Release Of Iron Ions Research Articles

In Vitro Study of the Toxicity Mechanisms of Nanoscale Zero-Valent Iron (nZVI) and Released Iron Ions Using Earthworm Cells.

During the last two decades, nanomaterials based on nanoscale zero-valent iron (nZVI) have ranked among the most utilized remediation technologies for soil and groundwater cleanup. The high reduction capacity of elemental iron (Fe0) allows for the rapid and cost-efficient degradation or transformation of many organic and inorganic pollutants. Although worldwide real and pilot applications show promising results, the effects of nZVI on exposed living organisms are still not well explored. The majority of the recent studies examined toxicity to microbes and to a lesser extent to other organisms that could also be exposed to nZVI via nanoremediation applications. In this work, a novel approach using amoebocytes, the immune effector cells of the earthworm Eisenia andrei, was applied to study the toxicity mechanisms of nZVI. The toxicity of the dissolved iron released during exposure was studied to evaluate the effect of nZVI aging with regard to toxicity and to assess the true environmental risks. The impact of nZVI and associated iron ions was studied in vitro on the subcellular level using different toxicological approaches, such as short-term immunological responses and oxidative stress. The results revealed an increase in reactive oxygen species production following nZVI exposure, as well as a dose-dependent increase in lipid peroxidation. Programmed cell death (apoptosis) and necrosis were detected upon exposure to ferric and ferrous ions, although no lethal effects were observed at environmentally relevant nZVI concentrations. The decreased phagocytic activity further confirmed sublethal adverse effects, even after short-term exposure to ferric and ferrous iron. Detection of sublethal effects, including changes in oxidative stress-related markers such as reactive oxygen species and malondialdehyde production revealed that nZVI had minimal impacts on exposed earthworm cells. In comparison to other works, this study provides more details regarding the effects of the individual iron forms associated with nZVI aging and the cell toxicity effects on the specific earthworms’ immune cells that represent a suitable model for nanomaterial testing.

Critical effect of iron red pigment on photoaging behavior of polypropylene microplastics in artificial seawater

Microplastics (MPs) containing chemical additives undergo extensive aging in the environment, but the effect of additives on aging behavior of MPs is not fully understood. This study evaluated the effects of iron red pigment on the photoaging behavior of polypropylene (PP) MPs and the release kinetics of Fe(II) and Fe(III) under simulated sunlight. Based on analyses in surface property and aging products of leachate, the incorporated iron red pigment significantly decreased the photoaging rate of PP MPs. The critical effect mainly depended on the light shielding and the competition of pigment for electrons and reactive oxygen species generated from irradiated MPs. Light irradiation also caused the production of homologous series of organic products containing dicarboxylic acid end groups. Moreover, aging of pigmented MPs enhanced the release of Fe ions in leachates, and the types of released iron ions were different between dark and light conditions, where the iron ion in dark system was mainly as Fe(III), while Fe(II) was the dominant form in light irradiation, since the released Fe(III) reacted with MP-derived organic acids and reactive oxygen species in light condition. The findings highlight the critical role of inorganic pigments in the environmental fate and risk of MPs.

Amplified Activity of Artesunate Mediated by Iron Oxide Nanoparticles Loaded on a Graphene Oxide Carrier for Cancer Therapeutics.

Development of drugs to tackle the ever-increasing cases of cancer and many other diseases including any pandemic is itself challenging. Repurposing existing drugs is an upcoming drug development strategy established for the reuse of existing licensed drugs to ensure accessible, sustainable, and affordable care against cancer. Herein, we presented a nanochemotherapeutic approach based on PEGylated graphene oxide (GO-PEG) loaded with superparamagnetic iron oxide nanoparticles (NPs) and a sustainable natural origin drug, artesunate (ART) to kill cancerous cells. GO-PEG provided a larger surface area to load the dual cargo, iron oxide NPs (∼40%) and ART (∼13%), at a high loading efficiency and simultaneously affected nanotization and crystallinity of the iron oxide NPs. The morphology and internalization of NPs were determined qualitatively and quantitatively by atomic force microscopy (AFM)-Raman imaging and atomic absorption spectroscopy (AAS) analysis, respectively. Furthermore, the loading and unloading of iron reserves were characterized by high-resolution transmission electron microscopy (TEM) images. The loaded iron oxide NPs underwent a pH-triggered release of iron ions, which is higher in acidic pH than in neutral pH. A ∼sevenfold reduction in the IC50 value of ART upon treatment with the designed nanoconjugate is observed. ART is repositioned as a therapeutic drug against cancer cells, and its efficacy is amplified by the Fenton reaction due to iron oxide NPs, as confirmed by a high oxidative stress generated within the cells. The current work suggests that ART and iron oxide NPs loaded on GO-PEG, a biocompatible carrier, are a promising drug-nanoparticle conjugate for cancer treatment.

