Search Results (20)

Goal: This study evaluates the feasibility and outcome of a personalized MRI-based liver SBRT treatment planning platform with the SPION contrast agent Ferumoxytol^® (Sandoz Inc.; Princeton, NJ, USA) to maintain a superior real-time visualization of liver tumors and volumes of functional hepatic parenchyma for radiotherapy planning throughout multi-fractionated liver SBRT with online plan adaptations on an Elekta Unity 1.5 T MR-Linac (Elekta; Stockholm, Sweden). Materials and Methods: Patients underwent SPION-enhanced MRI on the Elekta Unity MR-Linac for improved tumor and functional hepatic parenchyma visualization. An automated contouring algorithm was applied for the delineation and subsequent guided avoidance of functional liver parenchyma volumes (FLVs) on the SPION-enhanced MR-Linac. Radiation dose constraints were adapted exclusively to FLV. Local control, toxicity, and survival were assessed with at least 6-month radiographic follow-up. Pre- and post-transplant outcomes were analyzed in the subset of patients with HCC and hepatic cirrhosis who completed SBRT as a bridge to liver transplant. Model of End-Stage Liver Disease (MELD-Na) was used to score hepatic function before and after SBRT. Results: With a median follow-up of 23 months (range: 3–40 months), 23 HCC patients (26 lesions treated) and 9 patients (14 lesions treated) with hepatic metastases received SBRT (mean dose: 48 Gy, range: 36–54 Gy) in 1–5 fractions. Nearly all patients in this study had pe-existing liver conditions, including hepatic cirrhosis (23), prior TACE (7), prior SBRT (18), or history of hepatic resection (2). Compared to the non-contrast images, SPIONs improved tumor visibility on post-SPION images on the background of negatively enhancing functionally active hepatic parenchyma. Prolonged SPION-contrast retention within hepatic parenchyma enabled per-fraction treatment adaptation throughout the entire multi-fraction treatment course. FLV loss (53%, p < 0.0001) was observed in cirrhotic patients, but functional and anatomic liver volumes remained consistent in non-cirrhotic patients. Mean dose to FLV was maintained within the liver threshold tolerance to radiation in all patients after the optimization of Step-and-Shoot Intensity-Modulated Radiotherapy (SS-IMRT) on the SPION-enhanced MRI-Linac. No radiation-induced liver disease was observed within 6 months post-SBRT, and the MELD-Na score in cirrhotic patients was not significantly elevated at 3-month intervals after SBRT completion. Conclusions: SPION Ferumoxytol^® administered intravenously as an alternative MRI contrast agent on the day of SBRT planning produces a long-lasting contrast effect between tumors and functional hepatic parenchyma for precision targeting and guided avoidance during the entire course of liver SBRT, enabling fast and accurate online plan adaptation on the 1.5 T Elekta Unity MR-Linac. This approach demonstrates a safe and effective bridging therapy for patients with hepatic cirrhosis, leading to low toxicity and favorable transplant outcomes. Full article

Nanotechnology has provided considerable advancements in an array of disciplines. Recently, it has been shown that ferumoxytol, a magnetite (Fe₃O₄) nanoparticle, can be oxidized by ionizing radiation. Ferumoxytol nanoparticles have high stability, and thus can be hypothesized that they have dosimetric potential. In this study, it has been observed that xylenol orange, a colorimetric detector of Fe³⁺ used for conventional Fricke dosimetry, was not able to detect radiolytic changes in ferumoxtyol. Electron paramagnetic resonance (EPR) spectroscopy was more readily able to evaluate the oxidation of ferumoxytol. EPR spectroscopy revealed that oxidation of 500 nM ferumoxytol in H₂O was linear up to 20 Gy. This concentration, however, was unable to estimate the delivered dose from a Small Animal Radiation Research Platform system, as a 6 Gy dose was estimated to be 1.37 Gy, which represents a 79.2% underestimation of the dose delivered. Thus, while the high stability of Fe₃O₄ nanoparticles is attractive for use in pre-clinical radiation dosimetry, further radiochemical evaluation may be required before considering them for this application. Full article

