumoxytol has been attributed to intracellular uptake in macrophages rather than vascular leakage. We compared imaging to histopathology and immunohistochemistry in meningiomas and dural metastases having ferumoxytol-enhanced MRI (FeMRI) and gadolinium-enhanced MRI (GdMRI) in order to correlate enhancement patterns to macrophage presence and vascular state. All patients having extraaxial CNS tumors were retrospectively selected from one of two ongoing FeMRI studies. Enhancement was compared between GdMRI and FeMRI. Diagnoses were confirmed histologically and/or by characteristic imaging. Tumor and vascular histology was reviewed. Immunohistochemical staining for CD68 (a macrophage marker), Connexin-43 (Cx43) (a marker of normal gap junctions), and smooth muscle actin (SMA) as a marker of vascularity, was performed in seven study cases with available tissue. Immunohistochemistry was performed on archival material from 33 subjects outside of the current study as controls: 20 WHO grade I cases of meningioma and 13 metastatic tumors. Metastases displayed marked delayed enhancement on FeMRI, similar to GdMRI. Four patients with dural metastases and one patient with meningioma showed similar enhancement on FeMRI and GdMRI. Five meningiomas with typical enhancement on GdMRI lacked enhancement on FeMRI. Enhancement on FeMRI was better associated with decreased Cx43 expression than intralesional macrophages. These pilot data suggest that FeMRI may better differentiate metastatic disease from meningiomas than GdMRI, and that differences in tumor vasculature rather than macrophage presence could underlie differences in contrast enhancement.

Nanoparticle (NP)-based approaches to cancer drug delivery are challenged by the heterogeneity of the enhanced permeability and retention (EPR) effect in tumors and the premature attrition of payload from drug carriers during circulation. Here we show that such challenges can be overcome by a magnetophoretic approach to accelerate NP delivery to tumors. Payload-bearing poly(lactic-co-glycolic acid) NPs were converted into polymer-iron-oxide nanocomposites (PINCs) by attaching colloidal Fe3O4 onto the surface, via a simple surface modification method using dopamine polymerization. PINCs formed stable dispersions in serum-supplemented medium and responded quickly to magnetic field gradients above 1 kG/cm. Under the field gradients, PINCs were rapidly transported across physical barriers and into cells and captured under flow conditions similar to those encountered in postcapillary venules, increasing the local concentration by nearly three orders of magnitude. In vivo magnetophoretic delivery enabled PINCs to accumulate in poorly vascularized subcutaneous SKOV3 xenografts that did not support the EPR effect. In vivo magnetic resonance imaging, ex vivo fluorescence imaging, and tissue histology all confirmed that the uptake of PINCs was higher in tumors exposed to magnetic field gradients, relative to negative controls., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The practice of contrast-enhanced magnetic resonance angiography (CEMRA) has changed significantly in the span of a decade. Concerns regarding gadolinium (Gd)-associated nephrogenic systemic fibrosis in those with severely impaired renal function spurred developments in low-dose CEMRA and non-contrast MRA as well as efforts to seek alternative MR contrast agents. Originally developed for MR imaging use, ferumoxytol (an ultra-small superparamagnetic iron oxide nanoparticle), is currently approved by the US Food and Drug Administration for the treatment of iron deficiency anaemia in adults with renal disease. Since its clinical availability in 2009, there has been rising interest in the scientific and clinical use of ferumoxytol as an MR contrast agent. The unique physicochemical and pharmacokinetic properties of ferumoxytol, including its long intravascular half-life and high r1 relaxivity, support a spectrum of MRI applications beyond the scope of Gd-based contrast agents. Moreover, whereas Gd is not found in biological systems, iron is essential for normal metabolism, and nutritional iron deficiency poses major public health challenges worldwide. Once the carbohydrate shell of ferumoxytol is degraded, the elemental iron at its core is incorporated into the reticuloendothelial system. These considerations position ferumoxytol as a potential game changer in the field of CEMRA and MRI. In this paper, we aim to summarise our experience with the cardiovascular applications of ferumoxytol and provide a brief synopsis of ongoing investigations on ferumoxytol-enhanced MR applications., (Copyright © 2016. Published by Elsevier Ltd.)

