Superparamagnetic Iron Oxide Contrast Research Articles

Unveiling the next generation of MRI contrast agents: current insights and perspectives on ferumoxytol-enhanced MRI.

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a pivotal tool for global disease diagnosis and management. Since its clinical availability in 2009, the off-label use of ferumoxytol for ferumoxytol-enhanced MRI (FE-MRI) has significantly reshaped CE-MRI practices. Unlike MRI that is enhanced by gadolinium-based contrast agents, FE-MRI offers advantages such as reduced contrast agent dosage, extended imaging windows, no nephrotoxicity, higher MRI time efficiency and the capability for molecular imaging. As a leading superparamagnetic iron oxide contrast agent, ferumoxytol is heralded as the next generation of contrast agents. This review delineates the pivotal clinical applications and inherent technical superiority of FE-MRI, providing an avant-garde medical-engineering interdisciplinary lens, thus bridging the gap between clinical demands and engineering innovations. Concurrently, we spotlight the emerging imaging themes and new technical breakthroughs. Lastly, we share our own insights on the potential trajectory of FE-MRI, shedding light on its future within the medical imaging realm.

A Method for Evaluating the T2∗-weighting Effect in MRI

To propose a method for evaluating the T2*-weighting effect in MRI. Multiple solutions with different concentrations of a superparamagnetic iron oxide contrast agent were made and their signal intensities on T2*-weighted images were measured. The relationship between iron concentration and signal intensity was determined, and we simulated an iron concentration map representing a simplified model of a brain microbleed and converted the pixel values in the map to signal intensity based on the determined relationship, generating a simulated T2*-weighted image. An 'S-value' parameter was defined to evaluate the low-intensity regions in the simulated image. S-values were obtained using T2*-weighted sequences acquired with different echo time (TE) values on three MRI scanners (Philips 1.5 T, GE 3.0 T, and Siemens 3.0 T). Another parameter (A-value) defined by the American Society for Testing and Materials (ASTM-F2119) for assessing artifacts was applied to evaluate the weighting effect in the T2*-weighted image of a laboratory-made susceptibility-effect phantom. With all three scanners, the S-values increased as the TE increased, indicating enhancement of the T2*-weighting effect. For every TE, the S-values obtained for the Philips scanner were the largest, followed by those for the GE and Siemens scanners. The results of this comparative evaluation were similar to those obtained using A-values. Comparisons with the established A-value parameter showed our proposed method for the quantitative evaluation of the T2*-weighting effect using S-values to be valid. The proposed method has the advantage that the S-values do not depend on a specific susceptibility-effect phantom.

Revealing vascular abnormalities and measuring small vessel density in multiple sclerosis lesions using USPIO

Background and PurposeMultiple Sclerosis (MS) is a progressive, inflammatory, neuro-degenerative disease of the central nervous system (CNS) characterized by a wide range of histopathological features including vascular abnormalities. In this study, an ultra-small superparamagnetic iron oxide (USPIO) contrast agent, Ferumoxytol, was administered to induce an increase in susceptibility for both arteries and veins to help better reveal the cerebral microvasculature. The purpose of this work was to examine the presence of vascular abnormalities and vascular density in MS lesions using high-resolution susceptibility weighted imaging (SWI). MethodsSix subjects with relapsing remitting MS (RRMS, age = 47.3 ± 11.8 years with 3 females and 3 males) and fourteen age-matched healthy controls were scanned at 3 T with SWI acquired before and after the infusion of Ferumoxytol. Composite data was generated by registering the FLAIR data to the high resolution SWI data in order to highlight the vascular information in MS lesions. Both the central vein sign (CVS) and, a new measure, the multiple vessel sign (MVS) were identified, along with any vascular abnormalities, in the lesions on pre- and post-contrast SWI-FLAIR fusion data. The small vessel density within the periventricular normal-appearing white matter (NAWM) and the periventricular lesions were compared for all subjects. ResultsAveraged across two independent raters, a total of 530 lesions were identified across all patients. The total number of lesions with vascularity on pre- and post-contrast data were 287 and 488, respectively. The lesions with abnormal vascular behavior were broken up into following categories: small lesions appearing only at the vessel boundary; dilated vessels within the lesions; and developmental venous angiomas. These vessel abnormalities observed within lesions increased from 55 on pre-contrast data to 153 on post-contrast data. Finally, across all the patients, the periventricular lesional vessel density was significantly higher (p < 0.05) than that of the periventricular NAWM. ConclusionsBy inducing a super-paramagnetic susceptibility in the blood using Ferumoxytol, the vascular abnormalities in the RRMS patients were revealed and small vessel densities were obtained. This approach has the potential to monitor the venous vasculature present in MS lesions, catalogue their characteristics and compare the vascular structures spatially to the presence of lesions. These enhanced vascular features may provide new insight into the pathophysiology of MS.

