Irinotecan-loaded magnetite-silica core-shell systems for colorectal cancer treatment.

Colorectal cancer represents a worldwide spread type of cancer and it is regarded as one of the leading death causes, along with lung, breast, and prostate cancers. Since conventional surgical resection and chemotherapy proved limited efficiency, the use of alternative drug delivery systems that ensure the controlled release of cytostatic agents possess immense potential for treatment. In this regard, the present study aimed to develop and evaluate the efficiency of a series of irinotecan-loaded magnetite-silica core-shell systems. The magnetite particles were obtained through a solvothermal treatment, while the silica shell was obtained through the Stöber method directly onto the surface of magnetite particles. Subsequently, the core-shell systems were physico-chemically and morpho-structurally evaluated trough X-ray diffraction (XRD) and (high-resolution) transmission electron microscopy ((HR-)TEM) equipped with a High Annular Angular Dark Field Detector (HAADF) for elemental mapping. After the irinotecan loading, the drug delivery systems were evaluated through Fourier-transform infrared spectroscopy (FT-IR), thermogravimetry and differential scanning calorimetry (TG-DSC), and UV-Vis spectrophotometry. Additionally, the Brunauer-Emmett-Teller (BET) method was employed for determining the surface area and pore volume of the systems. The biological functionality of the core-shells was investigated through the MTT assay performed on both normal and cancer cells. The results of the study confirmed the formation of highly crystalline magnetite particles comprising the core and mesoporous silica layers of sizes varying between 2 and 7 nm as the shell. Additionally, the drug loading and release was dependent on the type of the silica synthesis procedure, since the lack of hexadecyltrimethylammonium bromide (CTAB) resulted in higher drug loading but lower cumulative release. Moreover, the nanostructured systems demonstrated a targeted efficiency towards HT-29 colorectal adenocarcinoma cells, as in the case of normal L929 fibroblast cells, the cell viability was higher than for the pristine drug. In this manner, this study provides the means and procedures for developing drug delivery systems with applicability in the treatment of cancer.

A case of severe anaphylactic reaction after administration of diagnostic-dose ferumoxytol in a pediatric patient.

We describe a case of anaphylaxis during administration of intravenous (IV) ferumoxytol as a magnetic resonance imaging (MRI) contrast agent in a 4-year-old patient with complicated past medical history including YARS genetic mutation with resultant liver failure and deceased donor liver transplantation, stage IV chronic kidney disease (CKD), and hypertension. The patient was noted to have labored breathing 4 min after initiation of ferumoxytol infusion and was subsequently rapidly intubated and returned to the intensive care unit (ICU) for monitoring. Anaphylactic reactions to therapeutic doses of ferumoxytol led to issuance of a black box warning by the FDA in 2015. Adverse reactions to lower-dose ferumoxytol used in diagnostic imaging, however, are rare and there has been a paucity of documented anaphylactic reactions in the literature.

A randomized double-blind pilot study to evaluate the efficacy, safety, and tolerability of intravenous iron versus oral iron for the treatment of restless legs syndrome in patients with iron deficiency anemia.

Restless legs syndrome (RLS) is a neurological disorder that can have a profound effect on sleep and quality of life. Idiopathic RLS is associated with brain iron insufficiency despite normal peripheral iron stores. There is, however, a five- to six-fold increase in prevalence of RLS in patients with iron deficiency anemia (IDA). Several open-label trials have demonstrated symptomatic improvement in RLS following treatment of IDA using oral or intravenous iron supplementation. To date, there have been no randomized double-blind controlled trials of intravenous iron compared with oral iron for the treatment of RLS patients with IDA. In the current study, oral ferrous sulfate and ferumoxytol were compared for efficacy and speed of response for treatment of RLS occurring in patients with IDA. The planned recruitment for this study was 70 patients with RLS and IDA, to be randomly assigned 1:1 to oral or intravenous iron, using double-blind, double-dummy procedures. At Week 6, the primary outcomes of Clinical Global Impression-Improvement score and change from baseline in the International Restless Legs Syndrome Study Group rating scale score were assessed. Due to challenges, performing the clinical trial during the COVID-19 pandemic, final-week data were found missing for 30 patients. As a result, in order to maintain the prespecified statistical analysis, an additional 30 patients were recruited. Both IV and oral iron were associated with a marked improvement in RLS symptoms, with no statistically significant difference between treatment groups. No serious adverse events were observed in either treatment group.

Vascular mapping of the human hippocampus using Ferumoxytol-enhanced MRI.

