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The toxicity mechanism of superparamagnetic iron oxide nanoparticles (SPIONs) were examined multidimensionally to reduce the toxicity risks. A higher dosage and more suitable size of SPIONs enhanced the uptake amount into MCF7 cells, leading to a higher specific uptake rate of SPIONs with the formation of more reactive oxygen species (ROS). ROS was an intrinsic factor of cell death. Interestingly, the smaller SPIONs (S1) liked to produce more ROS in mitochondria to damage mitochondria, while the larger SPIONs (S2 and S3) promoted ROS yield in plasma to destroy cytomembrane. Furthermore, ROS synthesis pathways were the partial of cell death pathways, and ferroptosis pathway was the main contributor to mitochondrial and cytomembrane damage. Meanwhile, ROS amount was well coincided to gene expression level of these cell death pathways, which inferred RNA-seq might be a new method to evaluate the oxidative stress and potential toxicity of nanomaterials., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In this work, the internalization and distribution of citric acid-coated magnetite nanoparticles (here, Fe 3 O 4 -NPs) in soybean and alfalfa tissues and their effects on plant growth were studied. Both legumes were germinated in pots containing an inert growing matrix (vermiculite) to which Hoagland solution without (control, C), with Fe 3 O 4 -NPs (50 and 100 mgironL -1 , NP50 and NP100), or with the same amount of soluble iron supplied as Fe-EDTA (Fe50, Fe100) was added once before sowing. Then, plants were watered with the standard nutrient solution. The observation of superparamagnetic signals in root tissues at harvest (26 days after emergence) indicated Fe 3 O 4 -NPs uptake by both legumes. A weak superparamagnetic signal was also present in the stems and leaves of alfalfa plants. These findings suggest that Fe 3 O 4 -NPs are readily absorbed but not translocated (soybean) or scarcely translocated (alfalfa) from the roots to the shoots. The addition of both iron sources resulted in increased root weight; however, only the addition of Fe 3 O 4 -NPs resulted in significantly higher root surface; shoot weight also increased significantly. As a general trend, chlorophyll content enhanced in plants grown in vermiculite supplemented with extra iron at pre-sowing; the greatest increase was observed with NP50. The only antioxidant enzyme significantly affected by our treatments was catalase, whose activity increased in the roots and shoots of both species exposed to Fe 3 O 4 -NPs. However, no symptoms of oxidative stress, such as increased lipid peroxidation or reactive oxygen species accumulation, were evidenced in any of these legumes. Besides, no evidence of cell membrane damage or cell death was found. Our results suggest that citric acid-coated Fe 3 O 4 -NPs are not toxic to soybean and alfalfa; instead, they behave as plant growth stimulators., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In order to solve two issues of chlorine-resistant bacteria (CRB) and disinfection byproducts (DBPs) in tap water after the chlorine-containing treatment process, an innovative core-sheath nanostructured Cu/Cu 2 O-ZnO-Fe 3 O 4 was designed and synthesized. The fabrication mechanism of the materials was then systematically analyzed to determine the component and valence state. The properties of CRB inactivation together with trichloroacetic acid (TCAA) photodegradation by Cu/Cu 2 O-ZnO-Fe 3 O 4 were investigated in detail. It was found that Cu/Cu 2 O-ZnO-Fe 3 O 4 displayed excellent antibacterial activity with a relatively low cytotoxicity concentration due to its synergism of nanowire structure, ion release, and reactive oxygen species generation. Furthermore, the Cu/Cu 2 O-ZnO-Fe 3 O 4 nanocomposite also exhibited outstanding photocatalytic degradation activity on TCAA under simulated sunlight irradiation, which was verified to be dominated by the surface reaction through kinetic analysis. More interestingly, the cell growth rate of Cu/Cu 2 O-ZnO-Fe 3 O 4 was determined to be 50% and 10% higher than those of Cu/Cu 2 O and Cu/Cu 2 O-ZnO after 10 h incubation, respectively, manifesting a weaker cytotoxicity. Therefore, the designed Cu/Cu 2 O-ZnO-Fe 3 O 4 could be a promising agent for tap water treatment.

