Delayed Ferumoxtran-10-Enhanced Magnetic Resonance Neurography of the Lumbosacral Plexus: Impact on Vascular Suppression and Image Quality.

BACKGROUND: Intravenous Ferumoxtran-10 belongs to ultra-small superparamagnetic iron oxide particles and can be used for magnetic resonance neurography (MRN) as an alternative to other imaging methods which use contrast agents. PURPOSE: To examine the impact of intravenous Ferumoxtran-10 on vascular suppression and compare image quality to gadolinium (Gd)-enhanced image acquisition in MRN of lumbosacral plexus (LS). STUDY TYPE: Prospective. POPULATION/SUBJECTS: 17 patients with Ferumoxtran-10-enhanced MRN, and 20 patients with Gd-enhanced MRN. FIELDSTRENGTH/SEQUENCE: 3T/3D STIR sequence. ASSESSMENT: Image quality, nerve visibility and vascular suppression were evaluated by 3 readers using a 5-point Likert scale. STATISTICAL TESTS: Inter-reader agreement (IRA) was calculated using intraclass coefficients (ICC). Quantitative analysis of image quality was performed by signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) measurements and compared using Student's t-testing. RESULTS: Image quality, nerve visibility and vascular suppression were significantly higher for Ferumoxtran-10-enhanced MRN compared to Gd-enhanced MRN sequences (p < 0.05). IRA for image quality of nerves was good in Gd-enhanced and Ferumoxtran-10 MRN with ICC values of 0.76 and 0.89, respectively. IRA for nerve visibility was good in Gd- and Ferumoxtran-10 enhanced MR neurography (ICC 0.72 and 0.90). Mean SNR was significantly higher in Ferumoxtran-10-enhanced MRN for all analyzed structures, while mean CNR was for significantly better for S1 ganglion and femoral nerve in Ferumoxtran-10-enhanced MRN (p < 0.05). DATA CONCLUSION: Ferumoxtran-10-enhanced MRN of the LS plexus showed significantly higher image quality and nerve visibility with better vascular suppression as compared to Gd-enhanced MRN. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

IOP Injection, A Novel Superparamagnetic Iron Oxide Particle MRI Contrast Agent for the Detection of Hepatocellular Carcinoma: A Phase II Clinical Trial.

BACKGROUND: MRI is crucial in diagnosing hepatocellular carcinoma (HCC). Superparamagnetic iron oxide particles (SPIO) are liver-specific contrast agents which enhance lesions in T2 -weighted images. Iron oxide nano-particle m-PEG-silane (IOP) Injection, a newly developed SPIO, showed promising imaging effects and good safety profile in preclinical studies and in phase I clinical trial. PURPOSE: To evaluate the safety and clinical validity of IOP Injection as MRI contrast agent in diagnosing HCC. STUDY TYPE: Prospective. SUBJECTS: A total of 52 subjects (61.6 ± 11.05 years, 45 males/7 females) with suspected HCC. FIELD STRENGTH/SEQUENCE: 1.5 T, T1 -weighted in/opposed phase, T2 *-weighted gradient echo, T2 -weighted fast spin echo, true fast imaging with steady-state free precession. ASSESSMENT: Adverse effects and clinical monitoring were recorded throughout the 5-day study. Two independent readers (M.G.H. with 30 years of experience, S.P.K. with 26 years of experience) made the diagnosis. The diagnostic performance of IOP-enhanced MRI was evaluated with sensitivity and positive predictive value by comparing to the pathology reports from subsequent hepatic resection. The number of lesions with various sizes and degrees of differentiation detected by IOP-enhanced MRI was assessed. The relative change in signal intensities over time was indirectly measured from acquired images. STATISTICAL TESTS: Sensitivity and positive predictive value were used to evaluate the diagnostic performance of IOP-enhanced MRI. Prevalence-adjusted and bias-adjusted 𝜅 coefficient was used to assess the interreader variability. RESULTS: No serious adverse event related to IOP Injection was found. IOP Injection enhanced the lesion-to-liver contrast ratio in T2 *-weighted images by 50.1% ± 4.8%. IOP-enhanced MRI detected HCC with 100% sensitivity by subject and 96% sensitivity by lesion. IOP Injection visualized subtle vascular invasion as filling defect within vessels in true fast imaging with steady-state free precession (TrueFISP) images. DATA CONCLUSION: IOP Injection was safe and efficacious as MRI contrast agent in diagnosing HCC in a limited group of subjects. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 2.