The hippocampus is a small but complex grey matter structure that plays an important role in spatial and episodic memory and can be affected by a wide range of pathologies including vascular abnormalities. In this work, we introduce the use of Ferumoxytol, an ultra-small superparamagnetic iron oxide (USPIO) agent, to induce susceptibility in the arteries (as well as increase the susceptibility in the veins) to map the hippocampal micro-vasculature and to evaluate the quantitative change in tissue fractional vascular density (FVD), in each of its subfields. A total of 39 healthy subjects (aged 35.4 ± 14.2 years, from 18 to 81 years old) were scanned with a high-resolution (0.22×0.44×1 mm3) dual-echo SWI sequence acquired at four time points during a gradual increase in Ferumoxytol dose (final dose = 4 mg/kg). The volumes of each subfield were obtained automatically from the pre-contrast T1-weighted data. The dynamically acquired SWI data were co-registered and adaptively combined to reduce the blooming artifacts from large vessels, preserving the contrast from smaller vessels. The resultant SWI data were used to segment the hippocampal vasculature and to measure the FVD ((volume occupied by vessels)/(total volume)) for each subfield. The hippocampal fissure, along with the fimbria, granular cell layer of the dentate gyrus and cornu ammonis layers (except for CA1), showed higher micro-vascular FVD than the other parts of hippocampus. The CA1 region exhibited a significant correlation with age (R = -0.37, p < 0.05). demonstrating an overall loss of hippocampal vascularity in the normal aging process. Moreover, the vascular density reduction was more prominent than the age correlation with the volume reduction (R = -0.1, p > 0.05) of the CA1 subfield, which would suggest that vascular degeneration may precede tissue atrophy.

Fe3O4@piroctone olamine magnetic nanoparticles: Synthesize and therapeutic potential in cutaneous leishmaniasis.

BACKGROUND: In recent years, magnetic nanoparticles (NMP) as novel materials have been widely used for biomedical, diagnostic and therapeutic purposes like microbial infection therapy. The purpose of this study is to synthesize PO coated iron oxide magnetic nanoparticles (Fe3O4@PO NPs) and their anti-leishmanial effects in vitro and in vivo against cutaneous leishmaniasis. METHODS: Fe3O4 magnetic nanoparticles were synthesized by the coprecipitation of Fe2 + and Fe3 + ions and used as a nanocarrier for the production of Fe3O4@PO NPs. The in vitro antileishmanial effects of PO-coated Fe3O4 NPs and Fe3O4 NPs (10-200 µg/mL) was determined against the intracellular amastigotes of Leishmania major (MRHO/IR/75/ER) and, then, examined on cutaneous leishmaniasis induced in male BALB/c mice by L. major. The rate of infectivity, production of nitric oxide (NO), and cytotoxic activates of Fe3O4 NPs and Fe3O4@PO NPs on J774-A1 macrophage cells were determined. RESULTS: The size scattering of the Fe3O4 NPs and Fe3O4@PO NPs were in the range among 1-40 and 5-55 nm, respectively. The obtained IC50 values were 62.3 ± 2.15 µg/mL, 31.3 ± 2.26 µg/mL, and 52.6 ± 2.15 µg/mL for the Fe3O4 NPs and Fe3O4@PO NPs, and MA, respectively. The results revealed that the mean number of parasites and the mean diameter of the lesions was considerably (p < 0.05) decreased in the infected mice treated with Fe3O4 NPs and Fe3O4@PO NPs. The Fe3O4 NPs and Fe3O4@PO NPs significantly (p < 0.05) prompted the production of NO as a dose-dependent manner. The promastigotes pre-incubated in Fe3O4 NPs and Fe3O4@PO NPs at the concentration of 5 µg/mL had the ability to infect only 41.7% and 28.3% of the macrophages cells. The selectivity index of greater than 10 for Fe3O4 NPs and Fe3O4@PO NPs showed its safety to the J774-A1 macrophage cells and specificity to the parasite. CONCLUSION: The results of this survey indicated the high potency of Fe3O4@PO NPs to inhibit the growth of amastigote forms of L. major as well as recovery and improvement CL induced by L. major in BALB/c mice without significant cytotoxicity. The results also indicated that, although the possible anti-leishmanial mechanisms of Fe3O4@PO NPs have not been clearly understood, however, the triggering of NO may be considered as one of the possible anti-leishmanial mechanisms of these nanoparticles. However, additional studies, in particular in clinical contexts, are mandatory.

Can the biomolecular corona induce an allergic reaction?-A proof-of-concept study.