Histologic Distribution and Characteristics on MR Imaging of Ultrasmall Superparamagnetic Iron Oxide in Ethyl-nitrosourea-induced Endogenous Rat Glioma.

Purpose:(1) To evaluate the enhancement patterns of an ultrasmall superparamagnetic iron oxide contrast agent (USPIO-CA) compared with those of a gadolinium-based contrast agent (Gd-BCA). (2) To compare the histologic distribution of USPIO-related iron particles (USPIO-IPs) with the USPIO-enhancement area in the early vascular and in the cellular imaging phase (E- and L-phase, respectively) after intravenous CA administration.Methods:We performed USPIO-enhanced MRI of N-ethyl-N-nitrosourea (ENU)-induced endogenous rat glioma, including spin-echo (SE) T1-weighted images (T1WIs) and gradient-recalled-echo (GRE) T2-weighted images (T2WIs), before and at 3–6 h after USPIO-CA administration for E-phase images. For L-phase images, MRI was performed at 16–19 and 62–69 h after administration. Two observers determined the USPIO-enhancement area on E-phase images and Gd-enhancement areas. We compared the USPIO-enhancement size (USPIO-ES) and Gd-ES on SE T1WIs, and the hypo-intense USPIO-ES on GRE T2WIs and Gd-ES using the Wilcoxon signed-rank test. In addition, two raters visually evaluated the correspondence between the histologic distribution of USPIO-IPs and the USPIO-enhancement area on corresponding GRE T2WIs at each phase using a 3-rating scale.Results:Significantly smaller hyper-intense, hypo-intense and combined hyper-/hypo-intense areas were observed on USPIO-enhanced SE T1WIs compared with Gd-enhanced images (all P < 0.001). The hypo-intense USPIO-ES on GRE T2WIs was significantly smaller than the Gd-ES (P = 0.001). The distribution of USPIO-IPs on histopathological specimen and USPIO-enhancement on GRE T2WIs exhibited poor agreement in 5 of 9 tumors with enhancement from rats sacrificed early. The distribution of microglia containing USPIO-IPs corresponded with the pattern of USPIO-enhancement in the 2 tumors with late enhancement.Conclusion:The enhancement pattern and size of USPIO-CA in a rat glioma model were statistically different from those of Gd-BCA. Our histological data suggests that USPIO-enhanced MRI offers vascular bed imaging in E-phase and might depict the intra-tumoral distribution of immune effector cells in L-phase.