Myocardial and Systemic Inflammation in Acute Stress-Induced (Takotsubo) Cardiomyopathy.

BACKGROUND: Acute stress-induced (takotsubo) cardiomyopathy can result in a heart failure phenotype with a prognosis comparable with that of myocardial infarction. In this study, we hypothesized that inflammation is central to the pathophysiology and natural history of takotsubo cardiomyopathy. METHODS: In a multicenter study, we prospectively recruited 55 patients with takotsubo cardiomyopathy and 51 age-, sex-, and comorbidity-matched control subjects. During the index event and at the 5-month follow-up, patients with takotsubo cardiomyopathy underwent multiparametric cardiac magnetic resonance imaging, including ultrasmall superparamagnetic particles of iron oxide (USPIO) enhancement for detection of inflammatory macrophages in the myocardium. Blood monocyte subpopulations and serum cytokines were assessed as measures of systemic inflammation. Matched control subjects underwent investigation at a single time point. RESULTS: Subjects were predominantly middle-aged (64±14 years) women (90%). Compared with control subjects, patients with takotsubo cardiomyopathy had greater USPIO enhancement (expressed as the difference between pre-USPIO and post-USPIO T2*) in both ballooning (14.3±0.6 milliseconds versus 10.5±0.9 milliseconds; P<0.001) and nonballooning (12.9±0.6 milliseconds versus 10.5±0.9 milliseconds; P=0.02) left ventricular myocardial segments. Serum interleukin-6 (23.1±4.5 pg/mL versus 6.5±5.8 pg/mL; P<0.001) and chemokine (C-X-C motif) ligand 1 (1903±168 pg/mL versus 1272±177 pg/mL; P=0.01) concentrations and classic CD14++CD16- monocytes (90±0.5% versus 87±0.9%; P=0.01) were also increased whereas intermediate CD14++CD16+ (5.4±0.3% versus 6.9±0.6%; P=0.01) and nonclassic CD14+CD16++ (2.7±0.3% versus 4.2±0.5%; P=0.006) monocytes were reduced in patients with takotsubo cardiomyopathy. At 5 months, USPIO enhancement was no longer detectable in the left ventricular myocardium, although persistent elevations in serum interleukin-6 concentrations ( P=0.009) and reductions in intermediate CD14++CD16+ monocytes (5.6±0.4% versus 6.9±0.6%; P=0.01) remained. CONCLUSIONS: We demonstrate for the first time that takotsubo cardiomyopathy is characterized by a myocardial macrophage inflammatory infiltrate, changes in the distribution of monocyte subsets, and an increase in systemic proinflammatory cytokines. Many of these changes persisted for at least 5 months, suggesting a low-grade chronic inflammatory state. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02897739.

The capability of detecting small vessels beyond the conventional MRI sensitivity using iron-based contrast agent enhanced susceptibility weighted imaging.

Imaging brain microvasculature is important in cerebrovascular diseases. However, there is still a lack of non-invasive, non-radiation, and whole-body imaging techniques to investigate them. The aim of this study is to develop an ultra-small superparamagnetic iron oxide (USPIO) enhanced susceptibility weighted imaging (SWI) method for imaging micro-vasculature in both animal (~10 µm in rat) and human brain. We hypothesized that the USPIO-SWI technique could improve the detection sensitivity of the diameter of small subpixel vessels 10-fold compared with conventional MRI methods. Computer simulations were first performed with a double-cylinder digital model to investigate the theoretical basis for this hypothesis. The theoretical results were verified using in vitro phantom studies and in vivo rat MRI studies (n = 6) with corresponding ex vivo histological examinations. Additionally, in vivo human studies (n = 3) were carried out to demonstrate the translational power of the USPIO-SWI method. By directly comparing the small vessel diameters of an in vivo rat using USPIO-SWI with the small vessel diameters of the corresponding histological slide using laser scanning confocal microscopy, 13.3-fold and 19.9-fold increases in SWI apparent diameter were obtained with 5.6 mg Fe/kg and 16.8 mg Fe/kg ferumoxytol, respectively. The USPIO-SWI method exhibited its excellent ability to detect small vessels down to about 10 µm diameter in rat brain. The in vivo human study unveiled hidden arterioles and venules and demonstrated its potential in clinical practice. Theoretical modeling simulations and in vitro phantom studies also confirmed a more than 10-fold increase in the USPIO-SWI apparent diameter compared with the actual small vessel diameter size. It is feasible to use SWI blooming effects induced by USPIO to detect small vessels (down to 10 µm in diameter for rat brain), well beyond the spatial resolution limit of conventional MRI methods. The USPIO-SWI method demonstrates higher potential in cerebrovascular disease investigations.