Ferumoxytol injection, also known as Feraheme^®, is an approved IV injectable iron supplement and an experimental MRI contrast agent. Initially, it was approved as an IV bolus agent, but its use was later limited to a slow infusion drip due to high levels of infusion reactions. We collected various batches of ferumoxytol with expiration dates ranging from 2010 to 2025 and compared their size and zeta potential. Since nanoparticle surface properties can affect infusion reactions, we conducted a dot blot immunoassay to measure complement C3 opsonization with ferumoxytol preparations. We observed differences in nanoparticle size and zeta potential between batches and a 2.5-fold variation in complement activation. Interestingly, older batches from 2010 showed more uniform size distribution and lower complement activation than some of the newer batches. This finding may be valuable to the nanomedicine community and regulatory authorities. Full article

Superparamagnetic iron oxide nanoparticles (SPION) have attracted great attention not only for therapeutic applications but also as an alternative magnetic resonance imaging (MRI) contrast agent that helps visualize liver tumors during MRI-guided stereotactic body radiotherapy (SBRT). SPION can provide functional imaging of liver parenchyma based upon its uptake by the hepatic resident macrophages or Kupffer cells with a relative enhancement of malignant tumors that lack Kupffer cells. However, the radiomodulating properties of SPION on liver macrophages are not known. Utilizing human monocytic THP-1 undifferentiated and differentiated cells, we characterized the effect of ferumoxytol (Feraheme^®), a carbohydrate-coated ultrasmall SPION agent at clinically relevant concentration and therapeutically relevant doses of gamma radiation on cultured cells in vitro. We showed that ferumoxytol affected both monocytes and macrophages, increased the resistance of monocytes to radiation-induced cell death and inhibition of cell activity, and supported the anti-inflammatory phenotype of human macrophages under radiation. Its effect on human cells depended on the duration of SPION uptake and was radiation dose-dependent. The results of this pilot study support a strong mechanism-based optimization of SPION-enhanced MRI-guided liver SBRT for primary and metastatic liver tumors, especially in patients with liver cirrhosis awaiting a liver transplant. Full article

Iron deficiency (ID) is by far the most common nutritional disorder in developing and developed countries. When left untreated, ID leads to anemia. Although the usually recommended treatment for iron deficiency anemia (IDA) is oral iron therapy with countless products, such therapy necessitates administration for >3–6 months with questionable patient compliance since most oral iron products have an unpleasant metallic aftertaste and cause intestinal side effects. In addition, in certain gastrointestinal conditions, such as inflammatory bowel diseases or untreated gluten-sensitive enteropathy, oral iron therapy is contraindicated or unsuccessful. Intravenous iron is considered safe in adults, where adverse events are mild and easily managed. The experience with parenteral iron in children is much more limited, and many pediatricians appear reluctant to use it because of uncorroborated fears of serious anaphylactic reactions. In the current article, we thoroughly review the available pediatric literature on the use of all commercially available parenteral iron products except ferumoxytol, which was recently removed from the market. We conclude that parenteral iron appears to be safe in children; it works faster than oral iron, and the newer third-generation products allow replacement of the total iron deficit in a single sitting. Full article

Recently, the FDA-approved iron oxide nanoparticle, ferumoxytol, has been found to enhance the efficacy of pharmacological ascorbate (AscH⁻) in treating glioblastoma, as AscH⁻ reduces the Fe³⁺ sites in the nanoparticle core. Given the iron oxidation state specificity of T2* relaxation mapping, this study aims to investigate the ability of T2* relaxation to monitor the reduction of ferumoxytol by AscH⁻ with respect to its in vitro therapeutic enhancement. This study employed an in vitro glioblastoma MRI model system to investigate the chemical interaction of ferumoxytol with T₂* mapping. Lipofectamine was utilized to facilitate ferumoxytol internalization and assess intracellular versus extracellular chemistry. In vitro T₂* mapping successfully detected an AscH⁻-mediated reduction of ferumoxytol (25.6 ms versus 2.8 ms for FMX alone). The T₂* relaxation technique identified the release of Fe²⁺ from ferumoxytol by AscH⁻ in glioblastoma cells. However, the high iron content of ferumoxytol limited T2* ability to differentiate between the external and internal reduction of ferumoxytol by AscH⁻ (ΔT₂* = +839% for external FMX and +1112% for internal FMX reduction). Notably, the internalization of ferumoxytol significantly enhances its ability to promote AscH⁻ toxicity (dose enhancement ratio for extracellular FMX = 1.16 versus 1.54 for intracellular FMX). These data provide valuable insights into the MR-based nanotheranostic application of ferumoxytol and AscH⁻ therapy for glioblastoma management. Future developmental efforts, such as FMX surface modifications, may be warranted to enhance this approach further. Full article

