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Subcutaneous microbubble administration in connection with contrast enhanced ultrasound (CEUS) imaging is showing promise as a noninvasive and sensitive way to detect tumor draining sentinel lymph nodes (SLNs) in patients with breast cancer. Moreover, there is potential to harness the results from these approaches to directly estimate cancer burden, since some microbubble formulas, such as the Sonazoid used in this study, are rapidly phagocytosed by macrophages, and the macrophage concentration in a lymph node is inversely related to the cancer burden. This work presents a mathematical model that can approximate a rate constant governing macrophage uptake of Sonazoid, k i , given dynamic CEUS Sonazoid imaging data. Twelve healthy women were injected with 1.0 ml of Sonazoid in an upper-outer quadrant of one of their breasts and SLNs were imaged in each patient immediately after injection, and then at 0.25, 0.5, 1, 2, 4, 6, and 24 h after injection. The mathematical model developed was fit to the dynamic CEUS data from each subject resulting in a mean ± sd of 0.006 ± 0.005 h -1 and 0.4 ± 0.1 h -1 for relative lymphatic flow ( EF l ) and k i , respectively. Furthermore, the roughly 25% sd of the k i measurement was similar to the sd that would be expected from realistic noise simulations for a stable 0.4 h -1 value of k i , suggesting that macrophage concentration is highly consistent among cancer-free SLNs. These results, along with the significantly smaller variance in k i measurement observed compared to relative lymphatic flow suggest that k i may be a more precise and promising approach of estimating macrophage abundance, and inversely cancer burden. Future studies comparing tumor-free to tumor-bearing nodes are planned to verify this hypothesis., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Tattoo pigment is expected to migrate beyond the skin to regional lymph nodes and the liver. Modern tattoo ink commonly contains metals that may pose a clinical problem during MRI examinations. This study aimed to investigate the biodistribution of iron oxide pigment to internal organs in mice. Moreover, when exposed to a static magnetic field, we studied whether any reactions followed in the tattooed skin. Twenty-seven hairless C3.Cg-Hrhr/TifBomTac mice were included; 20 were tattooed with iron oxide ink in a rectangular 3 cm 2 pattern; seven were controls. Ten of the tattooed mice were exposed to a 3 T MRI scanner's static magnetic field. Following euthanasia, evaluations of dissected organs involved MRI T2*-mapping, light microscopy (LM) and metal analysis. T2*-mapping measures the relaxation times of hydrogen nuclei in water and fat, which may be affected by neighbouring ferrimagnetic particles, thus enabling the detection of iron oxide particles in organs. Elemental analysis detected a significant level of metals in the tattooed skin compared to controls, but no skin reactions occurred when exposed to a 3 T static magnetic field. No disparity was observed in the liver samples with metal analysis. T2* mapping found no significant difference between the two groups. Only minute clusters of pigment particles were observed in the liver by LM. Our results demonstrate a minimal systemic distribution of the iron oxide pigments to the liver, whereas the kidney and brain were unaffected. The static magnetic field did not trigger skin reactions in magnetic tattoos but may induce image artefacts during MRI., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Gadolinium (Gd)-based contrast agents are primarily used for contrast-enhanced magnetic resonance lymphangiography (MRL). However, overcoming venous contamination issues remains challenging. This study aims to assess the MRL efficacy of the newly developed iron-based contrast agent (INV-001) that is specially designed to mitigate venous contamination issues. The study further explores the optimal dosage, including both injection volume and concentration, required to achieve successful visualization of the popliteal lymph nodes and surrounding lymphatic vessels., Procedures: All animals utilized in this study were male Sprague-Dawley (SD) rats weighing between 250 and 300 g. The contrast agents prepared were injected intradermally in the fourth phalanx of both hind limbs using a 30-gauge syringe in SD rats. MRL was performed every 16 min on a coronal 3D time-of-flight sequence with saturation bands using a 9.4-T animal machine., Results: Contrary to Gd-DOTA, which exhibited venous contamination in most animals irrespective of injection dosages and conditions, INV-001 showed no venous contamination. For Gd-DOTA, the popliteal lymph nodes and lymphatic vessels reached peak enhancement 16 min after injection from the injection site and then rapidly washed out. However, with INV-001, they reached peak enhancement between 16 and 32 min after injection, with prolonged visualization of the popliteal lymph node and lymphatic vessels. INV-001 at 0.45 μmol (15 mM, 30 μL) and 0.75 μmol (15 mM, 50 μL) achieved high scores for qualitative image analysis, providing good visualization of the popliteal lymph nodes and lymphatic vessels without issues of venous contamination, interstitial space enhancement, or lymph node enlargement., Conclusion: In MRL, INV-001, a novel T 1 contrast agent based on iron, enables prolonged enhancement of popliteal lymph nodes and lymphatic vessels without venous contamination., (© 2024. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Visualization of transplanted stem cells in the brain is an important issue in the study of the mechanisms of their therapeutic action. MRI allowing visualization of single transplanted cells previously labeled with superparamagnetic iron oxide particles is among the most informative methods of non-invasive intravital imaging. Verification of MRI data using pathomorphological examination at the microscopic level helps to avoid errors in data interpretation. However, making serial sections of the whole brain and searching for transplanted cells under the microscope is laborious and time-consuming. We have developed a method for 3D modeling of the distribution of transplanted cells in the brain allowing navigating through various brain structures and identifying the areas of accumulation of transplanted cells, which significantly increases the efficiency and reduces the time of histological examination., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

The harnessing of the cancer X-ray radiation therapy by gold-decorated Fe 3 O 4 theranostic nanoparticles (Au-Fe 3 O 4 NPs) under electromagnetic field was articulated. The applied electromagnetic field could assemble the NPs inside cell in oriented field direction and enhance the local irradiation dose inside cell. By materializing NPs, the absorption of the energy exposed by X-ray radiation under electromagnetic field was restricted. The cytotoxic properties of the Au-Fe 3 O 4 NPs were assessed using MTT assay in L929, HeLa and PC3 cell lines under radiation and dark conditions. The efficiency of the Au-Fe 3 O 4 NPs under 2 Gy dose radiations was higher than 6 Gy radiations in untreated cells. The in vitro measurements showed that under electromagnetic field and X-ray radiation therapy with Au-Fe 3 O 4 NPs, around 90% of the cancer cells population was annihilated. The in vivo measurements indicated that the tumor shape and size under X-ray with Au-Fe 3 O 4 NPs after 3 weeks were efficiently deteriorated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This paper reports a smart intracellular nanocarrier for sustainable and controlled drug release in non-invasive neuroregeneration. The nanocarrier is composed by superparamagnetic iron oxide-gold (SPIO-Au) core-shell nanoparticles (NPs) conjugated with porous coordination cages (PCCs) through the thiol-containing molecules as bridges. The negatively charged PCC-2 and positively charged PCC-3 are compared for intracellular targeting. Both types result in intracellular targeting via direct penetration across cellular membranes. However, the pyrene (Py)-PEG-SH bridge enabled functionalization of SPIO-Au NPs with PCC-3 exhibits higher interaction with PC-12 neuron-like cells, compared with the rhodamine B (RhB)-PEG-SH bridge enabled case and the stand-alone SPIO-Au NPs. With neglectable toxicities to PC-12 cells, the proposed SPIO-Au-RhB(Py)-PCC-2(3) nanocarriers exhibit effective drug loading capacity of retinoic acid (RA) at 13.505 μg/mg of RA/NPs within 24 h. A controlled release of RA is achieved by using a low-intensity 525 nm LED light (100% compared to 40% for control group within 96 h)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Four high-spin Fe(III) macrocyclic complexes, including three dinuclear and one mononuclear complex, were prepared toward the development of more effective iron-based magnetic resonance imaging (MRI) contrast agents. All four complexes contain a 1,4,7-triazacyclononane macrocyclic backbone with two hydroxypropyl pendant groups, an ancillary aryl or biphenyl group, and a coordination site for a water ligand. The pH potentiometric titrations support one or two deprotonations of the complexes, most likely deprotonation of hydroxypropyl groups at near-neutral pH. Variable-temperature 17 O NMR studies suggest that the inner-sphere water ligand is slow to exchange with bulk water on the NMR time scale. Water proton T 1 relaxation times measured for solutions of the Fe(III) complexes at pH 7.2 showed that the dinuclear complexes have a 2- to 3-fold increase in r 1 relaxivity in comparison to the mononuclear complex per molecule at field strengths ranging from 1.4 T to 9.4 T. The most effective agent, a dinuclear complex with macrocycles linked through para-substitution of an aryl group (Fe 2 (PARA)), has an r 1 of 6.7 mM -1 s -1 at 37 °C and 4.7 T or 3.3 mM -1 s -1 per iron center in the presence of serum albumin and shows enhanced blood pool and kidney contrast in mice MRI studies.