Behaviour of adipose-derived canine mesenchymal stem cells after superparamagnetic iron oxide nanoparticles labelling for magnetic resonance imaging.

BACKGROUND: Therapy with mesenchymal stem cells (MSCs) has been reported to provide beneficial effects in the treatment of neurological and orthopaedic disorders in dogs. The exact mechanism of action is poorly understood. Magnetic resonance imaging (MRI) gives the opportunity to observe MSCs after clinical administration. To visualise MSCs with the help of MRI, labelling with an MRI contrast agent is necessary. However, it must be clarified whether there is any negative influence on cell function and viability after labelling prior to clinical administration. RESULTS: For the purpose of the study, seven samples with canine adipose-derived stem cells were incubated with superparamagnetic iron oxide nanoparticles (SPIO: 319.2 µg/mL Fe) for 24 h. The internalisation of the iron particles occurred via endocytosis. SPIO particles were localized as free clusters in the cytoplasm or within lysosomes depending on the time of investigation. The efficiency of the labelling was investigated using Prussian blue staining and MACS assay. After 3 weeks the percentage of SPIO labelled canine stem cells decreased. Phalloidin staining showed no negative effect on the cytoskeleton. Labelled cells underwent osteogenic and adipogenic differentiation. Chondrogenic differentiation occurred to a lesser extent compared with a control sample. MTT-Test and wound healing assay showed no influence of labelling on the proliferation. The duration of SPIO labelling was assessed using a 1 Tesla clinical MRI scanner and T2 weighted turbo spin echo and T2 weighted gradient echo MRI sequences 1, 2 and 3 weeks after labelling. The hypointensity caused by SPIO lasted for 3 weeks in both sequences. CONCLUSIONS: An Endorem labelling concentration of 319.2 µg/mL Fe (448 µg/mL SPIO) had no adverse effects on the viability of canine ASCs. Therefore, this contrast agent could be used as a model for iron oxide labelling agents. However, the tracking ability in vivo has to be evaluated in further studies.

The superparamagnetic iron oxide tracer: a valid alternative in sentinel node biopsy for breast cancer treatment.

The European Union has determined that from 2016 breast cancer patients should be treated in Specialist Breast Units that achieve the minimum standards for the mandatory quality indicators as defined by Eusoma. The existing standard for axillary lymph node staging in breast cancer is sentinel node biopsy (SNB), performed using Technetium-sulphur colloid (99m Tc) alone or with blue dye. The major limits of radioisotope consist in the problems linked to radioactivity, in the shortage of tracer and nuclear medicine units. Among existing alternative tracers, SentiMag® , which uses superparamagnetic iron oxide particles, can represent a valid option for SNB. We conducted a paired, prospective, multicentre study to evaluate the non-inferiority of SentiMag® vs. 99m Tc. The primary end point was the detection rate (DR) per patient. The study sample consists of 193 women affected by breast carcinoma with negative axillary assessment. The concordance rate per patients between 99m Tc and SentiMag® was 97.9%. The DR per patient was 99.0% for 99m Tc and 97.9% for SentiMag® . SentiMag® appears to be non-inferior to the radiotracer and safe. While 99m Tc remains the standard, SentiMag® DR appears adequate after a minimum learning curve. In health care settings where nuclear medicine units are not available, SentiMag/Sienna+® allows effective treatment of breast cancer patients.

Spin-lock MR enhances the detection sensitivity of superparamagnetic iron oxide particles.