Engineered magnetic nanoparticles (MNPs) are emerging as advanced tools for medical applications. The coating of MNPs using polyelectrolytes (PEs) is a versatile means to tailor MNP properties and is used to optimize MNP functionality. Dendritic cells (DCs) are critical regulators of adaptive immune responses. Functionally distinct DC subsets exist, either under steady-state or inflammatory conditions, which are explored for the specific treatment of various diseases, such as cancer, autoimmunity, and transplant rejection. Here, the impact of the PE coating of ferumoxytol for uptake into both inflammatory and steady-state DCs and the cellular responses to MNP labeling is addressed. Labeling efficiency by uncoated and PE-coated ferumoxytol is highly variable in different DC subsets, and PE coating significantly improves the labeling of steady-state DCs. Uncoated ferumoxytol results in increased cytotoxicity of steady-state DCs after labeling, which is abolished by the PE coating, while no increased cell death is observed in inflammatory DCs. Furthermore, uncoated and PE-coated ferumoxytol appear immunologically inert in inflammatory DCs, but they induce activation of steady-state DCs. These results show that the PE coating of MNPs can be applied to endow particles with desired properties for enhanced uptake and cell type-specific responses in distinct target DC populations. Full article

Cardiac magnetic resonance imaging and angiography have a crucial role in the diagnostic evaluation and follow up of pediatric and adult patients with congenital heart disease. Although much of the information required of advanced imaging studies can be provided by standard gadolinium-enhanced magnetic resonance imaging, the limitations of precise bolus timing, long scan duration, complex imaging protocols, and the need to image small structures limit more widespread use of this modality. Recent experience with off-label diagnostic use of ferumoxytol has helped to mitigate some of these barriers. Approved by the U.S. FDA for intravenous treatment of anemia, ferumoxytol is an ultrasmall superparamagnetic iron oxide nanoparticle that has a long blood pool residence time and high relaxivity. Once metabolized by macrophages, the iron core is incorporated into the reticuloendothelial system. In this work, we aim to summarize the evolution of ferumoxytol-enhanced cardiovascular magnetic resonance imaging and angiography and highlight its many applications for congenital heart disease. Full article

Prostate cancer (PCa) is one of the most common cancers in men. For detection and diagnosis of PCa, non-invasive methods, including magnetic resonance imaging (MRI), can reduce the risk potential of surgical intervention. To explore the molecular characteristics of the tumor, we investigated the applicability of ferumoxytol in PCa in a xenograft mouse model in two different tumor volumes, 500 mm³ and 1000 mm³. Macrophages play a key role in tumor progression, and they are able to internalize iron-oxide particles, such as ferumoxytol. When evaluating T2*-weighted sequences on MRI, a significant decrease of signal intensity between pre- and post-contrast images for each tumor volume (n = 14; p < 0.001) was measured. We, furthermore, observed a higher signal loss for a tumor volume of 500 mm³ than for 1000 mm³. These findings were confirmed by histological examinations and laser ablation inductively coupled plasma-mass spectrometry. The 500 mm³ tumors had 1.5% iron content (n = 14; σ = 1.1), while the 1000 mm³ tumors contained only 0.4% iron (n = 14; σ = 0.2). In vivo MRI data demonstrated a correlation with the ex vivo data (R² = 0.75). The results of elemental analysis by inductively coupled plasma-mass spectrometry correlated strongly with the MRI data (R² = 0.83) (n = 4). Due to its long retention time in the blood, biodegradability, and low toxicity to patients, ferumoxytol has great potential as a contrast agent for visualization PCa. Full article