Complex iron nanoparticle-based drugs are one of the oldest and most frequently administered classes of nanomedicines. In the US, there are seven FDA-approved iron nanoparticle reference drug products, of which one also has an approved generic drug product (i.e., sodium ferric gluconate (SFG)). These products are indicated for the treatment of iron deficiency anemia and are administered intravenously. On the molecular level, iron nanomedicines are colloids composed of an iron oxide core with a carbohydrate coating. This formulation makes nanomedicines more complex than conventional small molecule drugs. As such, these products are often referred to as nonbiological complex drugs (e.g., by the nonbiological complex drugs (NBCD) working group) or complex drug products (e.g., by the FDA). Herein, we report a comprehensive study of the physiochemical properties of the iron nanoparticle product SFG. SFG is the single drug for which both an innovator (Ferrlecit) and generic product are available in the US, allowing for comparative studies to be performed. Measurements focused on the iron core of SFG included optical spectroscopy, inductively coupled plasma mass spectrometry (ICP-MS), X-ray powder diffraction (XRPD), 57 Fe Mössbauer spectroscopy, and X-ray absorbance spectroscopy (XAS). The analysis revealed similar ferric-iron-oxide structures. Measurements focused on the carbohydrate shell comprised of the gluconate ligands included forced acid degradation, dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and gel permeation chromatography (GPC). Such analysis revealed differences in composition for the innovator versus the generic SFG. These studies have the potential to contribute to future quality assessment of iron complex products and will inform on a pharmacokinetic study of two therapeutically equivalent iron gluconate products.

Iron oxide particles (IOP) are commonly used for Cellular Magnetic Resonance Imaging (MRI) and in combination with several treatments, like Magnetic Fluid Hyperthermia (MFH), due to the rise in temperature they provoke under an Alternating Magnetic Field (AMF). Micrometric IOP have a high sensitivity of detection. Nevertheless, little is known about their internalization processes or their potential heat power. Two micrometric commercial IOP (from Bangs Laboratories and Chemicell) were characterized by Transmission Electron Microscopy (TEM) and their endocytic pathways into glioma cells were analyzed. Their Specific Absorption Rate (SAR) and cytotoxicity were evaluated using a commercial AMF inductor. T2-weighted imaging was used to monitor tumor growth in vivo after MFH treatment in mice. The two micron-sized IOP had similar structures and r 2 relaxivities (100 mM -1  s -1 ) but involved different endocytic pathways. Only ScreenMAG particles generated a significant rise in temperature following AMF (SAR = 113 W g -1 Fe). After 1 h of AMF exposure, 60% of ScreenMAG-labeled cells died. Translated to a glioma model, 89% of mice responded to the treatment with smaller tumor volume 42 days post-implantation. Micrometric particles were investigated from their characterization to their intracellular internalization pathways and applied in one in vivo cancer treatment, i.e. MFH.

Objective: To review the pharmacology, efficacy, and safety of ferric maltol (FM), an oral iron formulation, for iron deficiency anemia (IDA)., Data Sources: A MEDLINE/PubMed and EMBASE (January 1, 1985, to June 19, 2020) literature search was performed using the terms ferric maltol, accrufer, feraccru, iron maltol, ferric trimaltol, iron deficiency, iron deficiency anemia, inflammatory bowel disease , and chronic kidney disease . Additional data sources included prescribing information, abstracts, and the National Institutes of Health Clinical Trials Registry., Study Selection/data Extraction: English language literature evaluating FM pharmacology, pharmacokinetics, efficacy, or safety in the treatment of IDA were reviewed., Data Synthesis: FM is a ferric, non-salt-based oral iron formulation demonstrating improved tolerance in patients with previous intolerance to other iron formulations. Phase 3 trials demonstrated significant improvements in anemia and serum iron parameters in patients with inflammatory bowel disease (IBD) and chronic kidney disease (CKD). Common adverse effects were gastrointestinal intolerance., Relevance to Patient Care and Clinical Practice: FM is an effective and well-tolerated alternative to oral iron salts for patients with IBD or CKD and IDA. Emerging data suggest that FM is noninferior to intravenous (IV) ferric carboxymaltose in patients with IBD and IDA. Prior to selecting FM over IV iron products, consideration should be given to time to normalization of Hb, ease of administration, cost, and tolerability., Conclusion: FM is a relatively safe, effective oral iron therapy that may be better tolerated than other oral iron formulations. FM may be an effective alternative to IV iron in patients with IBD.

Introduction : Originally approved in Europe in 2009, ferric derisomaltose is the most recently authorized intravenous iron compound in the United States of America (2020). Ferric derisomaltose given as a rapid high-dose infusion can allow complete iron repletion in a single dose and it is now widely used in the treatment of iron deficiency. Areas covered : The chemistry, pharmacodynamics and pharmacokinetics of ferric derisomaltose are reviewed. Results from phase II, III and IV trials regarding efficacy and safety are presented. Mechanisms behind minor infusion reactions, hypersensitivity and hypophosphatemia are discussed. The economic impact of ferric derisomaltose use is presented. Data pertaining to the use of ferric derisomaltose in iron deficiency anemia, chronic kidney disease, inflammatory bowel disease, chronic heart failure, perioperative care and other patient groups are comprehensively covered. Expert opinion : Ferric derisomaltose is an effective intravenous iron formulation with a good safety profile, providing rapid, cost-effective iron repletion. Ferric derisomaltose releases low quantities of labile iron relative to older compounds. Anaphylaxis is extremely rare, and 'Fishbane' reactions are uncommon. Hypophosphatemia following ferric derisomaltose administration is infrequent in comparison to other intravenous irons such as ferric carboxymaltose. The scope of ferric derisomaltose use is growing with increasing research in these areas.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been employed in several biomedical applications where they facilitate both diagnostic and therapeutic aims. Although the potential benefits of SPIONs with different surface chemistry and conjugated targeting ligands/proteins are considerable, complicated interactions between these nanoparticles (NPs) and cells leading to toxic impacts could limit their clinical applications. Hence, elevation of our knowledge regarding the SPION-related toxicity is necessary. Here, the present review article will consider current studies and compare the potential toxic effect of SPIONs with or without identical surface chemistries on different cell lines. It centers on cellular and molecular mechanisms underlying toxicity of SPIONs. Likewise, emphasis is being dedicated for toxicity of SPIONs in various cell lines, in vitro and animal models, in vivo .

Nanosized iron is a promising candidate as an iron fortificant due to its good solubility and bioavailability. Here, ferric hydrolysis in the presence of salmon/herring sperm DNA yielded irregularly shaped, highly negatively charged DNA-stabilized ferric oxyhydroxide nanoparticles (DNA-FeONPs) aggregated from 2-4 nm primary spherical monomers, in which phosphodioxy groups of the DNA backbone served as the iron-nucleation sites with high molecular weight (>500 bp), double-stranded winding, and acidic environmental pH disfavoring DNA's iron-loading capacity. The calcein fluorescence-quenching kinetics of polarized Caco-2 cells revealed the involvement of divalent transporter 1, macropinocytosis and nucleolin-mediated endocytosis in intestinal iron absorption from DNA-FeONPs with low molecular weight (<500 bp) favoring the performance of DNA in aiding iron absorption. In anemic rats, dietary DNA-FeONPs showed >80% relative iron bioavailability compared to FeSO 4 as per hemoglobin regeneration efficiencies and delivered intestinally available nanosized iron, as determined by luminal iron speciation analysis. Overall, fish sperm DNA is promising in stabilizing and delivering bioavailable nanosized iron.