PURPOSE: To evaluate spin-lock MR for detecting superparamagnetic iron oxides and compare the detection sensitivity of quantitative T1ρ with T2 imaging. METHODS: In vitro experiments were performed to investigate the influence of iron oxide particle size and composition on T1ρ . These comprise T1ρ and T2 measurements (B0 = 1.41T) of agar (2%) with concentration ranges of three different iron oxide nanoparticles (IONs) (Sinerem, Resovist, and ION-Micelle) and microparticles of iron oxide (MPIO). T1ρ dispersion was measured for a range of spin-lock amplitudes (γB1 = 6.5-91 kHz). Under relevant in vivo conditions (B0 = 9.4T; γB1 = 100-1500 Hz), T1ρ and T2 mapping of the liver was performed in seven mice pre- and 24 h postinjection of Sinerem. RESULTS: Addition of iron oxide nanoparticles decreased T1ρ as well as the native T1ρ dispersion of agar, leading to increased contrast at high spin-lock amplitudes. Changes of T1ρ were highly linear with iron concentration and much larger than T2 changes. MPIO did not show this effect. In vivo, a decrease of T1ρ was observed with no clear influence on T1ρ dispersion. CONCLUSION: By suppression of T1ρ dispersion, iron oxide nanoparticles cause enhanced T1ρ contrast compared to T2 . The underlying mechanism appears to be loss of lock. Spin-lock MR is therefore a promising technique for sensitive detection of iron oxide contrast agents.

Visualization of acute focal lesions in rats with experimental autoimmune encephalomyelitis by magnetic nanoparticles, comparing different MRI sequences including phase imaging.

PURPOSE: To compare the sensitivity and specificity of phase imaging (PI) with other magnetic resonance imaging (MRI) methods in lesion detection in rats with experimental autoimmune encephalomyelitis (EAE), as an animal model for multiple sclerosis (MS). MATERIALS AND METHODS: EAE was induced in rats (n = 14) by subcutaneous (s.c.) injection of myelin basic protein (MBP) and complete Freund's adjuvant (CFA). Control animals (n = 4) were given an s.c. injection of phosphate-buffered saline mixed with CFA. The development of local inflammatory processes, demyelinations, and blood-brain barrier (BBB) disruptions were monitored over 7 weeks in a 4.7T animal scanner by T1-, T2-, T2*-weighted images, magnetization transfer, and PI in the presence or absence of very small superparamagnetic iron oxide particles (VSOP) and confirmed by immunostaining using CD31, CD68, MBP, and albumin antibodies and Gallyas silver staining. RESULTS: EAE rats developed time-dependent local inflammations and BBB disruptions but no clear demyelinizations. In histological stainings these processes were trackable as accumulations of phagocytic monocytes and extravasal albumin. In MRI without application of VSOP inflammatory processes were not detectable. MRI in the presence of VSOP revealed inflammatory processes by the appearance of hypointense spots (hs). The specificity of PI to detect hs was similar to T1- and T2*-weighted images The calculated sensitivity was less than in corresponding T2*-weighted images. CONCLUSION: The diagnostic use of PI without VSOP as contrast agent to detect lesions is not recommended at field strength of 4.7T or lower.

Ferumoxtran-10-enhanced 3-T Magnetic Resonance Angiography of Pelvic Arteries: Initial Experience.

BACKGROUND: Patients with renal impairment cannot undergo angiography because iodine and gadolinium contrast agents are contraindicated. Iron-containing ultrasmall superparamagnetic iron oxide particles, such as ferumoxtran-10, are not contraindicated in these patients. Thus, patients with renal failure can still undergo angiography with ferumoxtran-10. OBJECTIVE: To evaluate the visibility of pelvic vessels with magnetic resonance angiography (MRA) using ferumoxtran-10 as contrast agent. DESIGN, SETTING, AND PARTICIPANTS: Three hundred and eighty-one patients diagnosed with primary or recurrent prostate cancer underwent pelvic ferumoxtran-10 MRA. Eleven anatomical pelvic-vessel segments per patient were evaluated using qualitative and quantitative criteria for image quality (IQ), vessel visibility (VV), and the contrast-to-noise ratio (CNR). INTERVENTION: Ferumoxtran-10-enhaced MRA. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: IQ, VV, and CNR were assessed on a 5-point scale for each data set/vessel segment (very poor, poor, moderate, good, and excellent). RESULTS AND LIMITATIONS: IQ was good to excellent for 98.2% of the data sets and VV was good to excellent for 97.7% of all vessel segments. The mean CNR for all segments was 88.13 (standard deviation 4.22). Contrast bolus imaging cannot be performed with this technique, so it is impossible to visualize the arterial or venous phase separately. The timing of contrast administration is also a limitation, with MRA performed 1 d after contrast infusion. CONCLUSIONS: Ferumoxtran-10 MRA showed excellent image quality and visibility for pelvic vessels. In addition, the homogeneity of the intraluminal contrast was superior. Patients with preterminal or terminal renal function can benefit from ferumoxtran-10 MRA if visualization of their pelvic vessels is required. PATIENT SUMMARY: Magnetic resonance imaging of blood vessels using a contrast agent called ferumoxtran-10 is a promising technique for patients with impaired kidney function, as it provides high-quality visualization of blood vessels in the pelvis.