Ferumoxytol nanoparticles are being used clinically for the treatment of anemia and molecular imaging in patients. It is well documented that while most patients tolerate ferumoxytol well, a small percentage of patients (i.e., 0.01%) develop severe allergic reactions. The purpose of our proof-of-concept study was to determine whether patients with or without hypersensitivity reactions have specific protein corona profiles around ferumoxytol nanoparticles. In a retrospective, institutional review board approved pilot study, we enrolled 13 pediatric patients (5 girls, 8 boys, mean age 16.9 ± 8.2 years) who received a ferumoxytol-enhanced magnetic resonance imaging and who did (group 1, n = 5) or did not (group 2, n = 8) develop an allergic reaction. Blood samples of these patients were incubated with ferumoxytol, and the formation of a hard protein corona around ferumoxytol nanoparticles was measured by dynamic light scattering, zeta potential, and liquid chromatography-mass spectrometry. We also performed in vitro immune response analyses to randomly selected coronas from each group. Our results provide preliminary evidence that ex vivo analysis of the biomolecular corona may provide useful and predictive information on the possibility of severe allergic reactions to ferumoxytol nanoparticles. In the future, patients with predisposition of an allergic reaction to ferumoxytol may be diagnosed based on the proteomic patterns of the corona around ferumoxytol in their blood sample.

Efficacy of ferumoxytol versus sodium ferric gluconate in anemia management in outpatient hemodialysis patients: A prospective cohort study.

BACKGROUND: Intravenous iron is one of the main therapies for anemia management in hemodialysis-dependent patients. Data comparing the efficacy of ferumoxytol versus other parenteral iron supplements are scarce. The objective of the study was to compare the efficacy of ferumoxytol with that of sodium ferric gluconate in outpatient hemodialysis patients. MATERIALS AND METHODS: A prospective, observational study was conducted in outpatients receiving ferumoxytol 510 mg once or twice quarterly compared to sodium ferric gluconate 125 mg weekly in a single center hemodialysis center in Ontario, Canada. Patient demographics, hemoglobin levels, iron indices, iron doses, and erythropoiesis-stimulating agent (ESA) doses were collected. RESULTS: The study sample consisted of 291 observations from 173 patients. Generalized estimating equations of multiple linear regression modeling were conducted to compare the outcomes while adjusting for baseline scores. Approximately 25% of the study participants received ferumoxytol while 75% received sodium ferric gluconate. Patients treated were mainly males (58.4%), and the mean age was 68.73 (SD ± 13.03) years. Both groups did not show significant differences in their hemoglobin levels (Wald z = 0.54; p = 0.46), ESA utilization at 3 months (Wald z = 0.20; p = 0.65), and TSAT levels (Wald z = 3.45; p = 0.06). However, the iron levels (Wald z = 4.24; p = 0.04) and ferritin levels (Wald z = 5.14; p = 0.02) were higher in the ferric gluconate group (Wald z = 58.78; p ≤ 0.001), and patients who received ferumoxytol received more blood transfusions as compared to those who received sodium ferric gluconate (χ2 = 16.71; p ≤ 0.001). CONCLUSION: Both iron products maintained hemoglobin levels, but patients receiving ferumoxytol had lower iron indices and received more blood transfusions compared to patients who received sodium ferric gluconate.

Influence of the Aspect Ratio of Iron Oxide Nanorods on Hysteresis-Loss-Mediated Magnetic Hyperthermia.

Owing to the problems associated with conventional cancer treatment methods, magnetic hyperthermia-based cancer therapy has gained importance recently. Achieving the desired heating effect at the site of the tumor with a minimal concentration of iron oxide nanoparticles (IONPs) and a safer field is necessary to explore the advantages of hyperthermia. For one to address this challenge, biocompatible IONPs with a desirable magnetic response at a tolerable field are necessary. In this work, magnetic shape anisotropy of iron oxide nanorods (NR) of different lengths (70, 115, 170, and 210 nm) with different aspect ratios ranging from 1.55 to 3.2 was explored to achieve higher hysteresis loss, in turn leading to better hyperthermia efficiency. The magnetic properties of the NRs with respect to the applied field were studied using micromagnetic simulation. Even though the nanorods with high aspect ratio showed a higher hysteresis loss of 69485 J/m3 at 2000 Oe, the field required to attain it was high and well beyond the safety limit. From nanorods of various aspect ratios, the nanorod with a lower aspect ratio of 1.55 and a length of 70 nm exhibited a better hysteresis loss and specific absorption rate (SAR) value of 4214 W g-1 was achieved at a frequency and alternating magnetic field of 400 kHz and 800 Oe, respectively. The PEGylated GO-Nanorod of 70 nm exhibited excellent antitumor efficacy in 4T1 tumor model mice by obstructing the tumor progression within a safer dosage and field.