Background: Anemia of chronic kidney disease (CKD) is, in part, caused by hepcidin-mediated impaired iron absorption. However, phosphate binder, ferric citrate (FC) overcomes the CKD-induced impairment of iron absorption and increases serum iron, transferrin saturation, and iron stores and reduces erythropoietin requirements in CKD/ESRD patients. The mechanism and sites of intestinal absorption of iron contained in FC were explored here., Methods: Eight-week old rats were randomized to sham-operated or 5/6 nephrectomized (CKD) groups and fed either regular rat chow or rat chow containing 4% FC for 6 weeks. They were then euthanized, and tissues were processed for histological and biochemical analysis using Prussian blue staining, Western blot analysis to quantify intestinal epithelial tight junction proteins and real-time PCR to measure Fatty Acid receptors 2 (FFA2) and 3 (FFA3) expressions., Results: CKD rats exhibited hypertension, anemia, azotemia, and hyperphosphatemia. FC-treated CKD rats showed significant reductions in blood pressure, serum urea, phosphate and creatinine levels and higher serum iron and blood hemoglobin levels. This was associated with marked increase in iron content of the epithelial and subepithelial wall of the descending colon and modest iron deposits in the proximal tubular epithelial cells of their remnant kidneys. No significant difference was found in hepatic tissue iron content between untreated and FC-treated CKD or control groups. Distal colon's epithelial tight Junction proteins, Occludin, JAM-1 and ZO-1 were markedly reduced in the CKD groups. The FFA2 expression in the jejunum and FFA3 expression in the distal colon were significantly reduced in the CKD rats and markedly increased with FC administration., Conclusion: Iron contained in the phosphate binder, FC, is absorbed by the distal colon of the CKD animals via disrupted colonic epithelial barrier and upregulation of short chain fatty acid transporters., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Superparamagnetic iron oxide nanoparticles (SPIONs) have displayed multifunctional applications in cancer theranostics following systemic delivery. In an effort to increase the therapeutic potential of local therapies (including focal hyperthermia), nanoparticles can also be administered intratumorally. Therefore, the development of a reliable pharmacokinetic model for the prediction of nanoparticle distribution for both clinically relevant routes of delivery is of high importance., Materials and Methods: The biodistribution of SPIONs (of two different sizes - 130 nm and 60 nm) radiolabeled with zirconium-89 or technetium-99m following intratumoral or intravenous injection was investigated in C57/Bl6 mice bearing subcutaneous GL261 glioblastomas. Based on PET/CT biodistribution data, a novel pharmacokinetic model was established for a better understanding of the pharmacokinetics of the SPIONs after both administration routes., Results: The PET image analysis of the nanoparticles (confirmed by histology) demonstrated the presence of radiolabeled nanoparticles within the glioma site (with low amounts in the liver and spleen) at all investigated time points following intratumoral injection. The mathematical model confirmed the dynamic nanoparticle redistribution in the organism over a period of 72 h with an equilibrium reached after 100 h. Intravenous injection of nanoparticles demonstrated a different distribution pattern with a rapid particle retention in all organs (particularly in liver and spleen) and a subsequent slow release rate., Conclusion: The mathematical model demonstrated good agreement with experimental data derived from tumor mouse models suggesting the value of this tool to predict the real-time pharmacokinetic features of SPIONs in vivo. In the future, it is planned to adapt our model to other nanoparticle formulations to more precisely describe their biodistribution in in vivo model systems., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© 2020 Klapproth et al.)

Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH 2 ), are compared. Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r 1 relaxivity of the Fe(L1)(OH 2 ) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 °C in buffered solutions. However, variable-temperature 17 O-NMR experiments show that the inner-sphere water of Fe(L1)(OH 2 ) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH 2 ) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH 2 ) for development as an extracellular fluid contrast agent.

In this work we describe the formulation and characterisation of red-emitting polymeric nanocapsules (NCs) incorporating superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic tumour targeting. The self-fluorescent oligomers were synthesised and chemically conjugated to PLGA which was confirmed by NMR spectroscopy, FT-IR spectroscopy and mass spectrometry. Hydrophobic SPIONs were synthesised through thermal decomposition and their magnetic and heating properties were assessed by SQUID magnetometry and calorimetric measurements, respectively. Magnetic nanocapsules (m-NCs) were prepared by a single emulsification/solvent evaporation method. Their in vitro cytotoxicity was examined in CT26 colon cancer cells. The formulated fluorescent m-NCs showed good stability and biocompatibility both in vitro and in vivo in CT 26 colon cancer models. Following intravenous injection, accumulation of m-NCs in tumours was observed by optical imaging. A higher iron content in the tumours exposed to a magnetic field, compared to the contralateral tumours without magnetic exposure in the same animal, further confirmed the magnetic tumour targeting in vivo. The overall results show that the engineered red-emitting m-NCs have great potential as multifunctional nanocarriers for multi-model bioimaging and magnetic-targeted drug delivery.

3D multifunctional bone scaffolds have recently attracted more attention in bone tissue engineering because of addressing critical issues like bone cancer and inflammation beside bone regeneration. In this study, a 3D bone scaffold is fabricated from Mg 2 SiO 4 -CoFe 2 O 4 nanocomposite which is synthesized via a two-step synthesis strategy and then the scaffold's surface is modified with poly-3-hydroxybutyrate (P3HB)-ordered mesoporous magnesium silicate (OMMS) composite to improve its physicochemical and biological properties. The Mg 2 SiO 4 -CoFe 2 O 4 scaffold is fabricated through polymer sponge technique and the scaffold exhibits an interconnected porous structure in the range of 100-600 μm. The scaffold is then coated with OMMS/P3HB composite via dip coating and the physical, chemical, and biological-related properties of OMMS/P3HB composite-coated scaffold are assessed and compared to the non-coated and P3HB-coated scaffolds in vitro. It is found that, on the one hand, P3HB increases the cell attachment, proliferation, and compressive strength of the scaffold, but on the other hand, it weakens the bioactivity kinetic. Addition of OMMS to the coating composition is accompanied with significant increase in bioactivity kinetic. Besides, OMMS/P3HB composite-coated scaffold exhibits higher drug loading capacity and more controlled release manner up to 240 h than the other samples because of OMMS which has a high surface area and ordered mesoporous structure suitable for controlled release applications. The overall results indicate that OMMS/P3HB coating on Mg 2 SiO 4 -CoFe 2 O 4 scaffold leads to a great improvement in bioactivity, drug delivery potential, compressive strength, cell viability, and proliferation. Moreover, OMMS/P3HB composite-coated scaffold has heat generation capability for hyperthermia-based bone cancer therapy and so it is suggested as a multifunctional scaffold with great potentials for bone cancer therapy and regeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We studied the distribution of ferrihydrite nanoparticles isolated from bacteria Klebsiella oxytoca in the whole body in vivo and in a cultured isolated organ (liver). The possibility of controlling these nanoparticles in the body using a magnetic field was assessed. One hour after intravenous injection of ferrihydrite nanoparticles to mice, their accumulation was observed in the liver, lungs, and kidneys. Experiment with cultured isolated rat liver showed that these nanoparticles can be controlled by a magnetic field and the influence of magnetic nanoparticles on the liver over 1 h does not lead to destruction of liver cells associated with the release of the marker enzyme AST. These results show the possibility of using magnetic nanoparticles as a system for controlled drug delivery in the body.