Ferumoxytol ultrasmall superparamagnetic iron oxide nanoparticles can enhance contrast between neuroinflamed and normal-appearing brain tissue when used as a contrast agent for high-sensitivity magnetic resonance imaging (MRI). Here we used an anti-dextran antibody (Dx1) that binds the nanoparticle's carboxymethyldextran coating to differentiate ferumoxytol from endogenous iron and localize it unequivocally in brain tissue. Intravenous injection of ferumoxytol into immune-competent rats that harbored human tumor xenograft-induced inflammatory brain lesions resulted in heterogeneous and lesion-specific signal enhancement on MRI scans in vivo. We used Dx1 immunolocalization and electron microscopy to identify ferumoxytol in affected tissue post-MRI. We found that ferumoxytol nanoparticles were taken up by astrocyte endfeet surrounding cerebral vessels, astrocyte processes, and CD163(+)/CD68(+) macrophages, but not by tumor cells. These results provide a biological basis for the delayed imaging changes seen with ferumoxytol and indicate that ferumoxytol-MRI can be used to assess the inflammatory component of brain lesions in the clinic., (Published by Elsevier Inc.)

Background: Sentinel lymph node (SLN) dissection involves lymphatic mapping and selective removal of clinically negative lymph nodes at highest risk for harboring metastases. Lymphatic mapping is most often performed using radioisotope with or without blue dye (standard tracers). Sienna+(®), a superparamagnetic iron oxide that can be detected using the Sentimag(®) magnetometer, is an alternative mapping agent to identify SLNs that has been investigated in five clinical trials. This meta-analysis was performed to determine if Sienna+(®) is non-inferior for SLN detection when compared to standard tracers., Methods: Five clinical trials comparing Sienna+(®) to a standard technique were identified, and data from these studies were used to determine the agreement by Kappa statistic between Sienna+(®) and standard tracers in identifying SLNs and malignant SLNs. The trials included 1683 SLNs identified in 804 patients. Data from the studies were imbalanced, therefore additional agreement indices were utilized to compare techniques. The estimated difference between the techniques was analyzed and a margin of ≤5 % was used to determine non-inferiority., Results: Agreement between the Sienna+(®) and standard tracers was strong for SLN detection by patient [prevalence-adjusted bias-adjusted kappa (PABAK) 0.94, 95 % confidence interval (CI) 0.89-0.98], moderate to substantial for SLN detection by node (PABAK 0.68, 95 % CI 0.54-0.82), and strong for the detection of malignant SLNs by patient (PABAK 0.89, 95 % CI 0.84-0.95). Sienna+(®) demonstrated non-inferiority compared with standard tracers., Conclusions: The Sienna+(®) mapping agent is non-inferior to the standard method for SLN detection in patients with clinically node-negative breast cancer.

Suppression of the reticuloendothelial system (RES) uptake is one of the most challenging tasks in nanomedicine. Coating stratagems using polymers, such as poly(ethylene glycol) (PEG), have led to great success in this respect. Nevertheless, recent observations of immunological response toward these synthetic polymers have triggered a search for better alternatives. In this work, natural red blood cell (RBC) membranes are camouflaged on the surface of Fe3O4 nanoparticles for reducing the RES uptake. In vitro macrophage uptake, in vivo biodistribution and pharmacokinetic studies demonstrate that the RBC membrane is a superior alternative to the current gold standard PEG for nanoparticle 'stealth'. Furthermore, we systematically investigate the in vivo potential toxicity of RBC membrane-coated nanoparticles by blood biochemistry, whole blood panel examination and histology analysis based on animal models. The combination of synthetic nanoparticles and natural cell membranes embodies a novel and biomimetic nanomaterial design strategy and presents a compelling property of functional materials for a broad range of biomedical applications.

Multimodal nanoparticulate materials are described, offering magnetic, radionuclide, and fluorescent imaging capabilities to exploit the complementary advantages of magnetic resonance imaging (MRI), positron emission tomography/single-photon emission commuted tomography (PET/SPECT), and optical imaging. They comprise Fe3O4@NaYF4 core/shell nanoparticles (NPs) with different cation dopants in the shell or core, including Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm). These NPs are stabilized by bisphosphonate polyethylene glycol conjugates (BP-PEG), and then show a high transverse relaxivity (r2) up to 326 mM(-1) s(-1) at 3T, a high affinity to [(18)F]-fluoride or radiometal-bisphosphonate conjugates (e.g., (64)Cu and (99m)Tc), and fluorescent emissions from 500 to 800 nm under excitation at 980 nm. The biodistribution of intravenously administered particles determined by PET/MR imaging suggests that negatively charged Co0.16Fe2.84O4@NaYF4(Yb, Er)-BP-PEG (10K) NPs cleared from the blood pool more slowly than positively charged NPs Fe3O4@NaYF4(Yb, Tm)-BP-PEG (2K). Preliminary results in sentinel lymph node imaging in mice indicate the advantages of multimodal imaging.