Detection of Macrophage Localization in the Abdominal Aortic Aneurysm Wall Using Ex Vivo Superparamagnetic Iron Oxide–Enhanced Magnetic Resonance Imaging

Macrophages in the aneurysmal wall play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Superparamagnetic iron oxide (SPIO) is a macrophage-specific contrast agent that results in negative enhancement on magnetic resonance imaging (MRI). SPIO-enhanced MRI targeting the intraluminal thrombus of AAAs has been previously reported. However, macrophages in the media and adventitia of AAA wall have not been investigated in detail. This study aimed to evaluate macrophage localization using SPIO-enhanced MRI in the media and adventitia of AAA wall, as macrophages play a crucial role in AAA pathogenesis. Here, we included study and control patients planning to undergo open surgery for AAA. The study patients received SPIO injection 2days preoperatively (the SPIO group, n=7), whereas the control patients did not receive this injection (the control group). Exvivo MRI was performed on the harvested AAA wall in the SPIO group during the surgery. The concordance between the number of macrophages and berlin blue (BB)-stained areas was histologically evaluated in both groups. Moreover, the concordance between regions of interest in MR images and BB-stained areas was evaluated. The proportion of BB-stained macrophages was higher in the SPIO group (0.93; interquartile range [IQR], 0.83-0.95) than in the control group (0.03; IQR, 0.026-0.11) (P<0.05), indicating uptake of SPIO by macrophages in the AAA wall. A significant positive correlation was found between the number of BB-stained macrophages and BB-stained areas using Kendall rank correlation coefficient in the SPIO group (τ=0.58; P<0.05). Significant correlations were found in the distributions of the region of interest of SPIO-enhanced MRI and BB-stained areas in the media and adventitia in 5 of 7 patients. Macrophages present in the media and adventitia of the AAA wall showed an uptake of the SPIO contrast agent injected 2days prior, which were then detected by exvivo MRI. This suggests that SPIO-enhanced MR images help detect the localization of macrophages on the AAA wall, indicating its potential to serve as a novel index for AAA pathogenesis.

Cellular Magnetic Resonance Imaging with Superparamagnetic Iron Oxide: Methods and Applications in Cancer

Superparamagnetic iron oxide (SPIO) has been used as a contrast agent for magnetic resonance imaging (MRI) since the late 20th century. With the development of SPIO, cellular MRI has been recognized as a suitable and highly sensitive noninvasive modality with great potential to benefit translational research. In addition to its traditional diagnostic property, latest advances have conferred SPIO with multifunctionality. Several SPIO-based theranostic probes with targeting, therapeutic and diagnosis components have been successfully developed. The objective of this brief review is to summarize the characteristics, synthesizing methods, labeling approaches and current applications of SPIO-based cellular MRI in oncology. Herein, we first depict the history, classification and advantages of and the differences between T1- and T2/T2*-based SPIO contrast agents for cancer treatment. Second, we outline current coating materials that render SPIO less toxic and more biocompatible to mammalian cells. Finally, the cell labeling techniques and applications of SPIO-based MRI for tracking mesenchymal stem cell tumor–homing in preclinical models are introduced.

OA31 - Radiotherapy Guided by Ultrasmall Superparamagnetic Iron Oxide Contrast MRI Staging for Patients with High Risk, Clinically Node Positive or Recurrent Prostate Cancer

OA31 - Radiotherapy Guided by Ultrasmall Superparamagnetic Iron Oxide Contrast MRI Staging for Patients with High Risk, Clinically Node Positive or Recurrent Prostate Cancer

Abstract P3-03-26: Challenging dual modality as the gold standard for sentinel lymph node biopsy in breast cancer: A systematic review and network meta-analysis of novel and conventional techniques