Well-absorbed iron-based nanoparticulated materials are a promise for the oral management of iron deficient anemia. In this work, a battery of in vitro and in situ experiments are combined for the evaluation of the uptake, distribution and toxicity of new synthesized ultrasmall (4 nm core) Fe 2 O 3 nanoparticles coated with tartaric/adipic acid with potential to be used as oral Fe supplements. First, the in vitro simulated gastric acid solubility studies by TEM and HPLC-ICP-MS reveal a partial reduction of the core size of about 40% after 90 min at pH 3. Such scenario confirms the arrival of the nanoparticulate material in the small intestine. In the next step, the in vivo absorption through the small intestine by intestinal perfusion experiments is conducted using the sought nanoparticles in Wistar rats. The quantification of Fe in the NPs suspension before and after perfusion shows Fe absorption levels above 79%, never reported for other Fe treatments. Such high absorption levels do not seem to compromise cell viability, evaluated in enterocytes-like models (Caco-2 and HT-29) using cytotoxicity, ROS production, genotoxicity and lipid peroxidation tests. Moreover, regional differences in terms of Fe concentration are obtained among different parts of the small intestine as duodenum > jejunum > ileum. Complementary transmission electron microscopy (TEM) images show the presence of the intact particles around the intestinal microvilli without significant tissue damage. These studies show the high potential of these NP preparations for their use as oral management of anemia.

Bouillon cubes are widely consumed and when fortified with iron could contribute in preventing iron deficiency. We report the development (part I) and evaluation (current part II) of a novel ferric phytate compound to be used as iron fortificant in condiments such as bouillon. Ferric pyrophosphate (FePP), is the compound of choice due to its high stability in foods, but has a modest absorption in humans. Our objective was to assess iron bioavailability from a novel iron fortificant consisting of ferric iron complexed with phytic acid and hydrolyzed corn protein (Fe-PA-HCP), used in bouillon with and without an inhibitory food matrix. In a randomised single blind, cross-over study, we measured iron absorption in healthy adult women (n = 22). In vitro iron bioaccessibility was assessed using a Caco-2 cell model. Iron absorption from Fe-PA-HCP was 1.5% and 4.1% in bouillon with and without inhibitory matrix, respectively. Relative iron bioavailability to FeSO 4 was 2.4 times higher than from FePP in bouillon (17% vs 7%) and 5.2 times higher when consumed with the inhibitory meal (41% vs 8%). Similar results were found in vitro. Fe-PA-HCP has a higher relative bioavailability versus FePP, especially when bouillon is served with an inhibitory food matrix.

Delivery efficiencies of theranostic nanoparticles (NPs) based on passive tumor targeting strongly depend either on their blood circulation time or on appropriate modulations of the tumor microenvironment. Therefore, predicting the NP delivery efficiency before and after a tumor microenvironment modulation is highly desirable. Here, we present a new erythrocyte membrane-camouflaged magnetofluorescent nanocarrier (MMFn) with long blood circulation time (92 h) and high delivery efficiency (10% ID for Ehrlich murine tumor model). MMFns owe their magnetic and fluorescent properties to the incorporation of manganese ferrite nanoparticles (MnFe 2 O 4 NPs) and IR-780 (a lipophilic indocyanine fluorescent dye), respectively, to their erythrocyte membrane-derived camouflage. MMFn composition, morphology, and size, as well as optical absorption, zeta potential, and fluorescent, magnetic, and magnetothermal properties, are thoroughly examined in vitro . We then present an analytical pharmacokinetic (PK) model capable of predicting the delivery efficiency (DE) and the time of peak tumor uptake ( t max ), as well as changes in DE and t max due to modulations of the tumor microenvironment, for potentially any nanocarrier. Experimental PK data sets (blood and tumor amounts of MMFns) are simultaneously fit to the model equations using the PK modeling software Monolix. We then validate our model analytical solutions with the numerical solutions provided by Monolix. We also demonstrate how our a priori nonmechanistic model for passive targeting relates to a previously reported mechanistic model for active targeting. All in vivo PK studies, as well as in vivo and ex vivo biodistribution studies, were conducted using two noninvasive techniques, namely, fluorescence molecular tomography (FMT) and alternating current biosusceptometry (ACB). Finally, histopathology corroborates our PK and biodistribution results.

The application of current soil quality standards based on total arsenic (As) fails to assess the ecological risks of soil arsenic or to ensure the safety of crops and foods. In this study, bioavailable arsenic instead of total arsenic was applied to improve predictive models for arsenic transfer from soil to wheat (Triticum turgidum L.). The stepwise multiple-linear regression analysis showed that bioavailable arsenic and amorphous iron oxides (Fe OX ) were the two most important factors contributing to arsenic accumulation in wheat grain, with the explained percentage of variation being up to 82%. Compared with the bioavailable arsenic extracted by NH 4 H 2 PO 4 , bioavailable arsenic extracted by HNO 3 from soils generated better predictions of the amount of arsenic in grain. The best reliable model was log[As grain ] = 0.917 log[HNO 3 -As] - 0.452 log[Fe OX ] - 1.507 (R 2  = 0.82, P <  0.001). Consistently, bioavailable arsenic and Fe OX were also the key factors to predict arsenic accumulation in wheat straw, leaves and spikes. Our prediction models was successfully verified for three independent soils. Our results highlight the role of soil bioavailable heavy metals in predicting their transfer in soil-plant systems and can be used to improve existing Chinese soil quality standards., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Iron deficiency (ID) is one of the most commonly known nutritional deficiencies and is considered the primary cause of anemia (iron-deficiency anemia). Ferric carboxymaltose (FCM), an intravenous iron preparation, has been widely used for >10 years for iron-deficiency anemia treatment worldwide because of its many advantages., Methods: This single-center, open-label, single dose escalation study in Chinese subjects was designed to assess the pharmacokinetic/pharmacodynamic parameters and safety of FCM in this population. The first 12 subjects received a 500-mg dose; after assessing safety data from the first 6 subjects in this cohort, another 12 subjects were assigned to the 1000-mg dose cohort., Findings: After an infusion of FCM over 15 min, a rapid dose-dependent increase in total serum iron levels was observed with a median T max of 30 min following the start of the infusion for both cohorts. The C max and AUC for the 1000-mg dose were ~1.8-fold (p = 0.2929) and 2.3-fold (p = 0.0318) those associated with the 500-mg dose, respectively. Mean terminal t 1/2 values were 12.3 and 10.5 h for the 2 cohorts. The renal elimination of FCM was negligible (<0.1%). Increase in mean serum iron levels and ferritin concentrations showed dose dependency. Iron-binding capacity was transiently well utilized after dosing, as indicated by transferrin saturation >88% with 500-mg FCM and >90% with 1000-mg FCM. Hemoglobin levels did not show significant changes during the 7-day observation period, whereas mean reticulocyte counts significantly increased in both cohorts, suggesting activation of the hematopoietic system. FCM was well tolerated in these Chinese subjects. No new or unexpected treatment-emergent adverse events were attributable to FCM., Implications: The pharmacokinetic/pharmacodynamic and safety profiles in Chinese subjects seemed comparable to those in white and Japanese populations. ChinaDrugTrials.org.cn identifier: CTR20160863., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The effect of the ligand shell on the cellular uptake efficiency was evaluated by a systematic study using fully dispersed 6 nm diameter superparamagnetic iron oxide nanoparticles (SPIONs), mono and bis-conjugated with glycerol phosphate (glyc), dopamine (dopa), 4,5-dihydroxy-1,3-benzenedisulfonic acid (tiron) and phosphorylethanolamine (pea). Negatively charged SPION-glyc was more efficiently incorporated than positively charged SPION-pea and SPION-dopa clearly evidencing that there are strong enough short-range interactions in addition to the long-range electrostatic interactions, as measured by the zeta potential, to reverse our expectation on cellular uptake. Those effects were pursued by correlating the nanoparticles incorporation efficiency as a function of the respective zeta potentials and the molar fractions of glyc and pea ligands co-conjugated on the SPION surface. The possibility of associating different ligands to modulate the physicochemical properties and biological events was demonstrated, showing promising perspectives for the development of multifunctional nanosystems for biomedical applications., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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