Magnetic particle imaging is a tracer-based imaging method that utilizes the non-linear magnetization response of iron-oxide for determining their spatial distribution. The method is based on a sampling scheme where a sensitive spot is moved along a trajectory that captured a predefined field-of-view (FOV). However, particles outside the FOV also contribute to the measurement signal due to their rotation and the non-sharpness of the sensitive spot. In the present work we investigate artifacts that are induced by particles not covered by the FOV and show that the artifacts can be mitigated by using a system matrix that covers not only the region of interest but also a certain area around the FOV. The findings are especially relevant when using a multi-patch acquisition scheme where the boundaries of neighboring patches have to be handled.

Nano-silicon dioxide (SiO2) is used nowadays in several biomedical applications such as drug delivery and cancer therapy, and is produced on an industrial scale as additive to paints and coatings, cosmetics and food. Data regarding the long-term biokinetics of SiO2 engineered nanoparticles (ENPs) is lacking. In this study, the whole-body biodistribution of SiO2 core-shell ENPs containing a paramagnetic core of Fe3O4 was investigated after a single exposure via intravenous injection or intratracheal instillation in mice. The distribution and accumulation in different organs was evaluated for a period of 84 days using several techniques, including magnetic resonance imaging, inductively coupled plasma mass spectrometry, X-ray fluorescence and X-ray absorption near edge structure spectroscopy. We demonstrated that intravenously administered SiO2 ENPs mainly accumulate in the liver, and are retained in this tissue for over 84 days. After intratracheal instillation, an almost complete particle clearance from the lung was seen after 84 days with distribution to spleen and kidney. Furthermore, we have strong evidence that the ENPs retain their original core-shell structure during the whole observation period. This work gives an insight into the whole-body biodistribution of SiO2 ENPs and will provide guidance for further toxicity studies.

Unlabelled: Given the limited regenerative capacity of the heart, cellular therapy with stem cell-derived cardiac cells could be a potential treatment for patients with heart disease. However, reliable imaging techniques to longitudinally assess engraftment of the transplanted cells are scant. To address this issue, we used ferumoxytol as a labeling agent of human embryonic stem cell-derived cardiac progenitor cells (hESC-CPCs) to facilitate tracking by magnetic resonance imaging (MRI) in a large animal model. Differentiating hESCs were exposed to ferumoxytol at different time points and varying concentrations. We determined that treatment with ferumoxytol at 300 μg/ml on day 0 of cardiac differentiation offered adequate cell viability and signal intensity for MRI detection without compromising further differentiation into definitive cardiac lineages. Labeled hESC-CPCs were transplanted by open surgical methods into the left ventricular free wall of uninjured pig hearts and imaged both ex vivo and in vivo. Comprehensive T2*-weighted images were obtained immediately after transplantation and 40 days later before termination. The localization and dispersion of labeled cells could be effectively imaged and tracked at days 0 and 40 by MRI. Thus, under the described conditions, ferumoxytol can be used as a long-term, differentiation-neutral cell-labeling agent to track transplanted hESC-CPCs in vivo using MRI., Significance: The development of a safe and reproducible in vivo imaging technique to track the fate of transplanted human embryonic stem cell-derived cardiac progenitor cells (hESC-CPCs) is a necessary step to clinical translation. An iron oxide nanoparticle (ferumoxytol)-based approach was used for cell labeling and subsequent in vivo magnetic resonance imaging monitoring of hESC-CPCs transplanted into uninjured pig hearts. The present results demonstrate the use of ferumoxytol labeling and imaging techniques in tracking the location and dispersion of cell grafts, highlighting its utility in future cardiac stem cell therapy trials., (©AlphaMed Press.)

Aims: The gold standard for detection of Sentinel Lymph Nodes (SLN) is a combined radioisotope and blue dye breast injection, using a gamma probe (GP). A new, non-radioactive method was developed, using a tracer (Sienna+(®)) of superparamagnetic iron oxide (SPIO) nanoparticles and a manual magnetometer (SentiMag(®)) (SM). The IMAGINE study was designed to show the non-inferiority of SM compared to GP, for the detection of SLN in breast cancer patients with SLN biopsy indication., Methods: From November 2013 to June 2014, 181 patients were recruited, and 321 nodes were excised and assessed ex-vivo. Readings from both SM and GP devices were recorded during transcutaneous, intraoperative, and ex-vivo detection attempts., Results: At the patient level, ex-vivo detection rates (primary variable) with SM and GP were 97.8% and 98.3% (concordance rate 99.4%). Transcutaneous and intraoperative detection rates were 95.5% vs 97.2%, and 97.2% vs 97.8% for SM and GP respectively (concordance rates > 97%). At the node level, intraoperative and ex-vivo detection rates were 92.5% vs 89.3% and 91.0% vs 86.3% for SM and GP respectively. In all cases the non-inferiority of SM compared to SM was shown by ruling out a predefined non-inferiority margin of 5%., Conclusions: Our study showed the non-inferiority of SM as compared to GP. Moreover, the ex-vivo and intraoperative detection rates at the node level were slightly higher with SM., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