Assessment and mechanisms of microalgae growth inhibition by phosphonates: Effects of intrinsic toxicity and complexation

The effects of phosphonates, the heavily-used antiscalants in reverse osmosis systems, on microalgae are controversial, although they are harmless to most aquatic organisms. Herein, we assessed the inhibitory effects of etidronic acid (HEDP) and diethylenetriamine penta(methylene phosphonic acid) (DTPMP) on algal growth and revealed the mechanisms involved in both intrinsic toxicity and complexation. The phosphonates showed weak influences on Scenedesmus sp. LX1 in the first 4 d of cultivation. In contrast, a significant growth inhibition was observed subsequently with half maximal effective concentrations of 57.6 and 35.7 mg/L for HEDP and DTPMP, respectively, at 10 d. The phosphonates had little effect on cellular energy transfer and oxidative stress, quantified by adenosine triphosphate level and superoxide dismutase activity, respectively, demonstrating weak intrinsic toxicities to algal cells. Phosphonates blocked the algal assimilation of iron ions through complexation. Severe iron deficiency limited photosynthetic activity and caused chlorophyll decline, resulting in a functional loss of the photosystem followed by complete algal growth inhibition at the late cultivation stage. Our findings point to a potential ecological impact wherein harmful algal blooms are induced by the natural degradation of phosphonates due to the release of both iron and phosphate ions that stimulate algal regrowth after disinhibition.

Prospects for the use of regulators of oxidative stress in the comprehensive treatment of the novel Coronavirus Disease 2019 (COVID-19) and its complications.

Some surface proteins of the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can bind to the hemoglobin molecule of an erythrocyte, which leads to the destruction of the structure of the heme and the release of harmful iron ions to the bloodstream. The degradation of hemoglobin results in the impairment of oxygen-carrying capacity of the blood, and the accumulation of free iron enhances the production of reactive oxygen species. Both events can lead to the development of oxidative stress. In this case, oxidative damage to the lungs leads then to the injuries of all other tissues and organs. The use of uridine, which preserves the structure of pulmonary alveoli and the air-blood barrier of the lungs in the course of experimental severe hypoxia, and dihydroquercetin, an effective free radical scavenger, is promising for the treatment of COVID-19. These drugs can also be used for the recovery of the body after the severe disease.

Injectable multi-responsive micelle/nanocomposite hybrid hydrogel for bioenzyme and photothermal augmented chemodynamic therapy of skin cancer and bacterial infection

Activatable theranostic strategy with high specificity and sensitivity for simultaneous skin cancer therapy and anti-infection remains a major challenge. Here, we developed an injectable multi-responsive micelle/nanocomposite hybrid hydrogel (CFMG) for bioenzyme and photothermal augmented chemodynamic therapy (CDT) of both skin tumor and bacterial invasion. The multifunctional hybrid hydrogel was successfully fabricated through incorporating MoS2@MnFe2O4 nanocomposites into a dynamic Schiff-based chemical cross-linked hydrogel of chitosan-grafted-dihydrocaffeic acid (CS-DA) and aldehyde Pluronic F127 (F127-CHO) micelles loaded with glucose oxidase (GOx). The sustained release of GOx induced by the pH-responsive biodegradation of the hybrid hydrogel could continuously consume the intratumoral glucose, produce H2O2, and increase acidity. In the gradually enhanced acidic environment, the accelerated release of catalytic iron ions from MoS2@MnFe2O4 nanocomposites catalyzed the decomposition of H2O2 into highly toxic OH via Fenton-like reaction to induce cell death. Remarkably, by combining with a spatiotemporal controllable photothermal hyperthermia, the CFMG hydrogel exhibited bioenzyme and photothermal synergistically enhanced CDT of skin tumor, and demonstrated an almost complete tumor suppression both in vitro (98.8%) and in vivo (97.6%). Moreover, due to the cationic chitosan and the augmented production of OH, the CFMG hydrogel also demonstrated an effective bacterial eradication (≥99%) both in vitro and in vivo. Taken together, the CFMG hydrogel indicated a great potential for simultaneous skin cancer treatment and antibacterial infection.