Introduction: Nanoparticles are used worldwide because of their unique properties, with large-scale application in various fields, such as medicine, cosmetics and industries. In view of their widespread use, the potential adverse effects of nanoparticles have become a significant cause for concern, in terms of not only human health and safety but also the environment. The present investigation focused on establishing the bioaccumulation patterns and ultrastructural changes induced by retained iron oxide nanoparticles (IONPs) in various target organs of rats., Methods: Twenty-four male Wistar rats were randomly divided into four groups. Experimental animals were intravenously administered different doses of IONPs (7.5 mg/kg, 15 mg/kg and 30 mg/kg) once in a week for 4 weeks. Urine and feces samples were collected on a daily basis to assess nanoparticle clearance and analyzed via atomic absorption spectroscopy (AAS). At the end of the experiment, rats were euthanized and different organs, including spleen, liver, kidney, lung, heart, testis and brain, were dissected. Bioaccumulation of iron in organs and ultrastructural changes induced by IONPs were determined., Results: The maximal concentration of iron was detected in spleen and minimal concentration in the brain. The level of iron accumulation in organs was as follows: spleen>blood>liver>kidney>lung>heart>testis>brain. The excretion profile in urine revealed maximum excretion on the day following administration that was maintained until day 28, whereas the iron content in feces remained high during the first three days after injection. A similar pattern was observed throughout the duration of the experiment. Ultrastructural alterations were detected in spleen, kidney, lung, heart, testis, brain and liver, indicative of cellular damage induced by accumulating nanoparticles in these organs., Conclusion: Intravenous administration of IONPs results in ultrastructural changes and dose-dependent bioaccumulation in different organs of rats., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Gaharwar et al.)

Synergistic therapeutic strategies for bacterial infection have attracted extensive attentions owing to their enhanced therapeutic effects and less adverse effects compared with monotherapy. Herein, we report a novel synergistic antibacterial platform that integrates the nanocatalytic antibacterial therapy and photothermal therapy (PTT) by hemoglobin-functionalized copper ferrite nanoparticles (Hb-CFNPs). In the presence of a low concentration of hydrogen peroxide (H 2 O 2 ), the excellent Fenton and Fenton-like reaction activity of Hb-CFNPs can effectively catalyze the decomposition of H 2 O 2 to produce hydroxyl radicals (·OH), rendering an increase in the permeability of the bacterial cell membrane and the sensitivity to heat. With the assistance of NIR irradiation, hyperthermia generated by Hb-CFNPs can induce the death of the damaged bacteria. Additionally, owing to the outstanding magnetic property of Hb-CFNPs, it can improve the photothermal efficiency by about 20 times via magnetic enrichment, which facilitates to realize excellent bactericidal efficacy at a very low experimental dose (20 μg/mL). In vitro antibacterial experiment shows that this synergistic antibacterial strategy has a broad-spectrum antibacterial property against Gram-negative Escherichia coli ( E. coli , 100%) and Gram-positive Staphylococcus aureus ( S. aureus , 96.4%). More importantly, in vivo S. aureus -infected abscess treatment studies indicate that Hb-CFNPs can serve as an antibacterial candidate with negligible toxicity to realize synergistic treatment of bacterial infections through catalytic and photothermal effects. Accordingly, this study proposes a novel, high-efficiency, and multifunctional therapeutic system for the treatment of bacterial infection, which will open up a new avenue for the design of synergistic antibacterial systems in the future.

Chemodynamic therapy based on Fe 2+ -catalyzed Fenton reaction holds great promise in cancer treatment. However, low-produced hydroxyl radicals in tumor cells constitute its severe challenges because of the fact that Fe 2+ with high catalytic activity could be easily oxidized into Fe 3+ with low catalytic activity, greatly lowering Fenton reaction efficacy. Here, we codeliver CuS with the iron-containing prodrug into tumor cells. In tumor cells, the overproduced esterase could cleave the phenolic ester bond in the prodrug to release Fe 2+ , activating Fenton reaction to produce the hydroxyl radical. Meanwhile, CuS could act as a nanocatalyst for continuously catalyzing the regeneration of high-active Fe 2+ from low-active Fe 3+ to produce enough hydroxyl radicals to efficiently kill tumor cells as well as a photothermal therapy agent for generating hyperthermia for thermal ablation of tumor cells upon NIR irradiation. The results have exhibited that the approach of photothermal therapy nanomaterials boosting transformation of Fe 3+ into Fe 2+ in tumor cells can highly improve Fenton reaction for efficient chemodynamic therapy. This strategy was demonstrated to have an excellent antitumor activity both in vitro and in vivo, which provides an innovative perspective to Fenton reaction-based chemodynamic therapy.

Aim: The primary goal of this work was to synthesize low-cost superparamagnetic iron oxide nanoparticles (SPIONs) with the aid of coconut water and evaluate the ability of macrophages to internalize them. Our motivation was to determine potential therapeutic applications in drug-delivery systems associated with magnetic hyperthermia. Materials & methods: We used the following characterization techniques: x-ray and electron diffractions, electron microscopy, spectrometry and magnetometry. Results: The synthesized SPIONs, roughly 4 nm in diameter, were internalized by macrophages, likely via endocytic/phagocytic pathways. They were randomly distributed throughout the cytoplasm and mainly located in membrane-bound compartments. Conclusion: Nanoparticles presented an elevated intrinsic loss power value and were not cytotoxic to mammalian cells. Thus, we suggest that low-cost SPIONs have great therapeutic potential.

The impact of the surface modification on the subcellular distribution of nanoparticles in the brain remains elusive. The nanoparticles prepared by conjugating polyethylene glycol and maleic anhydride-coated superparamagnetic iron oxide nanoparticles (Mal-SPIONs) with bovine serum albumin (BSA/Mal-SPIONs) and with Arg-Gly-Asp peptide (RGD/Mal-SPIONs) were injected into the rat substantia nigra. Observation of transmission electron microscopy (TEM) samples obtained 24 h after perfusion showed that abundant RGD/Mal-SPIONs accumulated in the myelin sheath, dendrites, axon terminals and mitochondria, and on cell membranes in the brain tissue near the injection site. For rats injected with BSA/Mal-SPIONs, a few nanoparticles accumulated in the myelin sheath, axon terminals, endoplasmic reticulum, mitochondria, Golgi, and lysosomes of neurons and glial cells while least SPIONs in rats injected with Mal-SPIONs were found. TEM pictures showed some Mal-SPIONs were expelled out of the brain. RGD/Mal-SPIONs diffused extensively to the thalamus, frontal cortex, temporal lobe, olfactory bulb, and brain stem after injection. Only a few BSA/Mal-SPIONs diffused to the afore-mentioned brain areas. This work reveals different surface modifications on the iron oxide nanoparticles play crucial roles in their distribution and diffusion in the rat brains., (© 2019 Wiley Periodicals, Inc.)

The toxicity of arsenic in drinking water is hazardous for human health. Different strategies are used for arsenic removal from drinking water. Nanoparticles with higher adsorption capacities are useful for arsenic remediation. In the current study, magnesium ferrite nanoparticles were synthesised by three different methods followed by their characterisation XRD, SEM, and EDX. The SEM morphology and the porosity of magnesium ferrite nanoparticles were best in case of auto-combustion method. These particles had an average particle size of about 20-50 nm with spherical shape. These particles showed efficient remediation of arsenic up to 96% within 0.5 h. However, the co-precipitation and sol-gel-based nanoparticles showed arsenic remediation upto85 and 87% at 0.5-h time point. Moreover, the minimum inhibitory concentration of nanoparticles against two strains E.coli and Pseudomonas aeruginosa was found to be4.0 mg/L of these nanoparticles. However, the sol-gel-based nanoparticles showed efficient anti-microbial activity against E.coli at 4.0 and 8.0 mg/L against Pseudomonas aeruginosa. The co-precipitation-based nanoparticles were least efficient both for arsenic remediation and anti-microbial purposes. Thus, the synthesised auto-combustion-based nanoparticles are multifunctional in nature.