This research, for the first time, report the synthesis of core-shell magnetic nanoparticles (NPs) consisting poly acrylic acid (PAA) coated cobalt ferrite (CF) using a simple co-precipitation route. Nanocrystalline PAA@CF-NPs, particle size of 9.2 nm, exhibited saturation magnetization as 28.9 emu/g, remnant magnetization as 8.37 emu/g, and coercivity as 543 Oe. Keeping biomedical applications into consideration, PAA@CF-NPs were further analysed to evaluate antimicrobial performance against Gram positive (Staphylococcus aureus and Bacillus subtilis) and Gram negative (Pseudomonas aeruginosa and Escherichia coli) bacteria, and biocompatibility with reference to activated splenic cells. The PAA@CF-NPs were viable to the normal splenic cells (up to 1000 μg/ml) and do not affect the ability of fast dividing ability of the cells (activated splenic cells). An optimized dose of PAA@CF-NPs was intramuscularly administrated (100 μg/ml) into Albino mice to evaluate acute toxicity. The results of these studies suggest that injected PAA@CF-NPs do not affect vital organs mainly including liver and kidneys that confirmed the heptic/renal biocompatibility. The outcomes of this research project such developed nano-system for biomedical applications, mainly for magnetically guided drug delivery and image guided therapies development. However, to support the proposed claims, extended in-vivo studies are required to explore bio-distribution, chronic toxicity, and homeostatic conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A systematic study was carried out to evaluate the uptake and cytotoxicity of methotrexate (MTX) conjugated to superparamagnetic iron oxide nanoparticles (SPIONs) modified with glycerol phosphate (Glyc) and phosphorylethanolamine (PEA), using MCF-7 cancer cell line as model. The ligand shell composition was controlled in such a way to get SPIONs with nine different surface functionalization and up to three co-conjugated ligands but the very iron oxide core, in order to test and compare uptake and cytotoxicity, and verify possible additive effects. Folic acid (FA), the non-toxic analogue of MTX, was also explored as ligand for SPIONs. Glyc was shown to enhance dramatically the cellular uptake despite the high negative zeta potentials, whereas PEA, FA and MTX was found to have a much lower effect on the cellular uptake. Also, a significant ten times lowering of IC 50 was observed for the co-conjugated MTX in the SPION-Glyc/PEA/MTX as compared to the free drug, whereas the analogue SPION-Glyc/PEA/FA nanoparticles exhibited no significant cytotoxicity. In short, the conjugation of MTX to SPIONs enhanced dramatically its cytotoxicity and decreased the IC 50 value against MCF-7 tumor cells as compared to the free drug, probably due to the enhanced uptake of SPIONs as a result of their surface modification with Glyc/PEA, demonstrating that SPION-Glyc/PEA is a good nanocarrier for co-conjugated methotrexate.

Pre-conceptual sex selection is still a highly debatable process whereby X and Y chromosome bearing spermatozoa are isolated before oocyte fertilization. Recently, magnetic nanoparticles (MNP) have been used to determine X and Y chromosomes bearing spermatozoa as a result of searching for a cheap, highly efficient method using non-toxic materials. This study aimed to recover the sperm bearing X chromosomes in ram with different concentrations of MNP and then evaluate the success of this method using polymerase chain reaction (PCR). Ram sperms were divided into four groups, treated with 0 (control), 50, 100 and 200 μg/ml MNP, respectively. MNP was used to restore sperm cells bearing X chromosomes. Upon recovery, the PCR was performed to identify the X and Y sperms, Methyl ThiazoleTetrazolium (MTT), to assess MNP toxicity and sperm viability and acridine orange (AO) to evaluate sperm DNA integrity. The results of PCR revealed that the treatment of spermatozoa- bearing X chromosomes with 50 μg/ml MNP had the highest effects on the recovery of X sperm rather than the other concentrations of MNP. However, the concentrations of MNP did not have any toxic effects on spermatozoa, sperm viability and, DNA integrity, but the high concentration of MNP (200 μg/ml) significantly reduced DNA integrity. According to MTT and AO results, the concentrations of MNP used in this study had no toxic effects on spermatozoa and did not reduce the sperm viability and DNA integrity, except that 200 μg/ml MNP significantly reduced DNA integrity., (© 2020 Wiley-VCH GmbH.)