Iron Nanoparticle Composite Hydrogels for Studying Effects of Iron Ion Release on Red Blood Cell In Vitro Production

Growing numbers of complex surgical interventions increase the need for blood transfusions, which cannot be fulfilled by the number of donors. Therefore, the interest in producing erythrocytes from their precursors-the hematopoietic stem and progenitor cells (HSPCs)-in laboratories is rising. To enable this, in vitro systems are needed, which allow analysis of the effects of essential factors such as iron on erythroid development. For this purpose, iron ion-releasing systems based on poly(ethylene glycol) (PEG)-iron nanocomposites are developed to assess if gradual iron release improves iron bioavailability during in vitro erythroid differentiation. The nanocomposites are synthesized using surfactant-free pulsed laser ablation of iron directly in the PEG solution. The iron concentrations released from the material are sufficient to influence in vitro erythropoiesis. In this way, the production of erythroid cells cultured on flat PEG-iron nanocomposite hydrogel pads can be enhanced. In contrast, erythroid differentiation is not enhanced in the biomimetic macroporous 3D composite scaffolds, possibly because of local iron overload within the pores of the system. In conclusion, the developed iron nanoparticle-PEG composite hydrogel allows constant iron ion release and thus paves the way (i) to understand the role of iron during erythropoiesis and (ii) toward the development of biomaterials with a controlled iron release for directing erythropoiesis in culture.

A Graphdiyne Oxide-Based Iron Sponge with Photothermally Enhanced Tumor-Specific Fenton Chemistry.

Fenton reaction-mediated oncotherapy is an emerging strategy which uses iron ions to catalytically convert endogenous hydrogen peroxide into hydroxyl radicals, the most reactive oxygen species found in biology, for efficient cancer therapy. However, Fenton reaction efficiency in tumor tissue is typically limited due to restrictive conditions. One strategy to overcome this obstacle is to increase the temperature specifically at the tumor site. Herein, a tumor-targeting iron sponge (TTIS) nanocomposite based on graphdiyne oxide, which has a high affinity for iron is described. TTIS can accumulate in tumor tissue by decoration with a tumor-targeting polymer to enable tumor photoacoustic and magnetic resonance imaging. With its excellent photothermal conversion efficiency (37.5%), TTIS is an efficient photothermal therapy (PTT) agent. Moreover, the heat produced in the process of PTT can accelerate the release of iron ions from TTIS and simultaneously enhance the efficiency of the Fenton reaction, thus achieving a combined PTT and Fenton reaction-mediated cancer therapy. This work introduces a graphdiyne oxide-based iron sponge that exerts an enhanced antitumor effect through PTT and Fenton chemistry.

Phase Transformation and Dissolution Behavior of Pyrite in the Roasting-Sulfuric Acid Leaching Process of Vanadium-Bearing Stone Coal

The selective leaching of vanadium and iron has been one of the main concerns in the field of vanadium recovery from stone coal, but the source of iron ions and their release characteristics were still unclear. In this work, the dissolution of pyrite and its roasted product, under conditions in accordance with the vanadium leaching process from stone coal by blank roasting-acid leaching, were studied. The results indicated that the leaching performances of V and Fe in stone coal were significantly correlated, with both depending on the leaching parameters of the H2SO4 concentration, the leaching temperature, the leaching time and the solid to liquid ratio. Under air conditions, with a roasting temperature of 700 °C, the roasted product of pyrite was hematite. Approximately 45% of the roasted product dissolved at its optimal leaching condition—35% higher than that of the raw pyrite. However, any further improvement was difficult, due to the difference in texture between its outer sphere and inner core. The results demonstrated that the roasting treatment led to a significant increase in the release of iron ions during the vanadium leaching process. The pre-removal of pyrite from the raw ore was necessary to reduce the concentration of iron ions in the leachate.