To facilitate targeting drug delivery and combined therapy, we develop titanium dioxide-encapsulated Fe3O4 nanoparticles (Fe3O4@TiO2 NPs). Titanium dioxide (TiO2), which is employed as a sonosensitizer for sonodynamic therapy (SDT), can also be used for the loading of doxorubicin (DOX). The fabricated Fe3O4@TiO2 NPs exhibit pH-dependent loading and release of doxorubicin (DOX) in vitro. After incubation with cancer cells, reactive oxygen species (ROS) are generated efficiently upon the irradiation of ultrasound. In the biodistribution experiments, extremely high in vivo tumor accumulation of Fe3O4@TiO2 NPs and long-time retention effect are observed. Compared with chemotherapy or sonodynamic treatment alone, the combined therapy demonstrated a synergistic effect, resulting in stronger cytotoxicity and higher therapeutic efficacy. Thus, the constructed NPs are endowed with multifunctions which allow them to selectively deliver combinatorial therapeutic payload to tumor with enhanced therapeutic effectiveness and minimal side effects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Ferumoxytol is a parenteral iron therapy that the Food and Drug Administration recently approved for the treatment of iron-deficiency anemia. The form of the iron, ultrasmall superparamagnetic iron oxide nanoparticles, causes T1, T2, and T2* shortening on magnetic resonance imaging, which can mimic hemosiderosis. We report such a case, with laboratory findings that demonstrate normal iron stores, and discuss the potential implications.

This paper reports the synthesis and characterization of amoxicillin- functionalized magnetite nanostructures (Fe3O4@AMO), revealing and discussing several biomedical applications of these nanomaterials. Our results proved that 10 nm Fe3O4@AMO nanoparticles does not alter the normal cell cycle progression of cultured diploid cells, and an in vivo murine model confirms that the nanostructures disperse through the host body and tend to localize in particular sites and organs. The nanoparticles were found clustered especially in the lungs, kidneys and spleen, next to the blood vessels at this level, while being totally absent in the brain and liver, suggesting that they are circulated through the blood flow and have low toxicity. Fe3O4@AMO has the ability to be easily circulated through the body and optimizations may be done so these nanostructures cluster to a specific target region. Functionalized magnetite nanostructures proved a great antimicrobial effect, being active against both the Gram positive pathogen S. aureus and the Gram negative pathogen E. coli. The fabricated nanostructures significantly reduced the minimum inhibitory concentration (MIC) of the active drug. This result has a great practical relevance, since the functionalized nanostructures may be used for decreasing the therapeutic doses which usually manifest great severe side effects, when administrated in high doses. Fe3O4@AMO represents also a suitable approach for the development of new alternative strategies for improving the activity of therapeutic agents by targeted delivery and controlled release.