Malaria is one of the deadliest infectious diseases threatening half of the world population. With the deterioration of the parasiticidal effect of the current antimalarials, novel approaches such as screening of more specific inhibitors and targeted delivery of drugs have been under intensive research. Herein, we prepare hollow mesoporous ferrite nanoparticles (HMFNs) of 200 nm with ferromagnetic properties using a one-pot hydrothermal reaction. A magnetically targeted drug-delivery system coloaded with artemisinin in the inner magnetite shell and heparin on the outer mesoporous shell (HMFN@ART@HEP) is developed. Specific targeting of the magnetic nanoparticles to the parasite-infected erythrocytes is achieved by the attraction between the HMFNs and hemozoin (paramagnetic), a vital metabolite of plasmodium in the erythrocytic stage. With the hemozoin production reaching the maximum during the schizont period of the parasite, HMFN@ART@HEPs are adsorbed to the infected red blood cells (iRBCs), which not only interferes with the release of merozoites but also significantly enhances the inhibitory efficacy due to the increased local concentration of artemisinin. Subsequently, the heparin coated on the surface of the nanoparticles can efficiently interfere with the invasion of freshly released merozoites to new RBCs through the specific interaction between the parasite-derived ligands and heparin, which further increases the inhibitory effect on malaria. As a cluster of heparin, heparin-coated nanoparticles provide stronger blocking capability than free heparin, resulting from multivalent interactions with surface receptors on merozoite. Thus, we have developed a HMFN-based delivery system with considerable antimalarial efficacy, which is a promising platform for treatment against malaria.

Fe 3 O 4 nanoparticles were obtained by chemical coprecipitation of iron chloride and sodium hydroxide. The morphology and sizes of the obtained nanoparticles were characterized using laser Doppler velocimetry, transmission electron and atomic force microscopy. Then the nanoparticles were stabilized by three polycations (polyethylenimine (PEI), poly(allylamine hydrochloride) (PAH), poly(diallyldimethylammonium chloride) (PDADMAC)) to increase their biocompatibility. The cytotoxicity of the obtained polymer-stabilized nanoparticles was studied using a human lung carcinoma cell line (A549). The biodistribution of nanoparticles stabilized by polycations in human lung carcinoma cells was analyzed by transmission electron microscopy, and the toxicity of nanomaterials was evaluated using toxicity tests and flow cytometry. As a result, the most biocompatible nanoparticle-biopolymer complex was identified. PAH stabilized magnetic nanoparticles demonstrated the best biocompatibility, and the PEI-magnetic nanoparticle complex was the most toxic., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Nanoparticle induced hyperthermia has been considered as a promising approach for cancer treatment for decades. The local heating ability and drug delivery potential highlight a diversified possibility in clinical application, therefore a variety of nanoparticles has been developed accordingly. However, currently, only a few of them are translated into the clinical stage indicating a 'medically underexplored nanoparticles' situation, which encourages their comprehensive biomedical exploration. This study presents a thorough biological evaluation of previous well-developed dual pH- and thermo-responsive magnetic doxorubicin-nanocarriers (MNC-DOX) in multiple cancer cell lines. The cytotoxicity of the nanocomposites has been determined by the MTT assay on primary cell lines. Histology and fluorescence microscopy imaging revealed the efficiency of cellular uptake of nanocarriers in different cell lines. The IC50 of MNC-DOX is significantly higher than that of free DOX without an alternating magnetic field (AMF), which implied the potential to lower the systemic cytotoxicity in clinical research. The concurrent thermo-chemotherapy generated by this platform has been successfully achieved under an AMF. Promising effective synergistic results have been demonstrated through in vitro study in multi-model cancer cell lines via both trypan blue exclusion and bioluminescence imaging methods. Furthermore, the two most used magnetic hyperthermia modalities, namely intracellular and extracellular treatments, have been compared on the same nanocarriers in all 3 cell lines, which showed that treatment after internalization is not required but preferable. These results lead to the conclusion that this dual responsive nanocarrier has extraordinary potential to serve as a novel broad-spectrum anticancer drug and worth pursuing for potential clinical applications.