Comparison of respiratory toxicity of TiO2 and Fe3O4 nanoparticles after intravenous instillation: an experimental study.

OBJECTIVE: Nanomaterials consist of particles smaller than 100 nm - nanoparticles (NPs). Their nano dimensions allow them to penetrate through various membranes and enter into the bloodstream and disseminate into different body organs. Massive expansion of nanotechnologies together with production of new nanoparticles which have not yet been in contact with living organisms may pose a potential health problem. It is therefore necessary to investigate the health impact of NPs after experimental exposure. Comparison of the effect of TiO2 and NPs Fe3O4 in Wistar rats at time intervals 1, 7, 14 and 28 days was performed by studying the cytotoxic effect in the isolated inflammatory cells from bronchoalveolar lavage (BAL). METHODS: Wistar rats were intravenously (i.v.) given a suspension of NPs TiO2 or Fe3O4 (coated by sodium oleate) via the tail vein. After time intervals of 1, 7, 14 and 28 days, we sacrificed the animals under anaesthesia, performed BAL and isolated the cells. The number of animals in the individual groups was 7-8. We examined the differential count of BAL cells (alveolar macrophages - AM, polymorphonuclear leukocytes - PMN, lymphocytes - Ly); viability and phagocytic activity of AM; the proportion of immature and polynuclear cells and enzymes - cathepsin D - CAT D, lactate dehydrogenase - LDH and acid phosphatase - ACP. RESULTS: We found that TiO2 NPs are relatively inert - without induction of inflammatory and cytotoxic response. Exposure to nanoparticles Fe3O4 induced - under the same experimental conditions - in comparison with the control and TiO2 a more extensive inflammatory and cytotoxic response, albeit only at 1, 7 and 14 days after injection. CONCLUSIONS: The results suggest that TiO2 and Fe3O4 nanoparticles used in our study were transferred from the bloodstream to the respiratory tract, but this effect was not observed at 28 days after i.v. injection, probably due to their removal from the respiratory tract.

Brain Iron Assessment after Ferumoxytol-enhanced MRI in Children and Young Adults with Arteriovenous Malformations: A Case-Control Study.

Background Iron oxide nanoparticles are an alternative contrast agent for MRI. Gadolinium deposition has raised safety concerns, but it is unknown whether ferumoxytol administration also deposits in the brain. Purpose To investigate whether there are signal intensity changes in the brain at multiecho gradient imaging following ferumoxytol exposure in children and young adults. Materials and Methods This retrospective case-control study included children and young adults, matched for age and sex, with brain arteriovenous malformations who received at least one dose of ferumoxytol from January 2014 to January 2018. In participants who underwent at least two brain MRI examinations (subgroup), the first and last available examinations were analyzed. Regions of interests were placed around deep gray structures on quantitative susceptibility mapping and R2* images. Mean susceptibility and R2* values of regions of interests were recorded. Measurements were assessed by linear regression analyses: a between-group comparison of ferumoxytol-exposed and unexposed participants and a within-group (subgroup) comparison before and after exposure. Results Seventeen participants (mean age ± standard deviation, 13 years ± 5; nine male) were in the ferumoxytol-exposed (case) group, 21 (mean age, 14 years ± 5; 11 male) were in the control group, and nine (mean age, 12 years ± 6; four male) were in the subgroup. The mean number of ferumoxytol administrations was 2 ± 1 (range, one to four). Mean susceptibility (in parts per million [ppm]) and R2* (in inverse seconds [sec-1]) values of the dentate (case participants: 0.06 ppm ± 0.04 and 23.87 sec-1 ± 4.13; control participants: 0.02 ppm ± 0.03 and 21.7 sec-1 ± 5.26), substantia nigrae (case participants: 0.08 ppm ± 0.06 and 27.46 sec-1 ± 5.58; control participants: 0.04 ppm ± 0.05 and 24.96 sec-1 ± 5.3), globus pallidi (case participants: 0.14 ppm ± 0.05 and 30.75 sec-1 ± 5.14; control participants: 0.08 ppm ± 0.07 and 28.82 sec-1 ± 6.62), putamina (case participants: 0.03 ppm ± 0.02 and 20.63 sec-1 ± 2.44; control participants: 0.02 ppm ± 0.02 and 19.65 sec-1 ± 3.6), caudate (case participants: -0.1 ppm ± 0.04 and 18.21 sec-1 ± 3.1; control participants: -0.06 ppm ± 0.05 and 18.83 sec-1 ± 3.32), and thalami (case participants: 0 ppm ± 0.03 and 16.49 sec-1 ± 3.6; control participants: 0.02 ppm ± 0.02 and 18.38 sec-1 ± 2.09) did not differ between groups (susceptibility, P = .21; R2*, P = .24). For the subgroup, the mean interval between the first and last ferumoxytol administration was 14 months ± 8 (range, 1-25 months). Mean susceptibility and R2* values of the dentate (first MRI: 0.06 ppm ± 0.05 and 25.78 sec-1 ± 5.9; last MRI: 0.06 ppm ± 0.02 and 25.55 sec-1 ± 4.71), substantia nigrae (first MRI: 0.06 ppm ± 0.06 and 28.26 sec-1 ± 9.56; last MRI: 0.07 ppm ± 0.06 and 25.65 sec-1 ± 6.37), globus pallidi (first MRI: 0.13 ppm ± 0.07 and 27.53 sec-1 ± 8.88; last MRI: 0.14 ppm ± 0.06 and 29.78 sec-1 ± 6.54), putamina (first MRI: 0.03 ppm ± 0.03 and 19.78 sec-1 ± 3.51; last MRI: 0.03 ppm ± 0.02 and 19.73 sec-1 ± 3.01), caudate (first MRI: -0.09 ppm ± 0.05 and 21.38 sec-1 ± 4.72; last MRI: -0.1 ppm ± 0.05 and 18.75 sec-1 ± 2.68), and thalami (first MRI: 0.01 ppm ± 0.02 and 17.65 sec-1 ± 5.16; last MRI: 0 ppm ± 0.02 and 15.32 sec-1 ± 2.49) did not differ between the first and last MRI examinations (susceptibility, P = .95; R2*, P = .54). Conclusion No overall significant differences were found in susceptibility and R2* values of deep gray structures to suggest retained iron in the brain between ferumoxytol-exposed and unexposed children and young adults with arteriovenous malformations and in those exposed to ferumoxytol over time. © RSNA, 2020.