Purpose: Endogenous labeling of stem/ progenitor cells via intracerebroventricular injection of micron-sized particles of iron oxide (MPIOs) has become standard methodology for MRI of adult neurogenesis. While this method is well characterized in the naïve rodent brain, it has not been fully investigated in disease models. Here, we describe methodological challenges that can confound data analysis when this technique is applied to a rat model of stroke, the endothelin-1 model of focal cortical ischemia., Methods: We intended to track endogenous neuroblast migration from the subventricular zone to the stroke area using previously described methods for in vivo labeling of endogenous neuroblasts with MPIOs and following migration with high resolution MRI., Results: MPIOs accumulation in stroke regions of endothelin-1-treated brains involves two dynamic steps: an initial rapid cell independent mechanism, followed by slower MPIOs accumulation. While the latter may in part be attributable to cell dependent delivery of the particles, the cell independent mechanism complicates the interpretation of the data. Strategies aimed at prelabeling the stem cell niche reduced cell independent MPIOs accumulation, but failed to abolish it., Conclusion: We conclude that MRI-based neural stem/progenitor cell tracking via direct injection of MPIOs into the lateral and third ventricles, requires significant validation in models of brain disease/trauma., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: To investigate the cytotoxicity, cellular intake and magnetic field interaction of three superparamagnetic iron oxide (SPIO) and one ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles on ARPE-19 cells., Methods: Two FDA-approved SPIO nanoparticles (Endorem and Lumirem), one commercial SPIO(FluidMag-L) and one FDA-approved USPIO (Feraheme) were tested. Nanoparticle suspensions were diluted and prepared in high- (1000 Fe-ug/ml) and low- (100 Fe-ug/ml) dose suspensions. ARPE-19 cells were incubated in four 24-well plates and the medium changed every other day until cells attained 80% confluence. Nanoparticle cytotoxicity was evaluated using the XTT cytotoxicity assay. Cellular attraction was tested after digestion of the cells in collagenase A (1 mg/ml) overnight. A 3500 Gauss neodymium magnet was used to attract cells to the well walls. ARPE-19 cell ultrastructure was evaluated by transmission electron microscopy (TEM) to determine the specific locations of nanoparticles within the cell membranes., Results: Cytotoxicity assessment by the XTT assay revealed that ARPE-19 cells that were exposed to either concentration of Endorem, FLuidMag-L, Feraheme non-conjugated with protamine and heparin or Lumirem demonstrated no statistically significant toxicity. Cells exposed to Feraheme when conjugated with protamine and heparin presented severe toxicity in both concentrations. When a magnetic field was applied, all nanoparticle-containing samples, except Feraheme non-conjugated form, were promptly attracted. TEM and prussian blue staining examination revealed that Feraheme alone was not initially capable of cellular uptake. This issue was solved by conjugating Feraheme with protamine and heparin (although cytotoxicity was found on those samples). Endorem, FLuidMag-L, Feraheme conjugated form were found within the cytoplasm of ARPE-19 cells., Conclusions: Ferahame when conjugated with protamine and heparin was cytotoxic at the higher and lower doses, as revealed by the XTT assay. Endorem and FluidMag-L were not toxic at the studied concentrations. Feraheme non-conjugated solutions and Lumirem solutions provided were harmless but were not internalized by ARPE-19 cells. All the studied nanoparticles were attracted to the magnetic field except Feraheme in the non-conjugated form.

Metal oxide nanoparticles, hybridized with various polymeric chemicals, represent a novel and breakthrough application in drug delivery, hyperthermia treatment and imaging techniques. Radiolabeling of these nanoformulations can result in new and attractive dual-imaging agents as well as provide accurate in vivo information on their biodistribution profile. In this paper a comparison study has been made between two of the most promising hybrid core-shell nanosystems, bearing either magnetite (Fe3O4) or cobalt ferrite (CoFe2O4) cores, regarding their magnetic, radiolabeling, hyperthermic and biodistribution properties. While hyperthermic properties were found to be affected by the metal-core type, the radiolabeling ability and the in vivo fate of the nanoformulations seem to depend critically on the size and the shell composition.

Esophageal tumors provide unique challenges and opportunities for developing and testing surveillance imaging technology for different tumor microenvironment components, including assessment of immune cell modulation, with the ultimate goal of promoting early detection and response evaluation. In this context, accessibility through the lumen using a minimally invasive approach provides a means for repetitive evaluation longitudinally by combining fluorescent endoscopic imaging technology with novel fluorescent nanoparticles that are phagocytized by immune cells in the microenvironment. The agent we developed for imaging is synthesized from Feraheme (ferumoxytol), a Food and Drug Administration-approved monocrystaline dextran-coated iron oxide nanoparticle, which we conjugated to a near-infrared fluorochrome, CyAL5.5. We demonstrate a high level of uptake of the fluorescent nanoparticles by myeloid-derived suppressor cells (MDSCs) in the esophagus and spleen of L2Cre;p120ctnflox/flox mice. These mice develop esophageal dysplasia leading to squamous cell carcinoma; we have previously demonstrated that dysplastic and neoplastic esophageal lesions in these mice have an immune cell infiltration that is dominated by MDSCs. In the L2Cre;p120ctnflox/flox mice, evaluation of the spleen reveals that nearly 80% of CD45+ leukocytes that phagocytized the nanoparticle were CD11b+Gr1+ MDSCs. After dexamethasone treatment, we observed concordant decreased fluorescent signal from esophageal lesions during fluorescent endoscopy and decreased CyAL5.5-fluorescent-positive immune cell infiltration in esophageal dysplastic lesions by fluorescence-activated cell sorting analysis. Our observations suggest that this translatable technology may be used for the early detection of dysplastic changes and the serial assessment of immunomodulatory therapy and to visualize changes in MDSCs in the esophageal tumor microenvironment.