Atherosclerosis is a progressive inflammatory vascular disease characterized by endothelial dysfunction and plaque burden. Extracellular matrix (ECM)-associated plasma proteins play an important role in disease development. Our magnetic resonance imaging (MRI) study investigates the feasibility of using two different molecular MRI probes for the simultaneous assessment of ECM-associated intraplaque albumin deposits caused by endothelial damage and progressive inflammation in atherosclerosis. Male apolipoprotein E-deficient (ApoE^-/-)-mice were fed a high-fat diet (HFD) for 2 or 4 months. Another ApoE^-/--group was treated with pravastatin and received a HFD for 4 months. T1- and T2*-weighted MRI was performed before and after albumin-specific MRI probe (gadofosveset) administration and a macrophage-specific contrast agent (ferumoxytol). Thereafter, laser ablation inductively coupled plasma mass spectrometry and histology were performed. With advancing atherosclerosis, albumin-based MRI signal enhancement and ferumoxytol-induced signal loss areas in T2*-weighted MRI increased. Significant correlations between contrast-to-noise-ratio (CNR) post-gadofosveset and albumin stain (R² = 0.78, p < 0.05), and signal loss areas in T2*-weighted MRI with Perls’ Prussian blue stain (R² = 0.83, p < 0.05) were observed. No interference of ferumoxytol with gadofosveset enhancement was detectable. Pravastatin led to decreased inflammation and intraplaque albumin. Multi-target MRI combining ferumoxytol and gadofosveset is a promising method to improve diagnosis and treatment monitoring in atherosclerosis. Full article

Tumor-associated macrophages (TAMs) in breast cancer regulate inflammation, immunosuppression, angiogenesis, and metastasis. However, TAM imaging remains a clinical challenge. Ferumoxytol has long been an FDA-approved superparamagnetic iron oxide nanoparticle (SPION) preparation used as an intravenous (IV) treatment for iron-deficiency anemia. Given its high transverse relaxivity, ferumoxytol produces a negative image contrast upon cellular uptake in T₂-weighted magnetic resonance imaging (MRI) studies. Here we evaluated ferumoxytol as a contrast agent to image/quantify TAMs in an aggressive mouse model of breast cancer: We developed [Fe]MRI to measure the 5-dimensional function c(x,y,z,t), where c is the concentration of nanoparticle iron and {x,y,z,t} is the 4-dimensional set of tumor space-time coordinates. Ferumoxytol SPIONs are readily phagocytosed (~10⁴/cell) by the F4/80⁺CD11b⁺ TAMs within breast tumors. Quantitative [Fe]MRIs served to determine both the spatial and the temporal distribution of the SPION iron, and hence to measure [Fe] = c(x,y,z,t), a surrogate for TAM density. In single-dose pharmacokinetic studies, after an IV dose of 5 mg/Kg iron, [Fe]MRI measurements showed that c(x,y,z,t) within breast tumors peaked around [Fe] = 70 μM at 42 h post-administration, and decayed below the [Fe]MRI detection limit (~2 μM) by day 7. There was no SPION uptake in control organs (muscle and adipose tissue). Optical microscopy of tissue sections confirmed that F4/80⁺CD11b⁺ TAMs infiltrated the tumors and accumulated SPION iron. Our methodology and findings have translational applications for breast cancer patients. Full article

Anemia affects millions of patients with chronic kidney disease (CKD) and prompt iron supplementation can lead to reductions in the required dose of erythropoiesis-stimulating agents, thereby reducing medical costs. Oral and intravenous (IV) traditional iron preparations are considered far from ideal, primarily due to gastrointestinal intolerability and the potential risk of infusion reactions, respectively. Fortunately, the emergence of novel iron replacement therapies has engendered a paradigm shift in the treatment of iron deficiency anemia in patients with CKD. For example, oral ferric citrate is an efficacious and safe phosphate binder that increases iron stores to maintain hemoglobin levels. Additional benefits include reductions in fibroblast growth factor 23 levels and the activation of 1,25 dihydroxyvitamin D. The new-generation IV iron preparations ferumoxytol, iron isomaltoside 1000, and ferric carboxymaltose are characterized by a reduced risk of infusion reactions and are clinically well tolerated as a rapid high-dose infusion. In patients undergoing hemodialysis (HD), ferric pyrophosphate citrate (FPC) administered through dialysate enables the replacement of ongoing uremic and HD-related iron loss. FPC transports iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Moreover, this paper summarizes recent advancements of hypoxia-inducible factor prolyl hydroxylase inhibitors and future perspectives in renal anemia management. Full article