A multicenter study evaluating the effectiveness and safety of single-dose low molecular weight iron dextran vs single-dose ferumoxytol for the treatment of iron deficiency.

There are multiple intravenous (IV) iron formulations available, of which several may be administered as single-dose infusions such as low-molecular weight iron dextran (LMWID), ferumoxytol, ferric carboxymaltose, and ferric derisomaltose. However, administration of ferumoxytol as a single-dose infusion is off-label as it is approved as a two-dose series. Previous studies of ferumoxytol alone support the effectiveness and safety of the single-dose regimen, but there is a paucity of data directly comparing single-dose ferumoxytol to other single-dose IV iron formulations. This multicenter cohort study sought to affirm the safety and effectiveness of single-dose ferumoxytol compared to single-dose LMWID. Overall, 906 patients who received single-dose LMWID (n = 439) or ferumoxytol (n = 467) were identified, of whom 351 met criteria for the primary effectiveness endpoint defined as median change in hemoglobin (Hb), hematocrit (Hct), and ferritin 8 to 12 weeks from baseline. All 906 patients were included for the secondary analysis evaluating the incidence of adverse events (AE) and requirement of additional IV iron infusions. Median change in Hb (LMWID 0.5 g/dL; ferumoxytol 0.8 g/dL; P = .24), Hct (LMWID 1.1%; ferumoxytol 1.25%; P = .89), and ferritin (LMWID 87 ng/dL; ferumoxytol 71 ng/dL; P = .47) was not significantly different between groups. Both groups experienced similar rates of AEs (LMWID 2.3%; ferumoxytol 2.8%; P = .63). The LMWID patients more frequently required additional IV iron infusions (LMWID 28.5%; ferumoxtyol 16.1%; P < .001). These findings support that single-dose ferumoxytol is effective and safe, and that patients may require fewer additional infusions compared to patients who received LMWID.