Superparamagnetic iron oxide nanoparticles (SPIO) can be used to image physiological processes and anatomical, cellular and molecular changes in diseases. The clinical applications range from the imaging of tumors and metastases in the liver, spleen and bone marrow, the imaging of lymph nodes and the CNS, MRA and perfusion imaging to atherosclerotic plaque and thrombosis imaging. New experimental approaches in molecular imaging describe undirected SPIO trapping (passive targeting) in inflammation, tumors and associated macrophages as well as the directed accumulation of SPIO ligands (active targeting) in tumor endothelia and tumor cells, areas of apoptosis, infarction, inflammation and degeneration in cardiovascular and neurological diseases, in atherosclerotic plaques or thrombi. The labeling of stem or immune cells allows the visualization of cell therapies or transplant rejections. The coupling of SPIO to ligands, radio- and/or chemotherapeutics, embedding in carrier systems or activatable smart sensor probes and their externally controlled focusing (physical targeting) enable molecular tumor therapies or the imaging of metabolic and enzymatic processes. Monodisperse SPIO with defined physicochemical and pharmacodynamic properties may improve SPIO-based MRI in the future and as targeted probes in diagnostic magnetic resonance (DMR) using chip-based µNMR may significantly expand the spectrum of in vitro analysis methods for biomarker, pathogens and tumor cells. Magnetic particle imaging (MPI) as a new imaging modality offers new applications for SPIO in cardiovascular, oncological, cellular and molecular diagnostics and therapy., (© Georg Thieme Verlag KG Stuttgart · New York.)

The current study aimed to investigate adipose tissue-derived stem cells (ADSCs) in vivo by multimodality imaging following implantation for cellular therapy. The biological characteristics of ADSCs co-labeled with Molday ION Rhodamine B™ (MIRB) and green fluorescent protein (GFP) were studied in vitro. Following rat ADSC isolation and culture, a combined labeling strategy for ADSCs based on genetic modification of the reporter gene GFP with lentiviral vector expression enhancement and physical MIRB labeling was performed. Cell viability, proliferation, membrane-bound antigens and multiple differentiation ability were compared between the labeled and unlabeled ADSCs. The ADSCs were successfully labeled with GFP and MIRB, showing various fluorescent colors for marker identification. The fluorescence emitted by the GFP protein was sustained and exhibited stable expression, while MIRB fluorescence decreased with time. Compared with the unlabeled ADSCs, no significant differences were detected in cell viability, proliferation, membrane-bound antigens and multiple differentiation ability in the co-labeled samples (P>0.05). No significant effects on the biophysical properties of ADSCs were observed following co-labeling with lentiviral vectors encoding the gene for emerald green fluorescent protein and MIRB. The ADSCs were able to be efficiently tracked in vitro and in vivo by multimodality imaging thus, the co-labeling approach provides a novel strategy for therapeutic gene studies.

Objective: Ultrasmall superparamagnetic iron oxide nanoparticles, such as ferumoxytol, produce decreased MR signal on susceptibility-inducing T2*-weighted sequences in tissues of the reticuloendothelial system. However, acute iron deposition in the adrenals has not been reported. The purpose of this article is to report our initial observations of the imaging behavior of the normal adrenals on ferumoxytol-enhanced T2*-weighted magnetic resonance imaging., Subjects and Methods: Quantitative T2* imaging was performed at 3 T using a breath-hold monopolar multiecho gradient echo sequence with six equally spaced in-phase echoes in nine patients. Changes in signal-to-noise ratio (SNR) were analyzed prior to and 48 hours after ferumoxytol administration in the adrenals, liver and spleen (positive controls), and pancreas and skeletal muscle (negative controls)., Results: In comparison with unenhanced images, there was an average SNR decrease of 67.4% in the right adrenal, 77.6% in the left adrenal, 68.4% in the liver, 89.1% in the spleen, 15.0% in the pancreas, and 9.5% in skeletal muscle on T2*-weighted images obtained 48 hours after ferumoxytol administration. The decrease in SNR observed in the adrenals was significantly greater than that seen in the pancreas and skeletal muscle (left adrenal, p < 0.0001; right adrenal, p = 0.0002) and similar to that seen in the liver and spleen., Conclusion: The normal adrenal loses signal on ferumoxytol-enhanced T2*-weighted MRI. Acute iron deposition within the adrenals has not been previously described. The mechanism of ferumoxytol uptake in the adrenal and potential clinical applications warrant further investigation.