Abstract The current gold standard for sentinel lymph node biopsy in breast cancer patients is the dual modality technique (radioisotope and blue dye). Owing to the limitations inherent to the use of radioisotopes, the uptake of this method is limited to approximately 50-60% of breast cancer patients in developed countries. In most centers worldwide with no access to radioisotopes, blue dye is the most commonly employed technique as it is relatively cheap, easy to administer with no radiation exposure risk. However, the use of blue dye is associated with a high false negative rate. We performed a systematic review and network meta-analysis to compare the performance of blue dye and radioisotope against three novel techniques, namely indocyanine green fluorescence (ICG), superparamagnetic iron oxide (SPIO) nanoparticles and contrast enhanced ultrasound (CEUS) using microbubbles. This is the first network meta-analysis synthesizing direct as well as indirect comparisons of performance among different techniques in terms of sentinel lymph node detection and false negative rate, thereby allowing a more robust quantitative analysis. In comparison to a published systematic review on this topic in 2014, the current review had almost double the number of patients and trials included with a total of 35 cohort studies and 4,244 patients. Our systematic review suggested that two of the techniques, indocyanine green fluorescence (ICG) and superparamagnetic iron oxide (SPIO) nanoparticles have consistently performed better than the blue dye technique and similar to gold standard dual modality. Hence, in centres where blue dye was used as a single modality, perhaps ICG and SPIO can offer a viable alternative with improved performance. Future research should focus on the economic evaluations of various techniques as well as to explore the cost-effectiveness and cost-utility of adopting new techniques in the clinical setting. Table 2Pooled estimates of RR and averages on detection rate and false negative rate from network meta-analysis (RR)ICG1.03 (0.96, 1.11)1.08 (1.00, 1.15)1.03 (0.99, 1.06)1.05 (0.96, 1.14)1.12 (1.07, 1.16)*0.67 (0.21, 2.08)SPIO1.03 (0.95, 1.12)0.99 (0.93, 1.06)1.01 (0.95, 1.07)1.09 (1.01, 1.18)*0.16 (0.52, 0.05)0.24 (0.05, 1.08)CEUS0.96 (0.89, 1.02)0.98 (0.90, 1.06)1.03 (0.98, 1.11)0.64 (0.36, 1.13)0.96 (0.34, 2.75)4.00 (1.17, 13.7)*Tc1.00 (0.91, 1.10)1.09 (1.04, 1.15)*0.56 (0.14, 2.23)0.84 (0.36, 1.93)3.49 (0.67, 18.2)0.87 (0.24, 3.23)Tc/BD1.09 (0.98, 1.16)0.29 (0.16, 0.54)*0.45 (0.14, 1.45)1.85 (0.68, 6.06)0.44 (0.20, 0.96)*0.57 (0.13, 2.51)BDBD: Blue dye; CEUS: Contrast-enhanced ultrasound; ICG: Indocyanine green; SPIO: Superparamagnetic iron oxide; Tc: Technetium-99; Tc/BD: Combined used of Technetium-99 and blue dye Top right panel reported the pooled RRs of detection rate from network meta-analysis, and the technique name below each RR was the reference group; Bottom left panel reported the pooled RRs of false negative rate from network meta-analysis, and the technique name to the right of each RR was the reference group; *: Statistical significant with P value &amp;lt; 0.05 Citation Format: Mok CW, Zheng Q, Shi L, Tan S-M. Challenging dual modality as the gold standard for sentinel lymph node biopsy in breast cancer: A systematic review and network meta-analysis of novel and conventional techniques [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-26.

A Multimodal Molecular Imaging Study Evaluates Pharmacological Alteration of the Tumor Microenvironment to Improve Radiation Response.