Sodium Cholate Bile Acid-Stabilized Ferumoxytol-Doxorubicin-Lipiodol Emulsion for Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To develop bile acid-stabilized multimodal magnetic resonance (MR) imaging and computed tomography (CT)-visible doxorubicin eluting lipiodol emulsion for transarterial chemoembolization of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Ferumoxytol, a US Food and Drug Administration-approved iron oxide nanoparticle visible under MR imaging was electrostatically complexed with doxorubicin (DOX). An amphiphilic bile acid, sodium cholate (SC), was used to form a stable dispersion of ferumoxytol-DOX complex in lipiodol emulsion. Properties of the fabricated emulsion were characterized in various component ratios. Release kinetics of DOX were evaluated for the chemoembolization applications. Finally, in vivo multimodal MR imaging/CT imaging properties and potential therapeutic effects upon intra-arterial (IA) infusion bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion were evaluated in orthotopic McA-Rh7777 HCC rat models. RESULTS: DOX complexed with ferumoxytol through electrostatic interaction. Amphiphilic SC bile acid at the interface between the aqueous ferumoxytol-DOX complexes and lipiodol enabled a sustained DOX release (17.2 ± 1.6% at 24 hours) at an optimized component ratio. In McA Rh7777 rat HCC model, IA-infused emulsion showed a significant contrast around tumor in both T2-weighted MR imaging and CT images (P = .044). Hematoxylin and eosin and Prussian blue staining confirmed the local deposition of IA-infused SC bile acid-stabilized emulsion in the tumor. The deposited emulsion induced significant increases in TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) stain-positive cancer cell apoptosis compared to those in a group treated with the nonstabilized emulsion. CONCLUSIONS: SC bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion demonstrated sustained drug release and multimodal MR imaging/CT imaging capabilities. The new lipiodol-based formulation may enhance the therapeutic efficacy of chemoembolization in HCC.

Brain iron deposition after Ferumoxytol-enhanced MRI: A study of Porcine Brains.

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

DOX@Ferumoxytol-Medical Chitosan as magnetic hydrogel therapeutic system for effective magnetic hyperthermia and chemotherapy in vitro.

Magnetic fluid hyperthermia has been one clinical treatment method in malignancy on account of the sufficient heat generation, which originates from hysteresis loss of magnetic nanomedicine in alternating magnetic field. Magnetic nanomedicine can also be employed as drug carrier for chemotherapy. Nevertheless few magnetic nanocarries has been approved in clinic, owing to the high pharmaceutical demand. For broadening the clinical application of current magnetic nanomedicine, novel magnetic hydrogel complex (DOX@FMT-MC) constituted by Doxorubicin, Ferumoxytol and Medical Chitosan was produced for hyperthermia and chemo synergistic therapy. The three materials were approved in clinic. Heat induction in vitro and rheology mesurements suggested this complex succeed in transforming into physical hydrogel when reaching hyperthermia temperature in alternating magnetic field. Drug release experiment implied the complex has the temperature-dependent slow drug release behaviour. Cell apoptosis assay presented that DOX@FMT-MC complex gave enhanced synergistic efficacy with 32.4 % on colon carcinoma cell treatment in vitro, compared to other therapeutic groups. Heat induction in mice subcutaneous xenografted tumour demonstrated the better heating performance of the complex than that of DOX@FMT. The novel hydrogel complex incorporated with three clinical available drugs promises the great potential in tumour synergistic treatment, motivating the clinical indication development of magnetic nanomedicine.

Differentiation of benign and malignant lymph nodes in pediatric patients on ferumoxytol-enhanced PET/MRI.

The composition of lymph nodes in pediatric patients is different from that in adults. Most notably, normal lymph nodes in children contain less macrophages. Therefore, previously described biodistributions of iron oxide nanoparticles in benign and malignant lymph nodes of adult patients may not apply to children. The purpose of our study was to evaluate if the iron supplement ferumoxytol improves the differentiation of benign and malignant lymph nodes in pediatric cancer patients on 18F-FDG PET/MRI. Methods: We conducted a prospective clinical trial from May 2015 to December 2018 to investigate the value of ferumoxytol nanoparticles for staging of children with cancer with 18F-FDG PET/MRI. Ferumoxytol is an FDA-approved iron supplement for the treatment of anemia and has been used "off-label" as an MRI contrast agent in this study. Forty-two children (7-18 years, 29 male, 13 female) received a 18F-FDG PET/MRI at 2 (n=20) or 24 hours (h) (n=22) after intravenous injection of ferumoxytol (dose 5 mg Fe/kg). The morphology of benign and malignant lymph nodes on ferumoxytol-enhanced T2-FSE sequences at 2 and 24 h were compared using a linear regression analysis. In addition, ADCmean-values, SUV-ratio (SUVmax lesion/SUVmean liver) and R2*-relaxation rate of benign and malignant lymph nodes were compared with a Mann-Whitney-U test. The accuracy of different criteria was assessed with a receiver operating characteristics (ROC) curve. Follow-up imaging for at least 6 months served as the standard of reference. Results: We examined a total of 613 lymph nodes, of which 464 (75.7%) were benign and 149 (24.3%) were malignant. On ferumoxytol-enhanced T2-FSE images, benign lymph nodes showed a hypointense hilum and hyperintense parenchyma, while malignant lymph nodes showed no discernible hilum. This pattern was not significantly different at 2 h and 24 h postcontrast (p=0.82). Benign and malignant lymph nodes showed significantly different ferumoxytol enhancement patterns, ADCmean values of 1578 and 852 x10-6 mm2/s, mean SUV-ratios of 0.5 and 2.8, and mean R2*-relaxation rate of 127.8 and 84.4 Hertz (Hz), respectively (all p<0.001). The accuracy of ADCmean, SUV-ratio and pattern (area under the curve (AUC): 0.99; 0.98; 0.97, respectively) was not significantly different (p=0.07). Compared to these three parameters, the accuracy of R2* was significantly lower (AUC: 0.93; p=0.001). Conclusion: Lymph nodes in children show different ferumoxytol-enhancement patterns on MRI than previously reported for adult patients. We found high accuracy (>90%) of ADCmean, SUV-ratio, pattern, and R2* measurements for the characterization of benign and malignant lymph nodes in children. Ferumoxytol nanoparticle accumulation at the hilum can be used to diagnose a benign lymph node. In the future, the delivery of clinically applicable nanoparticles to the hilum of benign lymph nodes could be harnessed to deliver theranostic drugs for immune cell priming.