IV iron is indicated in clinical conditions, where rapid anaemia alleviation and repletion of iron stores are required. The acute toxicity of IV iron is ascribed to the presence of labile iron in plasma. Thus, shorter plasma residence time might improve the safety profile, even for compounds holding-on the iron tightly. In this single-centre, open-label, single-dose escalation study, we evaluated the elimination kinetics of ferric bepectate (FBP) compared to those of ferric carboxymaltose (FCM). Thirty-three iron-depleted anaemic patients who had undergone cardiac surgery were included and received 200, 500 or 1500 mg FBP or 500 mg FCM. Plasma drug curves were subjected to model-free analysis. Because saturation kinetics was found, a compartmental model with limited elimination capacity was applied. Urinary iron excretion was also analysed. The initial non-compartmental analysis revealed an increasing AUC/dose ratio for FBP. For both drugs, the central distribution compartment corresponded to plasma volume, and elimination followed Michaelis-Menten saturation kinetics. Maximal elimination rates (V max ) were 224 mg/h and 81 mg/h for FBP 500 mg and FCM 500 mg, respectively; drug concentrations at half V max (K m ), 99 mg/L and 212 mg/L, respectively; and terminal plasma half-life (T½), 3.05 h and 8.96 h, respectively. Both drugs were equally effective in eliciting an early ferritin rise. Urinary iron excretion was measurable in all patients receiving FCM but not in those receiving FBP, which was well tolerated. Intravenous iron drugs are subject to capacity-limited elimination with different saturation thresholds. Urinary iron excretion can be used as a surrogate for labile plasma iron., (© 2019 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

In this paper, the application of a technique to evaluate in vivo biodistribution of magnetic nanoparticles (MNP) is addressed: the Multichannel AC Biosusceptometry System (MC-ACB). It allows real-time assessment of magnetic nanoparticles in both bloodstream clearance and liver accumulation, where a complex network of inter-related cells is responsible for MNP uptake. Based on the acquired MC-ACB images, we propose a mathematical model which helps to understand the distribution and accumulation pharmacokinetics of MNP. The MC-ACB showed a high time resolution to detect and monitor MNP, providing sequential images over the particle biodistribution. Utilizing the MC-ACB instrument, we assessed regions corresponding to the heart and liver, and we determined the MNP transfer rates between the bloodstream and the liver. The pharmacokinetic model resulted in having a strong correlation with the experimental data, suggesting that the MC-ACB is a valuable and accessible imaging device to assess in vivo and real-time pharmacokinetic features of MNP.

This study investigates the fate and impact of iron oxide or magnetite (Fe 3 O 4 , ∼13 nm in size) nanoparticles (NPs) in barley (Hordeum vulgare L.), a common crop cultivated around the world. Barley seedlings were grown in hydroponic culture for three weeks to include NPs (125, 250, 500, and 1000 mg/L). Transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM) techniques were used to assess their uptake and translocation. Photosynthesis marker genes were quantified by RT-qPCR. Results revealed that increasing doses of Fe 3 O 4 NPs were gradually enhanced the plant growth up to 500 mg/L, which promoted the fresh weight (FW) respectively ∼19% and ∼88% for leaf and root tissues than the ones for control. No phytotoxic effect was recorded even at high NPs doses. NPs inclusion increased some phenological parameters such as chlorophyll, total soluble protein, number of chloroplasts, and dry weight. High NPs doses dramatically reduced the catalase activity and hydrogen peroxide content, suggesting a possible function of NPs as nanozyme in vivo. TEM observations showed that Fe 3 O 4 NPs penetrated and internalized in the root cells. In leaves, they were mostly existed at the surrounding cell wall, suggesting their translocation from root to shoot without cellular penetration. Further analysis by using VSM confirmed the existence of Fe 3 O 4 NPs in leaves which result in dramatic alterations of the photosystem genes (PetA, psaA, BCA and psbA). In conclusion, barley plants uptake and translocate Fe 3 O 4 NPs, which promoted the plant growth probably due to the promoted gene expression and efficient photosynthetic activity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Glioblastomas are highly lethal cancers defined by resistance to conventional therapies and rapid recurrence. While new brain tumor cell-specific drugs are continuously becoming available, efficient drug delivery to brain tumors remains a limiting factor. We developed a multicomponent nanoparticle, consisting of an iron oxide core and a mesoporous silica shell that can effectively deliver drugs across the blood-brain barrier into glioma cells. When exposed to alternating low-power radiofrequency (RF) fields, the nanoparticle's mechanical tumbling releases the entrapped drug molecules from the pores of the silica shell. After directing the nanoparticle to target the near-perivascular regions and altered endothelium of the brain tumor via fibronectin-targeting ligands, rapid drug release from the nanoparticles is triggered by RF facilitating wide distribution of drug delivery across the blood-brain tumor interface.

Information on the environmental impact of magnetic TiO 2 -based nanophotocatalysts is scarce. This study evaluated the potential effects of an innovative magnetic nanophotocatalyst N-TiO 2 /Fe 3 O 4 @SiO 2 (NTFS) on plants using Arabidopsis thaliana grown in a hydroponic system. NTFS was detected in the vascular tissues and mesophyll of plants, thus confirming the uptake and upwards transport of NTFS from roots to leaves. Fourier transform infrared spectroscopy was applied to determine compositional and structural alterations in plant tissues exposed to NTFS, or its two main components (N-TiO 2 and Fe 3 O 4 @SiO 2 ), at concentrations ranging from 0 to 1000 mg/L, but no changes were detected in the lipids, pectins, proteins, cellulose, hemicellulose, and carbohydrates. The morphology and biomass of the plants were not affected by the NTFS or its components either. Biosensors for inorganic phosphate (Pi) and MgATP 2- were used to monitor the in vivo Pi and MgATP 2- levels in the plant cells. The results showed that NTFS and its components did not induce any adverse effects on the cytosolic Pi level or ATP synthesis, indicating the energy physiology of Arabidopsis was unaffected. In general, NTFS has inconsequential toxic effects on Arabidopsis, but can be taken up by plants, enter the food chain, and cause potential exposure and bioaccumulation in animals and human beings., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Arginine-glycine-aspartate (RGD)-carrying microbubbles (MBs) have been utilized as a specific contrast agent for glycoprotein IIb/IIIa (α IIb β 3 integrin)-expressing activated platelets in ultrasound molecular imaging. Recently, we found that surface modification with lactadherin provides the RGD motif on the surface of phosphatidylserine-containing clinically available MBs, Sonazoid. Here, we examined the potential of lactadherin-bearing Sonazoid MBs to be targeted MBs for glycoprotein IIb/IIIa using the custom-designed in vitro settings with recombinant α IIb β 3 integrin, activated platelets or erythrocyte-rich human clots. By modification of the surface with lactadherin, a large number of Sonazoid MBs were attached to the α IIb β 3 integrin-coated and platelet-immobilized plate. Additionally, the video intensity of clots after incubation with lactadherin-bearing Sonazoid MBs was significantly higher than that with unmodified Sonazoid MBs, implying the number of attached Sonazoid MBs was increased by the modification with lactadherin. Our results suggest that the lactadherin-bearing Sonazoid MBs have the potential to be thrombus-targeted MBs., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

IONP (iron oxide nanoparticles) commercialized for treatments of iron anemia or cancer diseases can be administered at doses exceeding 1 g per patient, indicating their bio-compatibility when they are prepared in the right conditions. Various parameters influence IONP biodistribution such as nanoparticle size, hydrophobicity/hydrophilicity, surface charge, core composition, coating properties, route of administration, quantity administered, and opsonization. IONP biodistribution trends include their capture by the reticuloendothelial system (RES), accumulation in liver and spleen, leading to nanoparticle degradation by macrophages and liver Kupffer cells, possibly followed by excretion in feces. To result in efficient tumor treatment, IONP need to reach the tumor in a sufficiently large quantity, using: (i) passive targeting, i.e. the extravasation of IONP through the blood vessel irrigating the tumor, (ii) molecular targeting achieved by a ligand bound to IONP specifically recognizing a cell receptor, and (iii) magnetic targeting in which a magnetic field gradient guides IONP towards the tumor. As a whole, targeting efficacy is relatively similar for different targeting, yielding a percentage of injected IONP in the tumor of 5.10 -4 % to 3%, 0.1% to 7%, and 5.10 -3 % to 2.6% for passive, molecular, and magnetic targeting, respectively. For the treatment of iron anemia disease, IONP are captured by the RES, and dissolved into free iron, which is then made available for the organism. For the treatment of cancer, IONP either deliver chemotherapeutic drugs to tumors, produce localized heat under the application of an alternating magnetic field or a laser, or activate in a controlled manner a sono-sensitizer following ultrasound treatment.