Rapid Magneto-Sonoporation of Adipose-Derived Cells.

By permeabilizing the cell membrane with ultrasound and facilitating the uptake of iron oxide nanoparticles, the magneto-sonoporation (MSP) technique can be used to instantaneously label transplantable cells (like stem cells) to be visualized via magnetic resonance imaging in vivo. However, the effects of MSP on cells are still largely unexplored. Here, we applied MSP to the widely applicable adipose-derived stem cells (ASCs) for the first time and investigated its effects on the biology of those cells. Upon optimization, MSP allowed us to achieve a consistent nanoparticle uptake (in the range of 10 pg/cell) and a complete membrane resealing in few minutes. Surprisingly, this treatment altered the metabolic activity of cells and induced their differentiation towards an osteoblastic profile, as demonstrated by an increased expression of osteogenic genes and morphological changes. Histological evidence of osteogenic tissue development was collected also in 3D hydrogel constructs. These results point to a novel role of MSP in remote biophysical stimulation of cells with focus application in bone tissue repair.

Fast field-cycling magnetic resonance detection of intracellular ultra-small iron oxide particles in vitro: Proof-of-concept.

PURPOSE: Inflammation is central in disease pathophysiology and accurate methods for its detection and quantification are increasingly required to guide diagnosis and therapy. Here we explored the ability of Fast Field-Cycling Magnetic Resonance (FFC-MR) in quantifying the signal of ultra-small superparamagnetic iron oxide particles (USPIO) phagocytosed by J774 macrophage-like cells as a proof-of-principle. METHODS: Relaxation rates were measured in suspensions of J774 macrophage-like cells loaded with USPIO (0-200 µg/ml Fe as ferumoxytol), using a 0.25 T FFC benchtop relaxometer and a human whole-body, in-house built 0.2 T FFC-MR prototype system with a custom test tube coil. Identical non-imaging, saturation recovery pulse sequence with 90° flip angle and 20 different evolution fields selected logarithmically between 80 µT and 0.2 T (3.4 kHz and 8.51 MHz proton Larmor frequency [PLF] respectively). Results were compared with imaging flow cytometry quantification of side scatter intensity and USPIO-occupied cell area. A reference colorimetric iron assay was used. RESULTS: The T1 dispersion curves derived from FFC-MR were excellent in detecting USPIO at all concentrations examined (0-200 µg/ml Fe as ferumoxytol) vs. control cells, p ≤ 0.001. FFC-NMR was capable of reliably detecting cellular iron content as low as 1.12 ng/µg cell protein, validated using a colorimetric assay. FFC-MR was comparable to imaging flow cytometry quantification of side scatter intensity but superior to USPIO-occupied cell area, the latter being only sensitive at exposures ≥ 10 µg/ml USPIO. CONCLUSIONS: We demonstrated for the first time that FFC-MR is capable of quantitative assessment of intra-cellular iron which will have important implications for the use of USPIO in a variety of biological applications, including the study of inflammation.

MRI Tracking of iPS Cells-Induced Neural Stem Cells in Traumatic Brain Injury Rats.