Nanoparticles (NPs) are being used or explored for the development of biomedical applications in diagnosis and therapy, including imaging and drug delivery. Therefore, reliable tools are needed to study the behavior of NPs in biological environment, in particular the transport of NPs across biological barriers, including the blood-brain tumor barrier (BBTB), a challenging question. Previous studies have addressed the translocation of NPs of various compositions across cell layers, mostly using only one type of cells. Using a coculture model of the human BBTB, consisting in human cerebral endothelial cells preloaded with ultrasmall superparamagnetic iron oxide nanoparticles (USPIO NPs) and unloaded human glioblastoma cells grown on each side of newly developed ultrathin permeable silicon nitride supports as a model of the human BBTB, we demonstrate for the first time the transfer of USPIO NPs from human brain-derived endothelial cells to glioblastoma cells. The reduced thickness of the permeable mechanical support compares better than commercially available polymeric supports to the thickness of the basement membrane of the cerebral vascular system. These results are the first report supporting the possibility that USPIO NPs could be directly transferred from endothelial cells to glioblastoma cells across a BBTB. Thus, the use of such ultrathin porous supports provides a new in vitro approach to study the delivery of nanotherapeutics to brain cancers. Our results also suggest a novel possibility for nanoparticles to deliver therapeutics to the brain using endothelial to neural cells transfer.

Recently, organic-inorganic hybrids composed of derivatives of dextran, a polysaccharide, and magnetite nanoparticles have attracted much attention as novel thermoseeds. If they can be fabricated into microspheres of size 20-30 μm, they are expected to show not only hyperthermia effects but also embolization effects in human liver and kidney cancers. In this study, we examined the fabrication of carboxymethyldextran/magnetite microspheres using a water/oil emulsion as the reaction medium. Improvement of the chemical stability of the microcapsules by coating with silica using a sol-gel process was also investigated. The obtained hollow microspheres contained particles of size 20-30 μm. Silica coating using an appropriate catalyst for hydrolysis and polycondensation of alkoxysilanes was found to be effective for preventing dissolution and collapse in simulated body environments.

Aims: The purpose of this clinical trial was to investigate whether cardiovascular magnetic resonance imaging (CMR) using ferumoxytol (Feraheme™, FH), an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), allows more detailed characterization of infarct pathology compared with conventional gadolinium-based necrosis/fibrosis imaging in patients with acute myocardial infarction., Methods and Results: Fourteen patients who had experienced an acute ST-elevation myocardial infarction were included in this study. Following coronary angiography, a first baseline study (pre-FH) was performed followed by subsequent CMR studies (post-FH) 48 h after intravenous ferumoxytol administration. The CMR studies comprised cine-CMR, T(2)-weighted short tau inversion recovery spin echo imaging, T(2)-mapping, and T(1)-weighted late gadolinium enhancement (LGE) imaging. The median extent of short-axis in-plane LGE was 30% [inter-quartile range (IQR) 26-40%]. The median in-plane extent of T(2)-weighted 'hypoenhancement' in the region of myocardial infarction, which was not present prior to ferumoxytol administration in any patient, was 19% (IQR 14-22%; P < 0.001 compared with the extent of LGE). The median in-plane extent of areas showing signal void in T(2)-mapping images post-FH in the region of myocardial infarction was 16% (IQR 12-18%; P < 0.001 compared with the extent of LGE; P = 0.34 compared with the extent of T(2)-weighted hypoenhancement). A substantial drop in absolute T(2)-values was observed not only in the infarct core and peri-infarct zone, but also in the remote 'healthy' myocardium, although there was only a minor change in the skeletal muscle. Substantial ferumoxytol uptake was detected only in cultured macrophages, but not in peripheral blood monocytes from study patients., Conclusion: We could demonstrate in humans that USPIO-based contrast agents enable a more detailed characterization of myocardial infarct pathology mainly by detecting infiltrating macrophages. Considering the multi-functionality of USPIO-based particles and their superior safety profile compared with gadolinium-based compounds, these observations open up new vistas for the clinical application of USPIO.

Rat liver was examined by transmission electron microscopy after a single intravenous injection of nanosized magnetite suspension (0.1 g (Fe(3)O(4))/kg body weight). Magnetite particles were found in Kupffer's cells and hepatocytes. Accumulation of the particles by these two cell types was different. Morphometry of magnetite-containing granules in Kupffer's cells and nanoparticle agglomerations in hepatocytes was carried out. The ultrastructure of Kupffer's cell granules was described and the mechanism of penetration of nanosized magnetite particles into the cells was suggested. Nanosized magnetite particles were not completely eliminated over 40 days after a single injection.