Endosome-triggered ion-releasing nanoparticles as therapeutics to enhance the angiogenic efficacy of human mesenchymal stem cells

Here, we report that Fe ions delivered into human mesenchymal stem cells (hMSCs) by bioreducible metal nanoparticles (NPs) enhance their angiogenic and cell-homing efficacy by controlling ion-triggered intracellular reactive oxygen species (ROS) and improve cell migration, while reducing cytotoxicity. Endosome-triggered iron-ion-releasing nanoparticles (ETIN) were designed to be low-pH responsive to take advantage of the low-pH conditions (4–5) of endosomes for in situ iron-ion release. Due to the different redox potentials of Fe and Au, only Fe could be ionized and released from our novel ETIN, while Au remained intact after ETIN endocytosis. Treatment with an optimal amount of ETIN led to a mild increase in intracellular ROS levels in hMSCs, which enhanced the expression of HIF-1α, a key trigger for angiogenic growth factor secretion from hMSCs. Treatmetn of hMSCs with ETIN significantly enhanced the expression of angiogenesis- and lesion-targeting-related genes and proteins. Transplantation of ETIN-treated hMSCs significantly enhanced angiogenesis and tissue regeneration in a wound-closing mouse model compared with those in untreated mice and mice that underwent conventional hMSC transplantation.

Cellular Uptake, Stability, and Safety of Hollow Carbon Sphere-Protected Fe₃O₄ Nanoparticles.

Magnetic iron oxide (Fe₃O₄) nanoparticles (NPs) have attracted extensive attentions in biomedical fields such as magnetic resonance imaging (MRI). However, the instability and unfavorable dispersity of bare Fe₃O₄ NPs is a challenge for biomedical applications. Herein, we proposed a strategy using hollow carbon sphere (HCS) as a shell structure to endow Fe₃O₄ NPs better stability, dispersity, as well as biocompatibility. To verify intracellular behaviors and biosafety of HCSdecorated Fe₃O₄ nanoparticles (Fe₃O₄@HCS NPs), the assessment of cellular effects of these NPs based on synchrotron radiation-based techniques were done to explore detailed interaction between Fe₃O₄@HCS NPs and liver cells, HepG2. We found that a large number of NPs were internalized by cells in a time-dependent manner determined by inductively coupled plasma mass spectrometry (ICP-MS), which was further supported by intracellular accumulation of iron via X-ray fluorescence (XRF) imaging. Moreover, confocal imaging showed that these NPs mainly located in the lysosomes where they remained stable and undissolved within 72 hours, which was verified by chemical form characterization of iron via Fe K-edge X-ray adsorption near edge structure (XANES). With the coating shell of HCS, the release of iron ions was prevented even in acidic lysosome and the integrity of lysosomal membrane remained unchanged during the storage of NPs. As a result, Fe₃O₄@HCS NPs exhibited low level of oxidative stress and induced negligible cytotoxicity towards HepG2 cells. Based on the powerful techniques, we demonstrated that the carbon outer layer provides a physical barrier that helps remain excellent properties of magnetic Fe₃O₄ NPs and good dispersity, chemical stability, as well as biocompatibility for potential applications in biomedical fields.

EDTA, oxalate, and phosphate ions enhanced reactive oxygen species generation and sulfamethazine removal by zero-valent iron

The activation rate of oxygen by zero-valent iron (Fe°) was very low. In this study, ethylenediaminetetraacetic acid (EDTA), oxalate (Ox), and phosphate ions (Na2HPO4) were used to enhance the oxygen activation by Fe° for sulfamethazine (SMT) removal. The addition of these ligands could significantly enhance the SMT degradation. SMT removal was improved from 10.5 % in the Fe° system (360 min) to 70.3 %, 85.2 % and 77.8 % in the Fe°/EDTA (60 min), Fe°/Ox (180 min) and Fe°/phosphate (360 min) systems, respectively. Scanning electron microscopy with energy dispersive X-ray (SEM-EDX), Fourier transform infrared reflection (FTIR), contact angle and X-ray photoelectron spectra (XPS) of Fe° in different systems were recorded. The presence of chelating agents hydroxylated Fe°, inhibited the iron oxide formation on the Fe° surface and promoted iron ion release from the solid. Moreover, the agents improved the recovery of surface Fe2+ which could subsequently enhance the activation of O2 to produce more H2O2 and reactive oxygen radicals for SMT removal. OH radical produced mainly through H2O2 decomposition was primarily responsible for removing SMT in all three systems. The Fe° system added with chelating agents is a new and promising approach for treating wastewaters containing ligands.