: Hypoxic zones in solid tumors contribute to radioresistance, and pharmacologic agents that increase tumor oxygenation prior to radiation, including antiangiogenic drugs, can enhance treatment response to radiotherapy. Although such strategies have been applied, imaging assessments of tumor oxygenation to identify an optimum time window for radiotherapy have not been fully explored. In this study, we investigated the effects of α-sulfoquinovosylacyl-1,3-propanediol (SQAP or CG-0321; a synthetic derivative of an antiangiogenic agent) on the tumor microenvironment in terms of oxygen partial pressure (pO2), oxyhemoglobin saturation (sO2), blood perfusion, and microvessel density using electron paramagnetic resonance imaging, photoacoustic imaging, dynamic contrast-enhanced MRI with Gd-DTPA injection, and T2*-weighted imaging with ultrasmall superparamagnetic iron oxide (USPIO) contrast. SCCVII and A549 tumors were grown by injecting tumor cells into the hind legs of mice. Five days of daily radiation (2 Gy) combined with intravenous injection of SQAP (2 mg/kg) 30 minutes prior to irradiation significantly delayed growth of tumor xenografts. Three days of daily treatment improved tumor oxygenation and decreased tumor microvascular density on T2*-weighted images with USPIO, suggesting vascular normalization. Acute effects of SQAP on tumor oxygenation were examined by pO2, sO2, and Gd-DTPA contrast-enhanced imaging. SQAP treatment improved perfusion and tumor pO2 (ΔpO2: 3.1 ± 1.0 mmHg) and was accompanied by decreased sO2 (20%-30% decrease) in SCCVII implants 20-30 minutes after SQAP administration. These results provide evidence that SQAP transiently enhanced tumor oxygenation by facilitating oxygen dissociation from oxyhemoglobin and improving tumor perfusion. Therefore, SQAP-mediated sensitization to radiation in vivo can be attributed to increased tumor oxygenation. SIGNIFICANCE: A multimodal molecular imaging study evaluates pharmacological alteration of the tumor microenvironment to improve radiation response.

Ultra-small superparamagnetic iron oxide contrast agents for lymph node staging of high-risk prostate cancer

Ultrasmall superparamagnetic particles of iron oxide (USPIOs) imaged with magnetic resonance imaging (MRI) have been proposed as an experimental method for visualizing lymph node (LN) metastases. The method does not require ionizing radiation, yet can detect small nodes that are involved with metastases. USPIOs are naturally taken up by macrophages that deposit in the normal LN creating a low signal region in normal areas; areas within the node that do not show this loss of signal are likely involved by tumor although there can be other causes (fibrosis or inflammation). However, the lack of approved USPIOs that are clinically available hinders adoption and larger studies. The proposed indications for USPIO MRI, including specific compounds and imaging methods are discussed.

Effects of mesoscopic susceptibility and transverse relaxation on diffusion NMR

Measuring molecular diffusion is based on the spatial encoding of spin-carrying molecules using external Larmor frequency gradients. Intrinsic variations of the Larmor frequency and of the local relaxation rate, commonly present in structurally complex samples, interfere with the external gradients, confounding the NMR-measured diffusion propagator. Here we consider, analytically and numerically, the effects of the mesoscopic magnetic structure (local susceptibility and transverse relaxation rate) on the NMR-measured “apparent” diffusion coefficient (ADC). We show that in the fast diffusion regime, when molecules spread past the correlation length of the magnetic structure, the deviation of ADC from the genuine diffusion coefficient increases as a power law of diffusion time. The effect of mesoscopically varying transverse relaxation rate is sequence-independent and always leads to the decrease of ADC with time, whereas the effect sign for the mesoscopic Larmor frequency variations depends on the presence of refocussing pulses in the diffusion sequence. We connect this unexpectedly diverging with time ADC discrepancy to the spatial statistics of the mesocopic magnetic structure. Our results establish a novel kind of NMR contrast tied to the microstructural complexity, and can be applied to discern the mesoscopic effects of hindrances to molecular diffusion, susceptibility variations, and varying local relaxation rate, on the measured diffusion propagator. In particular, we numerically show that the susceptibility effect of a microvascular network is sufficient to explain the observed ADC decrease due to superparamagnetic iron-oxide contrast injection in monkeys.

Ferucarbotran-loaded red blood cells as long circulating MRI contrast agents: first in vivo results in mice.

The encapsulation of superparamagnetic iron oxide contrast agents in red blood cells (RBCs) could overcome their rapid removal by reticulo-endothelial system improving their stability in blood circulation. Murine ferucarbotran-loaded RBCs were tested in vivo as new contrasting agents in MRI application. A superior visualization of organs and cerebral vessels was evidenced in ferucarbotran-loaded RBCs-treated mice compared with the controls. The signal enhancement lasted for days, while the contrast from bulk ferucarbotran disappeared after few minutes. Ferucarbotran-loaded RBCs showed to improve diagnostic imaging and their use may extend the time frame for MRI and magnetic resonance angiography since to date the time frame for data acquisition has been limited to the first pass.