Induced pluripotent stem cells (iPS cells) are promising cell source for stem cell replacement strategy applied to brain injury caused by traumatic brain injury (TBI) or stroke. Neural stem cell (NSCs) derived from iPS cells could aid the reconstruction of brain tissue and the restoration of brain function. However, tracing the fate of iPS cells in the host brain is still a challenge. In our study, iPS cells were derived from skin fibroblasts using the four classic factors Oct4, Sox2, Myc, and Klf4. These iPS cells were then induced to differentiate into NSCs, which were incubated with superparamagnetic iron oxides (SPIOs) in vitro. Next, 30 TBI rat models were prepared and divided into three groups (n = 10). One week after brain injury, group A&B rats received implantation of NSCs (labeled with SPIOs), while group C rats received implantation of non-labeled NSCs. After cell implantation, all rats underwent T2*-weighted magnetic resonance imaging (MRI) scan at day 1, and 1 week to 4 weeks, to track the distribution of NSCs in rats' brains. One month after cell implantation, manganese-enhanced MRI (ME-MRI) scan was performed for all rats. In group B, diltiazem was infused during the ME-MRI scan period. We found that (1) iPS cells were successfully derived from skin fibroblasts using the four classic factors Oct4, Sox2, Myc, and Klf4, expressing typical antigens including SSEA4, Oct4, Sox2, and Nanog; (2) iPS cells were induced to differentiate into NSCs, which could express Nestin and differentiate into neural cells and glial cells; (3) NSCs were incubated with SPIOs overnight, and Prussian blue staining showed intracellular particles; (4) after cell implantation, T2*-weighted MRI scan showed these implanted NSCs could migrate to the injury area in chronological order; (5) the subsequent ME-MRI scan detected NSCs function, which could be blocked by diltiazem. In conclusion, using an in vivo MRI tracking technique to trace the fate of iPS cells-induced NSCs in host brain is feasible.

A new method for neonatal rat ventricular myocyte purification using superparamagnetic iron oxide particles.

BACKGROUND: Neonatal rat ventricular myocytes (NRVMs) have proven to be an ideal research model for cardiac disease. However, the current methods to purify NRVMs have a limitation to obtain high purity. The purpose of this study was to develop a NRVM purification method by using superparamagnetic iron oxide particles (SIOP). METHODS: NRVMs were purified by using SIOP (SIOP group). The differential attachment with or without bromodeoxyuridine (BrdU) treatment served as control and BrdU groups, respectively. The Percoll gradient (Percoll) and magnetic-activated cell sorting (MACS) methods were performed to compare the purity and viability of NRVMs with SIOP method. RESULTS: The SIOP group enriched NRVMs up to 93.9 ±â€¯2.0% purity determined by flow cytometry (FCM) and 95.6 ±â€¯1.3% by immunofluorescence count (IF). In contrast, the control group gave purities of 71.9 ±â€¯2.9% (by FCM) and 66.8 ±â€¯8.9% (by IF), and the BrdU group obtained 82.0 ±â€¯1.3% (by FCM) and 83.1 ±â€¯2.4% (by IF). The purity of SIOP-isolated NRVMs was not different from that of Percoll and MACS groups. However, the cardiomyocytes separated by these methods, except SIOP protocol, were mixed with intrinsic cardiac adrenergic cells. NRVMs purified by SIOP shaped the similar three-dimensional morphology, with no difference in cell yield, viability and cytosolic Ca2+ homeostasis at 24 h after isolation compared with NRVMs in other groups. Furthermore, SIOP-purified NRVMs retained the responses to phenylephrine and lipopolysaccharide challenge. CONCLUSION: We first reported an efficient and novel method to purify NRVMs using SIOP, which may help accelerate innovative research in the field of cardiomyocyte biology.

Overendocytosis of superparamagnetic iron oxide particles increases apoptosis and triggers autophagic cell death in human osteosarcoma cell under a spinning magnetic field.

The toxicity of superparamagnetic iron oxide nanoparticles (SPIONs) is still a vital topic of debate and the mechanisms remain unclear. In the present study, overdose SPIONs could induce osteosarcoma cell death and the effects were exaggerated when combined with spinning magnetic field (SMF). In the combination group, mitochondrial transmembrane potential decrease more obviously and reactive oxygen species (ROS) was found to generate much higher in line with that of the apoptosis ratio. Meantime, amount of autophagy was induced. Inhibiting the autophagy generation by 3-methyladenine (3-MA) increase cell viability but decrease the caspase 3/7 and caspase 8 activities in combination groups, and inhibiting apoptosis took the same effect. In the end, the SPIONs effects on xenograft mice was examed by intratumoral injection. The result showed that the combination group could greatly decrease the tumor volume and prolong the lifespan of mice. In sum, the result indicated that overdose SPIONs induced ROS generation, and excessive ROS induced by combination of SPIONs and SMF contribute to autophagy formation, which play a apoptosis-promoting role that formed as a platform to recruits initiate the caspase activities.