Effects of Persulfate Activation with Pyrite and Zero-Valent Iron for Phthalate Acid Ester Degradation

Phthalic acid esters (PAEs) are often detected in remediated groundwater using appropriate oxidant materials by in situ groundwater treatment. The study compares zero-valent iron–persulfate with a pyrite–persulfate system to degrade three PAEs—di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and dimethyl phthalate (DMP). Column experiments were conducted, and rapid oxidation occurred in a pyrite–persulfate system due to sulfate radical generation. DMP concentration was found at about 60.0% and 53.0% with zero-valent iron (ZVI) and pyrite activation of persulfate, respectively. DBP concentration was measured as 25.0–17.2% and 23.2–16.0% using ZVI–persulfate and pyrite–persulfate systems, respectively. However, DEHP was not detected. The total organic carbon concentration lagged behind the Ʃ3 PAEs. Persulfate consumption with ZVI activation was half of the consumption with pyrite activation. Both systems showed a steady release of iron ions. Overall, the oxidation–reduction potential was higher with pyrite activation. The surface morphologies of ZVI and pyrite were investigated using scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), and XPS. Intensive corrosion occurs on the pyrite surface, whereas the ZVI surface is covered by a netting of iron oxides. The pyrite surface showed more oxidation and less passivation in comparison with ZVI, which results in more availability of Fe 2 + for persulfate activation. The pyrite–persulfate system is relatively preferred for rapid PAE degradation for contamination.

Erosion–corrosion behaviors of 1045 and J55 steels in crude oil

The erosion-corrosion behaviors of 1045 and J55 steels in crude oil with a variation in sand sizes between 500 and 2000 μm were studied using the impingement jet system incorporated with an electrochemical measurement and were characterized with a scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS), and an inductively couple plasma-optical emission spectrometer (ICP-OES). All the erosion-corrosion results agreed well with the ICP-OES measurement that the released iron ions increase with the high wastage of steels, particularly for the 1045 steel, which showed a greater number of released iron ions and a higher penetration rate than the J55 steel. The degree of synergism between the erosion and corrosion drastically changed with the impingement sand size and the microstructure of the steels. The XPS results showed a notable correlation between the erosion-corrosion behaviors and the compounds generated after the wastage of the specimens. A high atomic percentage (at%) of SiO2 and the high amount of COC + CO were found on the highly degraded-surface. Classification of the degradation mode was made distinct by considering the Fe(II)/Fe(III) atomic ratio. A high ratio of the Fe(II)/Fe(III) compounds represents better pure erosion resistance, whereas a low ratio demonstrates better pure corrosion resistance and total corrosion component resistance.

Antibacterial activity of SPIONs versus ferrous and ferric ions under aerobic and anaerobic conditions: a preliminary mechanism study.

In modern medicine, major attention has been paid to superparamagnetic iron oxide nanoparticles (SPIONs). Recent studies have shown the antibacterial properties of SPIONs against some Gram-positive and Gram-negative bacterial strains. These nanoparticles (NPs) can bind to bacterial membranes via hydrophobic or electrostatic interactions and pass through cell barriers. In this study, the authors evaluated the antibacterial activity of magnetic NPs in comparison with ferrous and ferric ions. The level of reactive oxygen species (ROS) in the treated Staphylococcus aureus and Escherichia coli bacteria were directly measured by fluorometric detection. The results showed that iron ions and SPIONs had significant dependent antimicrobial activities. SPIONs showed greater inhibitory effects than ferrous and ferric ions against the growth of treated bacterial strains under anaerobic conditions, while in aerobic conditions, ferrous showed the strongest antibacterial activity. In anaerobic conditions, they observed the greatest ROS formation and lowest minimum inhibitory concentration in the SPION-treated group in comparison with the other groups. It seems that the release of iron ions from SPIONs and subsequent activation of ROS pathway are the main antibacterial mechanisms of action. Nevertheless, the greater antibacterial effect of SPIONs in anaerobic conditions represents other mechanisms involved in the antibacterial activity of these NPs.