Real-time MRI for precise and predictable intra-arterial stem cell delivery to the central nervous system

Stem cell therapy for neurological disorders reached a pivotal point when the efficacy of several cell types was demonstrated in small animal models. Translation of stem cell therapy is contingent upon overcoming the challenge of effective cell delivery to the human brain, which has a volume ∼1000 times larger than that of the mouse. Intra-arterial injection can achieve a broad, global, but also on-demand spatially targeted biodistribution; however, its utility has been limited by unpredictable cell destination and homing as dictated by the vascular territory, as well as by safety concerns. We show here that high-speed MRI can be used to visualize the intravascular distribution of a superparamagnetic iron oxide contrast agent and can thus be used to accurately predict the distribution of intra-arterial administered stem cells. Moreover, high-speed MRI enables the real-time visualization of cell homing, providing the opportunity for immediate intervention in the case of undesired biodistribution.

A New Method for Preparing Mesenchymal Stem Cells and Labeling with Ferumoxytol for Cell Tracking by MRI

Mesenchymal stem cells (MSCs) are among the major stem cells used for cell therapy and regenerative medicine. In-vivo cell-tracking by magnetic resonance imaging (MRI) is crucial for regenerative medicine, allowing verification that the transplanted cells reach the targeted sites. Cellular MRI combined with superparamagnetic iron-oxide (SPIO) contrast agents is an effective cell-tracking method. Here, we are reporting a new “bio-mimicry” method by making use of the “in-vivo environment” of MSCs to prepare native MSCs, so that (i) the phagocytic activity of cultured MSCs can be recovered and expanded MSCs can be ex-vivo labeled with Ferumoxytol, which is currently the only FDA approved SPIO nanoparticles for human use. Using our new method, 7-day cultured MSCs regain the capability to take up Ferumoxytol and exhibit an intracellular iron concentration of 2.50 ± 0.50 pg/MSC, comparable to that obtained by using Ferumoxytol-heparin-protamine nanocomplex; and (ii) cells can be re-sized to more native size, reducing from 32.0 ± 7.2 μm to 19.5 ± 5.2 μm. Our method can be very useful for expanding MSCs and labeling with Ferumoxytol, without the need for transfection agents and/or electroporation, allowing cell-tracking by MRI in both pre-clinical and clinical studies.

Mechanistic interrogation of combination bevacizumab/dual PI3K/mTOR inhibitor response in glioblastoma implementing novel MR and PET imaging biomarkers.

Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Using an MR/PET molecular imaging biomarker approach, we investigated the response to combining BEV with the mTOR/PI3K inhibitor BEZ235. Tumours were established by orthotopically implanting U87MG-luc2 cells in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion-weighted-MRI, T2-weighted and T2*-weighted before and after administration of superparamagnetic iron oxide contrast agent. Maps for changes in relaxation rates (ΔR2, ΔR2* and apparent diffusion coefficient) were calculated. Vessel size index and microvessel density index were derived. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) PET and O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) PET were further performed and tumour endothelium/proliferation markers assessed by immunohistochemistry. Treatment with BEV resulted in a pronounced decrease in tumour volume (T2-weighted MRI). No additive effect on tumour volume was observed with the BEV/BEZ235 combination compared with BEV monotherapy. The Ki67 proliferation index and [(18)F]FLT uptake studies were used to support the observations. Using ΔR2* and ΔR2 values, respectively, the BEV/BEZ235 combination significantly reduced tumour microvessel volume in comparison to BEV alone. Decreased microvessel density index was further observed in animals treated with the combination, supported by von Willebrand factor (vWF) immunohistochemistry. [(18)F]FET uptake was decreased following treatment with BEV alone, but was not further reduced following treatment with the combination. vWF immunohistochemistry analysis showed that the mean tumour vessel size was increased in all cohorts. Assessing MR imaging biomarker parameters together with [(18)F]FET and [(18)F]FLT PET provided information on mechanism of action of the drug combination and clues as to potential clinical responses. Following translation to clinical use, treatment with a BEV/BEZ235 combination could reduce peritumoral oedema obviating the requirement for steroids. The use of hypothesis-driven molecular imaging studies facilitates the preclinical evaluation of drug response. Studies of this kind may more accurately predict the clinical potential of the BEV/BEZ235 combinationregimen as a novel therapeutic approach in oncology.