After relative erythropoietin deficiency, iron deficiency is the second most important contributing factor for anemia in chronic kidney disease (CKD) patients. Iron supplementation is a crucial part of the treatment of anemia in CKD patients, and intravenous (IV) iron supplementation is considered to be superior to per os (PO) iron supplementation. The differences between the available formulations are poorly characterized. This report presents results from pairwise and network meta-analyses carried out after a comprehensive search in sources of published and unpublished studies, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommendations (International prospective register of systematic reviews PROSPERO reference ID: CRD42020148155). Meta-analytic calculations were performed for the outcome of non-response to iron supplementation (i.e., hemoglobin (Hgb) increase of <0.5–1.0 g/dL, or initiation/intensification of erythropoiesis-stimulating agent (ESA) therapy, or increase/change of iron supplement, or requirements of blood transfusion). A total of 34 randomized controlled trials (RCT) were identified, providing numerical data for analyses covering 93.7% (n = 10.097) of the total study population. At the network level, iron supplementation seems to have a more protective effect against the outcome of non-response before the start of dialysis than once dialysis is initiated, and some preparations seem to be more potent (e.g., ferumoxytol, ferric carboxymaltose), compared to the rest of iron supplements assessed (surface under the cumulative ranking area (SUCRA) > 0.8). This study provides parameters for adequately following-up patients requiring iron supplementation, by presenting the most performing preparations, and, indirectly, by making it possible to identify good responders among all patients treated with these medicines. Full article

The therapeutic potential of mesenchymal stem cells (MSCs) is limited, as many cells undergo apoptosis following administration. In addition, the attraction of immune cells (predominately macrophages) to the site of implantation can lead to MSC rejection. We implemented a trimodal imaging technique to monitor the fate of transplanted MSCs and infiltrating macrophages in vivo. MSCs were labeled with an iron oxide nanoparticle (ferumoxytol) and then implanted within the hind limb muscle of 10 C57BI/6 mice. Controls received unlabeled MSCs (n = 5). A perfluorocarbon agent was administered intravenously for uptake by phagocytic macrophages in situ; 1 and 12 days later, the ferumoxytol-labeled MSCs were detected by proton (1H) magnetic resonance imaging (MRI) and magnetic particle imaging (MPI). Perfluorocarbon-labeled macrophages were detected by fluorine-19 (19F) MRI. 1H/19F MRI was acquired on a clinical scanner (3 T) using a dual-tuned surface coil and balanced steady-state free precession (bSSFP) sequence. The measured volume of signal loss and MPI signal declined over 12 days, which is consistent with the death and clearance of iron-labeled MSCs. 19F signal persisted over 12 days, suggesting the continuous infiltration of perfluorocarbon-labeled macrophages. Because MPI and 19F MRI signals are directly quantitative, we calculated estimates of the number of MSCs and macrophages present over time. The presence of MSCs and macrophages was validated with histology following the last imaging session. This is the first study to combine the use of iron- and fluorine-based MRI with MPI cell tracking. Full article

A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B₁-insensitive R₁ measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned at 3-T MRI including structural imaging, and R₁ and R₂* mapping. Participants were scanned (i) before and (ii) after USPIO (ferumoxytol) infusion, and again at (iii) 24–30 h and (iv) one month. Absolute and blood-normalised changes in R₁ and R₂* were measured in white matter (WM), deep grey matter (GM), white matter hyperintensity (WMH) and stroke lesion regions. R₁ measurements were accurate across a wide range of values. R₁ (p < 0.05) and R₂* (p < 0.01) mapping detected increases in relaxation rate in all tissues immediately post-USPIO and at 24–30 h. R₂* returned to baseline at one month. Blood-normalised R₁ and R₂* changes post-infusion and at 24–30 h were similar, and were greater in GM versus WM (p < 0.001). Narrower distributions were seen with R₂* than for R₁ mapping. R₁ and R₂* changes were correlated at 24–30 h (p < 0.01). MRI relaxometry permits quantitative evaluation of USPIO uptake; R₂* appears to be more sensitive to USPIO than R₁. Our data are explained by intravascular uptake alone, yielding estimates of cerebral blood volume, and did not support parenchymal uptake. Ferumoxytol appears to be eliminated at 1 month. The approach should be valuable in future studies to quantify both blood-pool USPIO and parenchymal uptake associated with inflammatory cells or blood-brain barrier leak. Full article