Synthesis and toxicity assessment of Fe3O4 NPs grafted by ∼ NH2-Schiff base as anticancer drug: modeling and proposed molecular mechanism through docking and molecular dynamic simulation

Superparamagnetic iron oxide nanoparticles have been synthesized using chain length of (3-aminopropyl) triethoxysilane for cancer therapy. First, we have developed a layer by layer functionalized with grafting 2,4‐toluene diisocyanate as a bi‐functional covalent linker onto a nano-Fe3O4 support. Then, they were characterized by Fourier transform infrared, X-ray powder diffraction, field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, and VSM techniques. Finally, all nanoparticles with positive or negative surface charges were tested against K562 (myelogenous leukemia cancer) cell lines to demonstrate their therapeutic efficacy by MTT assay test. We found that the higher toxicity of Fe3O4@SiO2@APTS ∼ Schiff base-Cu(II) (IC50: 1000 μg/mL) is due to their stronger in situ degradation, with larger intracellular release of iron ions, as compared to surface passivated NPs. For first time, the molecular dynamic simulations of all compounds were carried out afterwards optimizing using MM+, Semi-empirical (AM1) and Ab-initio (STO-3G), Forcite Gemo Opt, Forcite Dynamics, Forcite Energy and CASTEP in Materials studio 2017. The energy (eV), space group, lattice parameters (Å), unit cell parameters (Å), and electron density of the predicted structures were taken from the CASTEP module of Materials Studio. The docking methods were used to predict the DNA binding affinity, ribonucleotide reductase, and topoisomerase II.

Low frequency magnetic fields modification on hydrogen peroxide oxidized myoglobin-isolate and mechanisms underlying the chain reaction process

The effects of low frequency magnetic field (0–12 mT) on hydrogen peroxide oxidized myoglobin-isolate (MbI) were investigated. The results indicate that the primary target of the hydrogen peroxide oxidation was Met(FeIII)Mb, leading to the fall off of iron ions from the porphyrin ring. Additionally, the increased magnetic field (≥9 mT) enhanced the release of more iron ions to react with H2O2, giving rise to the production of more hydroxyl radicals and the shift of oxidation site from porphyrin ring to Mb skeleton. Moreover, the directional movement of iron ions induced by magnetic field caused the generation of local micro-electric field and the rearrangement of charged groups on the protein surface or near-surface, thus affecting Mb aggregation. Overall, the magnetic field interfered with the hydrogen peroxide chain reaction process, changed the redox equivalents of Mb, and shifted the oxidation sites of Mb.

Iron Oxide Nanoparticle-Induced Neoplastic-Like Cell Transformation in Vitro Is Reduced with a Protective Amorphous Silica Coating.

Iron oxide nanoparticles (IONP) have recently surged in production and use in a wide variety of biomedical and environmental applications. However, their potential long-term health effects, including carcinogenesis, are unknown. Limited research suggests IONP can induce genotoxicity and neoplastic transformation associated with particle dissolution and release of free iron ions. "Safe by design" strategies involve the modification of particle physicochemical properties to affect subsequent adverse outcomes, such as an amorphous silica coating to reduce IONP dissolution and direct interaction with cells. We hypothesized that long-term exposure to a specific IONP (nFe2O3) would induce neoplastic-like cell transformation, which could be prevented with an amorphous silica coating (SiO2-nFe2O3). To test this hypothesis, human bronchial epithelial cells (Beas-2B) were continuously exposed to a 0.6 μg/cm2 administered a dose of nFe2O3 (∼0.58 μg/cm2 delivered dose), SiO2-nFe2O3 (∼0.55 μg/cm2 delivered dose), or gas metal arc mild steel welding fumes (GMA-MS, ∼0.58 μg/cm2 delivered dose) for 6.5 months. GMA-MS are composed of roughly 80% iron/iron oxide and were recently classified as a total human carcinogen. Our results showed that low-dose/long-term in vitro exposure to nFe2O3 induced a time-dependent neoplastic-like cell transformation, as indicated by increased cell proliferation and attachment-independent colony formation, which closely matched that induced by GMA-MS. This transformation was associated with decreases in intracellular iron, minimal changes in reactive oxygen species (ROS) production, and the induction of double-stranded DNA damage. An amorphous silica-coated but otherwise identical particle (SiO2-nFe2O3) did not induce this neoplastic-like phenotype or changes in the parameters mentioned above. Overall, the presented data suggest the carcinogenic potential of long-term nFe2O3 exposure and the utility of an amorphous silica coating in a "safe by design" hazard reduction strategy, within the context of a physiologically relevant exposure scenario (low-dose/long-term), with model validation using GMA-MS.