Quantitative assessment of microvasculopathy in arcAß mice with USPIO-enhanced gradient echo MRI.

Magnetic resonance imaging employing administration of iron oxide-based contrast agents is widely used to visualize cellular and molecular processes in vivo. In this study, we investigated the ability of [Formula: see text] and quantitative susceptibility mapping to quantitatively assess the accumulation of ultrasmall superparamagnetic iron oxide (USPIO) particles in the arcAß mouse model of cerebral amyloidosis. Gradient-echo data of mouse brains were acquired at 9.4 T after injection of USPIO. Focal areas with increased magnetic susceptibility and [Formula: see text] values were discernible across several brain regions in 12-month-old arcAß compared to 6-month-old arcAß mice and to non-transgenic littermates, indicating accumulation of particles after USPIO injection. This was concomitant with higher [Formula: see text] and increased magnetic susceptibility differences relative to cerebrospinal fluid measured in USPIO-injected compared to non-USPIO-injected 12-month-old arcAß mice. No differences in [Formula: see text] and magnetic susceptibility were detected in USPIO-injected compared to non-injected 12-month-old non-transgenic littermates. Histological analysis confirmed focal uptake of USPIO particles in perivascular macrophages adjacent to small caliber cerebral vessels with radii of 2-8 µm that showed no cerebral amyloid angiopathy. USPIO-enhanced [Formula: see text] and quantitative susceptibility mapping constitute quantitative tools to monitor such functional microvasculopathies.

Iron oxide/manganese oxide co-loaded hybrid nanogels as pH-responsive magnetic resonance contrast agents.

This work described a proof of concept study of hybrid nanogel-based magnetic resonance contrast agents, SPIO@GCS/acryl/biotin@Mn-gel, abb. as SGM, for highly efficient, pH-responsive T1 and T2 dual-mode magnetic resonance imaging (MRI). SGM have been synthesized by assembling superparamagnetic iron oxide particles into polysaccharide nanoclusters, followed by in-situ reduction of the manganese species on the clusters and a final mild polymerization. The dual-mode SGM showed an interesting pH-responsiveness in in vitro MRI, with both T1 and T2 relaxivities turned "ON" in the acidic environment, along with an increase in the r1 and r2 relaxivity values by 1.7-fold (from 8.9 to 15.3 mM(-1) S(-1)) and 4.9-fold (from 45.7 to 226 mM(-1) S(-1)), due to desirable silencing and de-silencing effects. This interesting acidic-responsiveness was further verified in vivo with both significantly brightened signal of tumor tissue in T1-weighted MR images and a darkened signal in T2-weighted MR images 50 min post-injection of SGM. This smart hybrid nanogel may serve as a promising candidate for further studies of dual-mode (T1 and T2) contrast agents in MRI, due to its high stability, interesting pH-response mechanism and indicative imaging of tumors.

In vivo tracking of human adipose-derived stem cells labeled with ferumoxytol in rats with middle cerebral artery occlusion by magnetic resonance imaging.

Ferumoxytol, an iron replacement product, is a new type of superparamagnetic iron oxide approved by the US Food and Drug Administration. Herein, we assessed the feasibility of tracking transplanted human adipose-derived stem cells labeled with ferumoxytol in middle cerebral artery occlusion-injured rats by 3.0 T MRI in vivo. 1 × 10(4) human adipose-derived stem cells labeled with ferumoxytol-heparin-protamine were transplanted into the brains of rats with middle cerebral artery occlusion. Neurologic impairment was scored at 1, 7, 14, and 28 days after transplantation. T2-weighted imaging and enhanced susceptibility-weighted angiography were used to observe transplanted cells. Results of imaging tests were compared with results of Prussian blue staining. The modified neurologic impairment scores were significantly lower in rats transplanted with cells at all time points except 1 day post-transplantation compared with rats without transplantation. Regions with hypointense signals on T2-weighted and enhanced susceptibility-weighted angiography images corresponded with areas stained by Prussian blue, suggesting the presence of superparamagnetic iron oxide particles within the engrafted cells. Enhanced susceptibility-weighted angiography image exhibited better sensitivity and contrast in tracing ferumoxytol-heparin-protamine-labeled human adipose-derived stem cells compared with T2-weighted imaging in routine MRI.