Nanosized self-assemblies built from inorganic nanoparticles and polymer ligands have the potential to generate personalized theranostics systems for diagnostic imaging and cancer therapy. However, most of the theranostics systems suffer from poor targeting activity, insensitive diagnosis and drug leakage, leading to poor treatment results. In this study, a hierarchical tumor acidity-responsive magnetic nanobomb (termed HTAMN) was developed for photodynamic therapy and diagnostic imaging. The HTAMNs were formed through the self-assembly of chlorin e6 (Ce6)-functionalized polypeptide ligand, methoxy poly (ethyleneglycol)-block-poly (dopamine-ethylenediamine-2,3-dimethylmaleic anhydride)-L-glutamate-Ce6 [mPEG-b-P (Dopa-Ethy-DMMA)LG-Ce6] and superparamagnetic iron oxide nanoparticles (SPIONs). Negatively charged HTAMNs circulate in the blood for prolonged periods and promote tumor retention by passive targeting to the tumor. Once the HTAMNs arrive at the tumor location, the acidic extracellular tumor environment reverses the surface charge of the HTAMNs, resulting in tumor accumulation and cellular uptake. Moreover, in response to the more acidic environment inside cells, the photosensitizers are activated resulted in enhanced diagnostic imaging and cancer treatment. The in vitro and in vivo results indicate the effective tumor accumulation, internalization, diagnostic sensitivity and superior photodynamic therapy effect of the HTAMNs. Therefore, designing smart HTAMNs can promote the rapid development of cancer theranostics for clinical implementation., (Copyright © 2019. Published by Elsevier B.V.)

Iron Oxide Nanoparticles (IONPs) are used in several fields of application, mainly in the biomedical field for their magnetic properties and in food additive known as "E172" for their colour. In the present investigation, we focused on IONP effects on Wistar rat following acute oral exposure. We performed a multiscale physiopathological investigation in order to elucidate potential toxic effects linked to IONP ingestion, especially on cognitive capacities, trace element distribution, blood constituents, organ functions, organ structure and iron deposit. We demonstrated that oral exposure to IONPs induces disturbances of certain parameters depending on the dose. Interestingly, the histopathological examination evidenced inflammatory effects of IONPs in the liver with iron deposits in hepatocytes and Kuppfer cells. Neurobehavioral examination showed that oral exposure to IONPs did not affect nor rat emotions, exploration and locomotion capacities, nor spatial reference memory status. Furthermore, oral administration of IONPs did not disrupt the trace element homeostasis nor in the liver neither in the stomach. Altogether, our study evidenced low signs of toxicity, but some effects lead us to a careful use of these NPs. Thereby, their use in foods should be further studied to better evaluate the potential toxic risks of the oral exposure to IONPs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

It is suggested that both iron overload and chromium(III) deficiency may be risk factors of diabetes. It seems that both Fe and Cr(III) metabolism as well as copper and zinc metabolism are interrelated. However, the direction of these changes may depend on mutual proportions of these elements in the diet and organism. The aim of the study was to evaluate the combined effects of Cr(III) supplementation with Fe excess on the Cu and Zn status in female rats. Thirty-six healthy rats were divided into 6 experimental groups with different Fe levels in the diet. Groups marked with C (control) contained Fe at the recommended level (45 mg kg -1 ). The excess groups (E) contained Fe at 180 mg kg -1 . At the same time the animals were supplemented with Cr(III) of doses 1, 50 and 500 mg kg -1 of diet. The Cr, Fe, Cu and Zn dietary and tissular contents were measured with the AAS method.The excess Fe in the diet significantly decreased the Cu content in the liver and kidneys, but it increased the spleen Cu level. The Cr(III) supplementary did not affect the tissular Cu levels, regardless of Fe supply with diet. The experimental factors did not have significant interactional effect on the Cu status parameters under study.The Fe excess in the diet reduced the renal and splenic Zn content, but increased the heart Zn content. The Cr(III) supplementation decreased the Zn content in the kidneys. The Zn content in the liver and spleen tended to decrease as the Cr(III) supply in the diet increased. There was no significant interactional effect of Cr(III) supplementation and the Fe excessive supply in diet on the parameters of Zn metabolism in Wistar rats. Iron oversupply disturbed the rat's Cu and Zn status. However, Cr(III) supplementation did not affect the tissular levels of these elements, except the kidney Zn content. Simultaneous supplementation with the Cr(III) propionate complex did not deepen changes in tissular Cu and Zn levels caused by the Fe excess in the diet., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Nanometals are widely being used for diagnosis, treatment and monitoring of medical conditions. Majorly, nanometals are used to facilitate the delivery of drug to targeted site, minimize drug's penetration to healthy tissues, increase drug's bioavailability, and inhibit its uptake and elimination from the blood by reticuloendothelial process. Despite several benefits, use of nanoparticles as drug carriers is also associated with many problems including instability in blood during circulation, undesirable biodistribution, and toxicity. Research has shown that modification in physicochemical properties including shape, size, and surface can develop a nanometal with desired properties but devoid of associated problems. This review introduces the clinical impact of important physicochemical properties of nanometals such as surface modification, shape, and size. Further, the review focuses on evidence reporting the impact of these properties on pharmacokinetics of nanometals with focus on gold, silver, and iron oxide due to their wide use in the medical field., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Iron is administered intravenously (IV) to many dialysis patients at regular intervals and iron stores are evaluated through periodic measurements of ferritin and transferrin saturation (TSAT). In patients without kidney diseases, large single doses of IV iron lead to a transient rise in serum ferritin that does not reflect iron stores. It is not known whether and to what extent smaller IV iron doses used to maintain adequate stores in hemodialysis patients lead to transient spurious elevations of ferritin and TSAT., Methods: Ferritin and TSAT were serially determined over four weeks after the administration of ferric carboxymaltose (FCM) in hemodialysis patients on a stable maintenance FCM dosing regimen of 100 mg or 200 mg every four weeks., Results: Ferritin values increased by 113 ± 72.2 μg/l (P < 0.001) from baseline to the peak value and remained significantly elevated until two weeks after the administration of 100 mg FCM (n = 19). After the administration of 200 mg FCM (n = 12), ferritin values increased by 188.5 ± 67.56 μg/l (P < 0.001) and remained significantly elevated by the end of week three. TSAT values increased by 12.0 ± 9.7% (P < 0.001) and 23.1 ± 20.4% (P = 0.002) in patients receiving 100 or 200 mg FCM, respectively, and returned to baseline within four days., Conclusions: IV administration of FCM at doses of 100 or 200 mg in hemodialysis patients leads to dose-dependent transient ferritin elevations of extended duration. Temporal coordination of blood sampling for iron status evaluation with the maintenance IV iron dosing schedule is advisable., Trial Registration: ISRCTN12825165 (retrospectively registered 01/02/2019).