Enhancing the Wound Healing Effect of Conditioned Medium Collected from Mesenchymal Stem Cells with High Passage Number Using Bioreducible Nanoparticles.

Injecting human mesenchymal stem cells (hMSCs) at wound sites is known to have a therapeutic effect; however, hMSCs have several limitations, such as low viability and poor engraftment after injection, as well as a potential risk of oncogenesis. The use of a conditioned medium (CM) was suggested as an alternative method for treating various wounds instead of direct hMSC administration. In addition to not having the adverse effects associated with hMSCs, a CM can be easily mass produced and can be stored for long-term, thereby making it useful for clinical applications. In general, a CM is collected from hMSCs with low passage number; whereas, the hMSCs with high passage number are usually discarded because of their low therapeutic efficacy as a result of reduced angiogenic factor secretion. Herein, we used a CM collected from high passage number (passage 12, P12) hMSCs treated with gold-iron nanoparticles (AuFe NPs). Our AuFe NPs were designed to release the iron ion intracellularly via endocytosis. Endosomes with low pH can dissolve iron from AuFe NPs, and thus, the intracellularly released iron ions up-regulate the hypoxia-inducible factor 1α and vascular endothelial growth factor (VEGF) expression. Through this mechanism, AuFe NPs improve the amount of VEGF expression from P12 hMSCs so that it is comparable to the amount of VEGF expression from low passage number (passage 6, P6), without treatment. Furthermore, we injected the CM retrieved from P12 MSCs treated with AuFe NPs in the mouse skin wound model (AuFe P12 group). AuFe P12 group revealed significantly enhanced angiogenesis in the mouse skin wound model compared to the high passage hMSC CM-injected group. Moreover, the result from the AuFe P12 group was similar to that of the low passage hMSC CM-injected group. Both the AuFe P12 group and low passage hMSC CM-injected group presented significantly enhanced re-epithelization, angiogenesis, and tissue remodeling compared to the high passage hMSC CM-injected group. This study reveals a new strategy for tissue regeneration based on CM injection without considering the high cell passage count.

Iron Release Profile of Silica-Modified Zero-Valent Iron NPs and Their Implication in Cancer Therapy.

To evaluate the iron ion release profile of zero-valent iron (ZVI)-based nanoparticles (NPs) and their relationship with lysosomes in cancer cells, silica and mesoporous silica-coated ZVI NPs (denoted as ZVI@SiO2 and ZVI@mSiO2) were synthesized and characterized for the following study of cytotoxicity, intracellular iron ion release, and their underlying mechanisms. ZVI@mSiO2 NPs showed higher cytotoxicity than ZVI@SiO2 NPs in the OEC-M1 oral cancer cell line. In addition, internalized ZVI@mSiO2 NPs deformed into hollow and void structures within the cells after a 24-h treatment, but ZVI@SiO2 NPs remained intact after internalization. The intracellular iron ion release profile was also accordant with the structural deformation of ZVI@mSiO2 NPs. Burst iron ion release occurred in ZVI@mSiO2-treated cells within an hour with increased lysosome membrane permeability, which induced massive reactive oxygen species generation followed by necrotic and apoptotic cell death. Furthermore, inhibition of endosome–lysosome system acidification successfully compromised burst iron ion release, thereby reversing the cell fate. An in vivo test also showed a promising anticancer effect of ZVI@mSiO2 NPs without significant weight loss. In conclusion, we demonstrated the anticancer property of ZVI@mSiO2 NPs as well as the iron ion release profile in time course within cells, which is highly associated with the surface coating of ZVI NPs and lysosomal acidification.