A concise review of magnetic resonance molecular imaging of tumor angiogenesis by targeting integrin αvß3 with magnetic probes.

Angiogenesis is an essential step for the growth and spread of malignant tumors. Accurate detection and quantification of tumor angiogenesis is important for early diagnosis of cancers as well as post therapy assessment of antiangiogenic drugs. The cell adhesion molecule integrin αvß3 is a specific marker of angiogenesis, which is highly expressed on activated and proliferating endothelial cells, but generally not on quiescent endothelial cells. Therefore, in recent years, many different approaches have been developed for imaging αvß3 expression, for the detection and characterization of tumor angiogenesis. The present review provides an overview of the current status of magnetic resonance molecular imaging of integrin αvß3, including the new development of high sensitive contrast agents and strategies for improving the specificity of targeting probes and the biological effects of imaging probes on αvß3 positive cells.

Imaging of the peripheral nervous system.

This chapter summarizes progress in the evaluation of peripheral nerve (PN) lesions and disorders by imaging techniques encompassing magnetic resonance imaging (MRI) and nerve ultrasound (US). Due to the radiation exposure and limited sensitivity in soft tissue contrast, computed-tomography (CT) plays no significant role in the diagnostic work-up of PN disorders. MRI and US are complementary techniques for the evaluation of peripheral nerves, each having particular advantages and disadvantages. Nerve injury induces intrinsic MRI signal alterations on T2-weighted sequences in degenerating or demyelinating nerve segments as well as in corresponding muscle groups exhibiting denervation which can be exploited diagnostically. Nerve US is based on changes in the nerve echotexture due to tumor formation or focal enlargement caused by entrapment or inflammation. Both MRI and US provide morphological information on the precise site and extent of nerve injury. While US has the advantage of easy accessibility, providing images with superior spatial resolution at low cost, MRI shows better soft tissue contrast and better image quality for deep-lying nerve structures since imaging is not hindered by bone. Recent advances have remarkably increased spatial resolution of both MRI and US making imaging indispensible for the elucidation of causes of nerve compression, peripheral nerve tumors, and focal inflammatory conditions. Both MRI and US further guide neurosurgical exploration and can simplify treatment. Importantly, imaging can reveal treatable conditions even in the absence of gross electrophysiological alterations, illustrating its increasing role in clinical practice. In experimental settings, novel molecular and cellular MRI contrast agents allow in-vivo assessment of nerve regeneration as well as monitoring of neuroinflammation. Depending on further clinical development, contrast-enhanced MRI has the potential to follow cellular responses over time in vivo and to overcome the current limitations of histological assessment of nerve afflictions. Further advances in contrast-enhanced US has the potential for developing into a tool for the assessment of nerve blood perfusion, paving the way for better assessments of ischemic neuropathies.

Assessment of biological characteristics of mesenchymal stem cells labeled with superparamagnetic iron oxide particles in vitro.

Mesenchymal stem cell (MSC) transplantation provides a novel strategy for the treatment of human disease. MR imaging (MRI) is able to track transplanted stem cells labeled with superparamagnetic iron oxide (SPIO) in vivo. However, the effect of SPIO upon labeled MSCs remains unclear on a cellular level. In this study, the biological characteristics of rat MSCs labeled with home-synthesized SPIO particles were evaluated. The MSCs were isolated from the bone marrow of 5 adult Sprague-Dawley rats and labeled with home-synthesized SPIO particles at a final iron concentration of 20 µg/ml. Labeled MSCs were confirmed with Prussian blue staining and transmission electron microscopy. The quantity of iron per cell was determined by atomic absorption spectrometry. Cell viability, proliferation, membranous antigen and multiple differentiation ability were compared between labeled and unlabeled MSCs. The rat MSCs were effectively labeled and the labeling efficiency was approximately 100%, as revealed by Prussian blue staining. The SPIO particles located in the endosomal vesicles of the MSCs were confirmed by transmission electron microscopy. No significant differences were observed in cell viability, proliferation, membranous antigen and multiple differentiation ability between the labeled and unlabeled MSCs (P>0.05). In conclusion, MSCs are able to be effectively labeled by home-synthesized SPIO particles without influencing their main biological characteristics.