Herein, thermo- and pH-sensitive pectin-graft-poly(dimethylaminoethyl methacrylate) copolymer-coated magnetic nanoparticles were synthesized via a green and rapid synthetic approach based on microwave irradiation. Firstly, a novel thermo- and pH-sensitive pectin-graft-poly(dimethylaminoethyl methacrylate) copolymer (Pec-g-PolyDMAEMA) was synthesized and then, Pec-g-PolyDMAEMA based magnetic nanoparticles (Pec-g-PolyDMAEMA@Fe 3 O 4 ) were produced via microwave-assisted co-precipitation method. The thermo/pH/magnetic field multi-sensitive hybrid nanoparticle was characterized by techniques like TEM, VSM, FT-IR, and TGA/DSC. In vitro release studies of 5-Fluorouracil (FL) were carried out by altering the temperature (37 and 44°C), pH (5.5 and 7.4) and presence of an AMF. The FL release of Pec-g-PolyDMAEMA@Fe 3 O 4 @FL exhibited pH-sensitive behavior. They showed thermo/pH-sensitive FL release features with the greatest release of FL at 37°C (56%) than at 44°C (40%) and at pH of 7.4 (63%) than at pH of 5.5 (45%) within 48h. The FL release was also significantly increased (100%) with the presence of a 50 mT magnetic field. These results indicate that the developed Pec-g-PolyDMAEMA@Fe 3 O 4 nanoparticles are promising in the application of multi-stimuli-sensitive delivery of drugs., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2018. Published by Elsevier B.V.)

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 .

Iron-oxide nanoparticles are one of the most commercialized nanomaterials and have gained widespread acceptance in nanotherapeutics due to their ability for targeted drug delivery, bioimaging, and various other preclinical and clinical theranostic biomedical applications. However, the absence of regulations, guidelines, and harmonized standards as well as limitations associated with their use in clinical settings in the context of their safety and toxicity profiling necessitates in-depth understanding of their toxicological paradigms. Here we examine the toxicity of modified superparamagnetic iron oxide nanoparticles in Swiss albino mice in terms of body weight changes, organ coefficients, generalized and organ-specific biochemical, and various histological staining parameters after administration of bare (uncoated) magnetic nanoparticles (MNPs) and triple polymer-coated magnetic nanoparticles (MNP-AC-G2-pPEG). Both types of nanoparticles were administered intravenously, in three doses (5, 10, and 25 mg/kg body weight) and results of biochemical and histopathological assessment revealed that the highest dose of bare (uncoated) MNPs significantly altered biochemical and histoarchitectural aspects in vital organs, while coated NPs (MNP-AC-G2-pPEG) was found safe in almost all doses. Furthermore, results of toluidine blue (for mast cells) and Prussian blue (for iron deposition) staining also established that the highest dose administration of bare MNPs in animals significantly enhanced mast cell infiltration and iron deposition in tissue sections of most vital organs, while coated NPs did not demonstrate any such adverse effects. Overall, outcomes of this study aid in establishing that administration of uncoated (bare) magnetic NPs in vivo results in structural and functional toxicological modifications while the coating of these NPs with biocompatible and biodegradable polymers can significantly bring down the toxicity of these NPs.