Localized magnetic heating treatments (hyperthermia, thermal ablation) using superparamagnetic iron oxide nanoparticles (MNPs) continue to be an active area of cancer research. For generating the appropriate heat to sufficiently target cell destruction, adequate MNP concentrations need to be accumulated into tumors. Furthermore, the knowledge of MNP bio-distribution after application and additionally after heating is significant, firstly because of the possibility of repeated heating treatments if MNPs remain at the target region and secondly to study potential adverse effects dealing with MNP dilution from the target region over time. In this context, little is known about the behavior of MNPs after intra-tumoral application and magnetic heating. Therefore, the present in vivo study on the bio-distribution of intra-tumorally injected MNPs in mice focused on MNP long term monitoring of pre and post therapy over seven days using multi-channel magnetorelaxometry (MRX). Subsequently, single-channel MRX was adopted to study the bio-distribution of MNPs in internal organs and tumors of sacrificed animals. We found no distinct change of total MNP amounts in vivo during long term monitoring. Most of the MNP amounts remained in the tumors; only a few MNPs were detected in liver and spleen and less than 1% of totally injected MNPs were excreted. Apparently, the application of magnetic heating and the induction of apoptosis did not affect MNP accumulation. Our results indicate that MNP mainly remained within the injection side after magnetic heating over a seven-days-observation and therefore not affecting healthy tissue. As a consequence, localized magnetic heating therapy of tumors might be applied periodically for a better therapeutic outcome.

The two poorly soluble iron containing solid aerosols of siderite (FeCO₃) and magnetite (Fe₃O₄) were compared in a 4-week inhalation study on rats at similar particle mass concentrations of approximately 30 or 100 mg/m³. The particle size distributions were essentially identical (MMAD ≈1.4 μm). The iron-based concentrations were 12 or 38 and 22 or 66 mg Fe/m³ for FeCO₃ and Fe₃O₄, respectively. Modeled and empirically determined iron lung burdens were compared with endpoints suggestive of pulmonary inflammation by determinations in bronchoalveolar lavage (BAL) and oxidative stress in lung tissue during a postexposure period of 3 months. The objective of study was to identify the most germane exposure metrics, that are the concentration of elemental iron (mg Fe/m³), total particle mass (mg PM/m³) or particle volume (μl PM/m³) and their associations with the effects observed. From this analysis it was apparent that the intensity of pulmonary inflammation was clearly dependent on the concentration of particle-mass or -volume and not of iron. Despite its lower iron content, the exposure to FeCO₃ caused a more pronounced and sustained inflammation as compared to Fe₃O₄. Similarly, borderline evidence of increased oxidative stress and inflammation occurred especially following exposure to FeCO₃ at moderate lung overload levels. The in situ analysis of 8-oxoguanine in epithelial cells of alveolar and bronchiolar regions supports the conclusion that both FeCO₃ and Fe₃O₄ particles are effectively endocytosed by macrophages as opposed to epithelial cells. Evidence of intracellular or nuclear sources of redox-active iron did not exist. In summary, this mechanistic study supports previous conclusions, namely that the repeated inhalation exposure of rats to highly respirable pigment-type iron oxides cause nonspecific pulmonary inflammation which shows a clear dependence on the particle volume-dependent lung overload rather than any increased dissolution and/or bioavailability of redox-active iron.

Intravenous iron is standard for dialysis-associated anemia and its use is rising dramatically in other settings. Except for the dextrans, full iron replacement requires multiple visits. Nonetheless, safety concerns abound. Ferumoxytol, a recently approved modified dextran with a carbohydrate core that tightly binds the iron moiety, decreasing free iron and ostensibly increasing safety, was approved by the US FDA, in June 2009, for the treatment of iron deficiency associated with chronic kidney disease and end-stage renal disease. This formulation, uniquely, can be administered in a large dose as a short intravenous injection of 1 min or less, markedly facilitating care. Recent post-marketing safety issues have been raised resulting in a change in the package insert. This article examines existing clinical data and posits reasons for the labeling change. Potential future use of this formulation is opined.

Aqueous suspensions of 10 nm, 50 nm, or 1 μm Fe(3)O(4) particles were injected intraperitoneally (ip) to rats at a dose of 500 mg/kg in 4 mL of sterile deionized water 3 times a week for 5 weeks. Following exposure, functional and biochemical indices and histopathological examinations of spleen and liver tissues of exposed rats were evaluated for signs of toxicity. The iron content of the blood was measured photometrically, and that of the liver and the spleen by atomic adsorption spectroscopy (AAS) and electron paramagnetic resonance (EPR) methods. It was found that, given equal mass doses, Fe(3)O(4) nanoparticles possess considerably higher systemic toxicity than microparticles, but within the nanometric range the relationship between particle size and resorptive toxicity is intricate and nonunique. The latter fact may be attributed to differences in different nanoparticles' toxicokinetics, which are controlled by both more or less substantial direct penetration of nanoparticles through biological barriers and their unequal solubility.