The development of a highly efficient, low-toxicity, ultrasmall ferrite nanoparticle-based T 1 contrast agent for high-resolution magnetic resonance imaging (MRI) is highly desirable. However, the correlations between the chemical compositions, in vitro T 1 relaxivities, in vivo nano-bio interactions and toxicities remain unclear, which has been a challenge in optimizing the in vivo T 1 contrast efficacy. Methods : Ultrasmall (3 nm) manganese ferrite nanoparticles (Mn x Fe 3-x O 4 ) with different doping concentrations of the manganese ions (x = 0.32, 0.37, 0.75, 1, 1.23 and 1.57) were used as a model system to investigate the composition-dependence of the in vivo T 1 contrast efficacy. The efficacy of liver-specific contrast-enhanced MRI was assessed through systematic multiple factor analysis, which included the in vitro T 1 relaxivity, in vivo MRI contrast enhancement, pharmacokinetic profiles (blood half-life time, biodistribution) and biosafety evaluations ( in vitro cytotoxicity testing, in vivo blood routine examination, in vivo blood biochemistry testing and H&E staining to examine the liver). Results : With increasing Mn doping, the T 1 relaxivities initially increased to their highest value of 10.35 mM -1 s -1 , which was obtained for Mn 0.75 Fe 2.25 O 4 , and then the values decreased to 7.64 m M -1 s -1 , which was obtained for the Mn 1.57 Fe 1.43 O 4 nanoparticles. Nearly linear increases in the in vivo MRI signals (ΔSNR) and biodistributions (accumulation in the liver) of the Mn x Fe 3-x O 4 nanoparticles were observed for increasing levels of Mn doping. However, both the in vitro and in vivo biosafety evaluations suggested that Mn x Fe 3-x O 4 nanoparticles with high Mn-doping levels (x > 1) can induce significant toxicity. Conclusion : The systematic multiple factor assessment indicated that the Mn x Fe 3-x O 4 (x = 0.75-1) nanoparticles were the optimal T 1 contrast agents with higher in vivo efficacies for liver-specific MRI than those of the other compositions of the Mn x Fe 3-x O 4 nanoparticles. Our work provides insight into the optimization of ultrasmall ferrite nanoparticle-based T 1 contrast agents by tuning their compositions and promotes the translation of these ultrasmall ferrite nanoparticles for clinical use of high-performance contrast-enhanced MRI., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The efficacy of dynamic therapy for solid tumors suffers daunting challenges induced by tumor hypoxia. Herein, we report a biocompatible nanosystem containing Fe(OH) 3 -modified upconversion nanoparticles (UCNPs) for promoting synergetic chemo- and photodynamic therapy with the modulation of tumor hypoxia. In this system, UCNPs convert 808 nm near-infrared excitation to visible photon energy, which stimulates chlorin-e6 photosensitizers to generate toxic reactive oxygen species (ROS) by consumption of dissolved oxygen in cancer cells. Importantly, we employ Fe(OH) 3 compounds to enable continuous oxygen generation in cancer cells and, meanwhile, induce extra ROS formation through the Fenton-like reaction. The system consequently improves the tumor treatment efficacy in vitro and in vivo. This study puts forward a novel combinatorial therapeutic platform for tumor microenvironment modulation and enhanced cancer therapy.

The development of neurotherapeutics for many neurodegenerative diseases has largely been hindered by limited pharmacologic penetration across the blood-brain barrier (BBB). Previous attempts to target and clear amyloid-β (Aβ) plaques, a key mediator of neurodegenerative changes in Alzheimer's disease (AD), have had limited clinical success due to low bioavailability in the brain because of the BBB. Here we test the effects of inducing an inflammatory response to disrupt the BBB in the 5XFAD transgenic mouse model of AD. Lipopolysaccharide (LPS), a bacterial endotoxin recognized by the innate immune system, was injected at varying doses. 24 hours later, mice were injected with either thioflavin S, a fluorescent Aβ-binding small molecule or 30 nm superparamagnetic iron oxide (SPIO) nanoparticles, both of which are unable to penetrate the BBB under normal physiologic conditions. Our results showed that when pretreated with 3.0 mg/kg LPS, thioflavin S can be found in the brain bound to Aβ plaques in aged 5XFAD transgenic mice. Following the same LPS pretreatment, SPIO nanoparticles could also be found in the brain. However, when done on wild type or young 5XFAD mice, limited SPIO was detected. Our results suggest that the BBB in aged 5XFAD mouse model is susceptible to increased permeability mediated by LPS, allowing for improved delivery of the small molecule thioflavin S to target Aβ plaques and SPIO nanoparticles, which are significantly larger than antibodies used in clinical trials for immunotherapy of AD. Although this approach demonstrated efficacy for improved delivery to the brain, LPS treatment resulted in significant weight loss even at low doses, resulting from the induced inflammatory response. These findings suggest inducing inflammation can improve delivery of small and large materials to the brain for improved therapeutic or diagnostic efficacy. However, this approach must be balanced with the risks of systemic inflammation.

In this study, iron oxide nanoparticles (IO-NPs) with a mean diameter of 102.85 nm were firstly synthesized via a facile green route using Ulva spp. aqueous extract as a bioreductant agent. Then, IO-NPs were loaded into carbonated hydroxyapatite (c-Hap) and the final product was named as the iron oxide nanoparticles loaded carbonated hydroxyapatite (IO-NPs-Lc-Hap). Subsequently, IO-NPs-Lc-Hap was characterized by FT-IR, SEM, XRD and EDX analysis methods. MG colour removal efficiencies of Ulva spp., Hap, IO-NPs and IO-NPs-Lc-Hap materials were also evaluated by adsorption and/or Fenton-like reaction methods. IO-NPs-Lc-Hap with the highest decolourization capacity was chosen as a heterogeneous Fenton-like catalyst for Malachite Green (MG). For Fenton-like decolourization of MG, the optimum H 2 O 2 concentration, initial dye concentration and catalyst concentration were determined to be 30 mM, 100 mg/L and 1.0 g/L, respectively. At these optimum conditions, 100% decolourization efficiency and 33.3% COD removal were obtained. On the other hand, 94% decolourization efficiency and 42% COD removal were achieved for the real textile wastewater at the obtained optimum conditions. The experimental decolourization reaction rate for MG was determined as - r d = 0.0779 [(mg dye0 .3 ) (g cat -0.3 ) (min -1 )] × q t 0 .7 . Also, the catalyst had high decolourization efficiencies at the end of six sequence usages.

Medical imaging is an active field of research that fosters the necessity for novel multimodal imaging probes. In this line, nanoparticle-based contrast agents are of special interest, since those can host functional entities either within their interior, reducing potential toxic effects of the imaging tracers, or on their surface, providing high payloads of probes, due to their large surface-to-volume ratio. The long-term stability of the particles in solution is an aspect usually under-tackled during probe design in research laboratories, since their performance is generally tested briefly after synthesis. This may jeopardize a later translation into practical medical devices, due to stability reasons. To dig into the effects of nanoparticle aging in solution, with respect to their behavior in vivo, iron oxide stealth nanoparticles were used at two stages (3 weeks vs. 9 months in solution), analyzing their biodistribution in mice. Both sets of nanoprobes showed similar sizes, zeta potentials, and morphology, as observed by dynamic light scattering (DLS) and transmission electronic microscopy (TEM), but fresh nanoparticles accumulated in the kidneys after systemic administration, while aged ones accumulated in liver and spleen, confirming an enormous effect of particle aging on their in vivo behavior, despite barely noticeable changes perceived on a simple inspection of their structural integrity.

Nanodrug-delivery systems modified with targeting molecules allow antitumor drugs to localize to tumor sites efficiently. CD147 protein is expressed highly on hepatoma cells. Firstly, we synthesized magnetothermally responsive nanocarriers/doxorubicin (MTRN/DOX) which was composed of manganese zinc (Mn-Zn) ferrite magnetic nanoparticles, amphiphilic and thermosensitivity copolymer drug carriers together with DOX. Then CD147-MTRN/DOX was formed with MTRN/DOX and monoclonal antibody that specifically binds to CD147 protein. It could target hepatoma cells actively and improve the DOX concentration in the tumor sites. Subsequently, an external alternating magnetic field elevated the temperature of the thermomagnetic particles, resulting in structural changes in the thermosensitive copolymer drug carriers, thereby releasing DOX. Hence, CD147-MTRN/DOX could enhance the responsiveness of hepatoma cells to the pre-existing chemotherapy drugs owing to active targeting combined synergistically with thermotherapy and chemotherapy, which has more significant anticancer effects than MTRN/DOX.