Development and Assessment of Nano-Technologies for Cancer Treatment: Cytotoxicity and Hyperthermia Laboratory Studies.

Cancer treatment by magnetic hyperthermia offers numerous advantages, but for practical applications many variables still need to be adjusted before developing a controlled and reproducible cancer treatment that is bio-compatible (non-damaging) to healthy cells. In this work, Fe3O4 and CoFe2O4 were synthesized and systematically studied for the development of efficient therapeutic agents for applications in hyperthermia. The biocompatibility of the materials was further evaluated using HepG2 cells as biological model. Colorimetric and microscopic techniques were used to evaluate the interaction of magnetic nano-materials (MNMs) and HepG2 cells. Finally, the behavior of MNMs was evaluated under the influence of an alternating magnetic field (AMF), observing a more efficient temperature increment for CoFe2O4, a desirable behavior for biomedical applications since lower doses and shorter expositions to alternating magnetic field might be required.

Intermodality feature fusion combining unenhanced computed tomography and ferumoxytol-enhanced magnetic resonance angiography for patient-specific vascular mapping in renal impairment.

OBJECTIVE: The purpose of this study was to establish the feasibility of fusing complementary, high-contrast features from unenhanced computed tomography (CT) and ferumoxytol-enhanced magnetic resonance angiography (FE-MRA) for preprocedural vascular mapping in patients with renal impairment. METHODS: In this Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant study, 15 consecutive patients underwent both FE-MRA and unenhanced CT scanning, and the complementary high-contrast features from both modalities were fused to form an integrated, multifeature image. Source images from CT and MRA were segmented and registered. To validate the accuracy, precision, and concordance of fused images to source images, unambiguous landmarks, such as wires from implantable medical devices or indwelling catheters, were marked on three-dimensional (3D) models of the respective modalities, followed by rigid co-registration, interactive fusion, and fine adjustment. We then compared the positional offsets using pacing wires or catheters in the source FE-MRA (defined as points of interest [POIs]) and fused images (n = 5 patients, n = 247 points). Points within 3D image space were referenced to the respective modalities: x (right-left), y (anterior-posterior), and z (cranial-caudal). The respective 3D orthogonal reference axes from both image sets were aligned, such that with perfect registration, a given point would have the same (x, y, z) component values in both sets. The 3D offsets (Δx mm, Δy mm, Δz mm) for each of the corresponding POIs represent nonconcordance between the source FE-MRA and fused images. The offsets were compared using concordance correlation coefficients. Interobserver agreement was assessed using intraclass correlation coefficients and Bland-Altman analyses. RESULTS: Thirteen patients (aged 76 ± 12 years; seven female) with aortic valve stenosis and chronic kidney disease and two patients with thoracoabdominal vascular aneurysms and chronic kidney disease underwent FE-MRA for preprocedural vascular assessment, and unenhanced CT examinations were available in all patients. No ferumoxytol-related adverse events occurred. There were 247 matched POIs evaluated on the source FE-MRA and fused images. In patients with implantable medical devices, the mean offsets in spatial position were 0.31 ± 0.51 mm (ρ = 0.99; Cb = 1; 95% confidence interval [CI], 0.99-0.99) for Δx, 0.27 ± 0.69 mm (ρ = 0.99; Cb = 0.99; 95% CI, 0.99-0.99) for Δy, and 0.20 ± 0.59 mm (ρ = 1; Cb = 1; 95% CI, 0.99-1.00) for Δz. Interobserver agreement was excellent (intraclass correlation coefficient, >0.99). The mean difference in offset between readers was 1.5 mm. CONCLUSIONS: Accurate 3D feature fusion is feasible, combining luminal information from FE-MRA with vessel wall information on unenhanced CT. This framework holds promise for combining the complementary strengths of magnetic resonance imaging and CT to generate information-rich, multifeature composite vascular images while avoiding the respective risks and limitations of both modalities.