Labeling Human Melanoma Cells With SPIO: In Vitro Observations.

Objectives:To use the superparamagnetic iron oxide (SPIO) contrast agent Resovist (±transfection agent) to label human melanoma cells and determine its effects on cellular viability, microstructure, iron quantity, and magnetic resonance imaging (MRI) detectability.Materials and Methods:Human SK-Mel28 melanoma cells were incubated with Resovist (±liposomal transfection agent DOSPER). The cellular iron content was measured, and labeled cells were examined at 1.5 T and 3.0 T. The intracellular and extracellular distributions of the contrast agent were assessed by light and electron microscopy.Results:The incubation of melanoma cells with SPIO does not interfere with cell viability or proliferation. The iron is located both intracellularly and extracellularly as iron clusters associated with the exterior of the cell membrane. Despite thorough washing, the extracellular SPIO remained associated with the cell membrane. The liposomal transfection agent does not change the maximum achievable cellular iron content but promotes a faster iron uptake. The MRI detectability persists for at least 7 days.Conclusion:The transfection agent DOSPER facilitates the efficient labeling of human metastatic melanoma cells with Resovist. Our findings raise the possibility that other Resovist-labeled cells may collect associated extracellular nanoparticles. The SPIO may be available to other iron-handling cells and not completely compartmentalized during the labeling procedure.

Imaging Inflammation in Cerebrovascular Disease.

Imaging inflammation in large intracranial artery pathology may play an important role in the diagnosis of and risk stratification for a variety of cerebrovascular diseases. Looking beyond the lumen has already generated widespread excitement in the stroke community, and the potential to unveil molecular processes in the vessel wall is a natural evolution to develop a more comprehensive understanding of the pathogenesis of diseases, such as ICAD and brain aneurysms.

Evaluation of ultrasmall superparamagnetic iron oxide contrast agent labeling of equine cord blood and bone marrow mesenchymal stromal cells.

To evaluate the efficacy and effects of labeling equine umbilical cord blood (UCB)- and bone marrow (BM)-derived multipotent mesenchymal stromal cells (MSCs) with an ultrasmall superparamagnetic iron oxide (SPIO) contrast agent and the detection of labeled MSCs by use of MRI. UCB MSCs from placental tissues of 5 foals and BM MSCs from 5 horses. UCB and BM MSC cultures were seeded in duplicate (5,000 cells/cm(2)). One duplicate was incubated with SPIO (50 μg/mL); the other was processed identically, but without SPIO. Mesenchymal stromal cells were expanded in triplicates for 5 passages and assessed for viability and proliferative capacity, labeling efficacy, and labeled cell proportion. For MRI detection, 5 × 10(6) labeled BM MSCs from passage 1 or 2 were injected into a collagenase-induced superficial digital flexor tendon defect of an equine cadaveric forelimb from 2 horses. For passages 1, 2, and 3, labeling efficacy and cell proportion for UCB MSCs (99.6% [range, 98.8% to 99.9%], 16.6% [range, 6.5% to 36.1%], and 1.0% [range, 0.4% to 2.8%], respectively) were significantly higher than for BM MSCs (99.2% [range, 97.8% to 99.7%], 4.5% [range, 1.6% to 11.8%], and 0.2% [range, 0.1% to 0.6%], respectively). Labeling was not detectable after passage 3. Viability of MSCs was not affected, but cell doubling time increased in labeled MSCs, compared with that of unlabeled MSCs. On MRI 3-D T2*-weighted fast gradient echo sequences, decreased signal intensity was observed for BM passage 1 MSCs. Equine UCB and BM MSCs were labeled with SPIO at high efficiencies.

Long-Term MRI Cell Tracking after Intraventricular Delivery in a Patient with Global Cerebral Ischemia and Prospects for Magnetic Navigation of Stem Cells within the CSF

BackgroundThe purpose of the study was to evaluate the long-term clinical tracking of magnetically labeled stem cells after intracerebroventricular transplantation as well as to investigate in vitro feasibility for magnetic guidance of cell therapy within large fluid compartments.MethodAfter approval by our Institutional Review Board, an 18-month-old patient, diagnosed as being in a vegetative state due to global cerebral ischemia, underwent cell transplantation to the frontal horn of the lateral ventricle, with umbilical cord blood-derived stem cells labeled with superparamagnetic iron oxide (SPIO) contrast agent. The patient was followed over 33 months with clinical examinations and MRI. To evaluate the forces governing the distribution of cells within the fluid compartment of the ventricular system in vivo, a gravity-driven sedimentation assay and a magnetic field-driven cell attraction assay were developed in vitro.ResultsTwenty-four hours post-transplantation, MR imaging (MRI) was able to detect hypointense cells in the occipital horn of the lateral ventricle. The signal gradually decreased over 4 months and became undetectable at 33 months. In vitro, no significant difference in cell sedimentation between SPIO-labeled and unlabeled cells was observed (p = NS). An external magnet was effective in attracting cells over distances comparable to the size of human lateral ventricles.ConclusionsMR imaging of SPIO-labeled cells allows monitoring of cells within lateral ventricles. While the initial biodistribution is governed by gravity-driven sedimentation, an external magnetic field may possibly be applied to further direct the distribution of labeled cells within large fluid compartments such as the ventricular system.

Development and characterization of an antibody-labeled super-paramagnetic iron oxide contrast agent targeting prostate cancer cells for magnetic resonance imaging.

In this study we developed, characterized and validated in vitro a functional superparagmagnetic iron-oxide based magnetic resonance contrast agent by conjugating a commercially available iron oxide nanoparticle, Molday ION Rhodamine-B Carboxyl (MIRB), with a deimmunized mouse monoclonal antibody (muJ591) targeting prostate-specific membrane antigen (PSMA). This functional contrast agent is intended for the specific and non-invasive detection of prostate cancer cells that are PSMA positive, a marker implicated in prostate tumor progression and metastasis. The two-step carbodiimide reaction used to conjugate the antibody to the nanoparticle was efficient and we obtained an elemental iron content of 1958±611 per antibody. Immunofluorescence microscopy and flow cytometry showed that the conjugated muJ591:MIRB complex specifically binds to PSMA-positive (LNCaP) cells. The muJ591:MIRB complex reduced cell adhesion and cell proliferation on LNCaP cells and caused apoptosis as tested by Annexin V assay, suggesting anti-tumorigenic characteristics. Measurements of the T2 relaxation time of the muJ591:MIRB complex using a 400 MHz Innova NMR and a multi-echo spin-echo sequence on a 3T MRI (Achieva, Philips) showed a significant T2 relaxation time reduction for the muJ591:MIRB complex, with a reduced T2 relaxation time as a function of the iron concentration. PSMA-positive cells treated with muJ591:MIRB showed a significantly shorter T2 relaxation time as obtained using a 3T MRI scanner. The reduction in T2 relaxation time for muJ591:MIRB, combined with its specificity against PSMA+LNCaP cells, suggest its potential as a biologically-specific MR contrast agent.