Impact of ferumoxytol magnetic resonance imaging on the rhesus macaque maternal-fetal interface†.

Ferumoxytol is a superparamagnetic iron oxide nanoparticle used off-label as an intravascular magnetic resonance imaging (MRI) contrast agent. Additionally, ferumoxytol-uptake by macrophages facilitates detection of inflammatory sites by MRI through ferumoxytol-induced image contrast changes. Therefore, ferumoxytol-enhanced MRI holds great potential for assessing vascular function and inflammatory response, critical to determine placental health in pregnancy. This study sought to assess the fetoplacental unit and selected maternal tissues, pregnancy outcomes, and fetal well-being after ferumoxytol administration. In initial developmental studies, seven pregnant rhesus macaques were imaged with or without ferumoxytol administration. Pregnancies went to term with vaginal delivery and infants showed normal growth rates compared to control animals born the same year that did not undergo MRI. To determine the impact of ferumoxytol on the maternal-fetal interface (MFI), fetal well-being, and pregnancy outcome, four pregnant rhesus macaques at ~100 gestational day underwent MRI before and after ferumoxytol administration. Collection of the fetoplacental unit and selected maternal tissues was performed 2-3 days following ferumoxytol administration. A control group that did not receive ferumoxytol or MRI was used for comparison. Iron levels in fetal and MFI tissues did not differ between groups, and there was no significant difference in tissue histopathology with or without exposure to ferumoxytol, and no effect on placental hormone secretion. Together, these results suggest that the use of ferumoxytol and MRI in pregnant rhesus macaques does not negatively impact the MFI and can be a valuable experimental tool in research with this important animal model.

Ferumoxytol-enhanced cardiovascular magnetic resonance detection of early stage acute myocarditis.

BACKGROUND: The diagnostic utility of cardiovascular magnetic resonance (CMR) is limited during the early stages of myocarditis. This study examined whether ferumoxytol-enhanced CMR (FE-CMR) could detect an earlier stage of acute myocarditis compared to gadolinium-enhanced CMR. METHODS: Lewis rats were induced to develop autoimmune myocarditis. CMR (3 T, GE Signa) was performed at the early- (day 14, n = 7) and the peak-phase (day 21, n = 8) of myocardial inflammation. FE-CMR was evaluated as % myocardial dephasing signal loss on gradient echo images at 6 and 24 h (6 h- & 24 h-FE-CMR) following the administration of ferumoxytol (300µmolFe/kg). Pre- and post-contrast T2* mapping was also performed. Early (EGE) and late (LGE) gadolinium enhancement was obtained after the administration of gadolinium-DTPA (0.5 mmol/kg) on day 14 and 21. Healthy rats were used as control (n = 6). RESULTS: Left ventricular ejection fraction (LVEF) was preserved at day 14 with inflammatory cells but no fibrosis seen on histology. EGE and LGE at day 14 both showed limited myocardial enhancement (EGE: 11.7 ± 15.5%; LGE: 8.7 ± 8.7%; both p = ns vs. controls). In contrast, 6 h-FE-CMR detected extensive myocardial signal loss (33.2 ± 15.0%, p = 0.02 vs. EGE and p < 0.01 vs. LGE). At day 21, LVEF became significantly decreased (47.4 ± 16.4% vs control: 66.2 ± 6.1%, p < 0.01) with now extensive myocardial involvement detected on EGE, LGE, and 6 h-FE-CMR (41.6 ± 18.2% of LV). T2* mapping also detected myocardial uptake of ferumoxytol both at day 14 (6 h R2* = 299 ± 112 s- 1vs control: 125 ± 26 s- 1, p < 0.01) and day 21 (564 ± 562 s- 1, p < 0.01 vs control). Notably, the myocardium at peak-phase myocarditis also showed significantly higher pre-contrast T2* (27 ± 5 ms vs control: 16 ± 1 ms, p < 0.001), and the extent of myocardial necrosis had a strong positive correlation with T2* (r = 0.86, p < 0.001). CONCLUSIONS: FE-CMR acquired at 6 h enhance detection of early stages of myocarditis before development of necrosis or fibrosis, which could potentially enable appropriate therapeutic intervention.