Background: Nanoparticles (NPs) can enter cells and cause cellular dysfunction. For example, reactive oxygen species generated by NPs can damage the cytoskeleton and impair cellular adhesion properties. Previously, we reported that cell spreading and protrusion structures such as lamellipodia and filopodia was reduced when cells are treated with silica-coated magnetic nanoparticles incorporating rhodamine B isothiocyanate (MNPs@SiO 2 (RITC)), even at 0.1 μg/μL. These protruded structures are involved in a cell's rigidity sensing, but how these NPs affect rigidity sensing is unknown., Results: Here, we report that the rigidity sensing of human embryonic kidney (HEK293) cells was impaired even at 0.1 μg/μL of MNPs@SiO 2 (RITC). At this concentration, cells were unable to discern the stiffness difference between soft (5 kPa) and rigid (2 MPa) flat surfaces. The impairment of rigidity sensing was further supported by observing the disappearance of locally contracted elastomeric submicron pillars (900 nm in diameter, 2 μm in height, 24.21 nN/μm in stiffness k) under MNPs@SiO 2 (RITC) treated cells. A decrease in the phosphorylation of paxillin, which is involved in focal adhesion dynamics, may cause cells to be insensitive to stiffness differences when they are treated with MNPs@SiO 2 (RITC)., Conclusions: Our results suggest that NPs may impair the rigidity sensing of cells even at low concentrations, thereby affecting cell adhesion and spreading.

Cartilage injury is very common and results in considerable pain and osteoarthritis. Owing to its low self-renewal capability, cartilage regeneration is still a great challenge for clinicians. Stem cell therapy has been treated as the most promising treatment for cartilage regeneration in recent decades. However, increasing concerns about the potential biosafety of stem cell products such as immune rejection and neoplastic transformation restrict their further application in clinic. Herein, biomimetic stem cell membrane-disguised nanovehicles without biosafety risks are designed and prepared for cartilage regeneration. In this study, based on the disguise of the natural bone marrow mesenchymal stem cell (BMSC) membrane, Kartogenin (KGN) as a drug for cartilage regeneration was encapsulated into Fe3O4 nanoparticles as the core of biomimetic stem cell nanovehicles. In the core-shell structure of biomimetic stem cell nanovehicles, the fabricated KGN-loaded BMSC membrane-disguised Fe3O4 nanoparticles (KGN-MNPs) showed a stable hybrid structure with a uniform size and morphology in the physiological environments. Moreover, the prepared KGN-MNPs exhibited excellent biocompatibility when disguised with the natural membrane of BMSCs and good biosafety by eliminating the nuclei of BMSCs. In a cartilage defect rat model, compared with pure KGN, the intra-articularly injected KGN-MNPs were capable of regenerating an integrated organized structure with a layer of hyaline-like cartilage in a shorter time due to the retained natural activities of the BMSC membrane. In a word, KGN-MNPs as one kind of our designed biomimetic stem cell nanovehicles enable rapid and high quality cartilage regeneration, and provide a novel and standardized strategy for stem cell therapy in the future.

Multifunctional nanomedical platforms have broad prospects in imaging-guided combination therapy in cancer precision medicine. In this work, metal-organic framework (MOF)-derived novel porous Fe3O4@C nanocomposites were developed as an intelligent cancer nanomedical platform for combined cancer therapy with MRI-guided magnetic-triggered hyperthermia and chemotherapy functions. The magnetic behavior, porous character and good surface modification endowed this smart nanoplatform with favorable biocompatibility, high-efficiency MRI imaging, magnetic-triggered on-demand DOX release function, and synergistic therapy of magnetic hyperthermia and chemotherapy, which proposed an all-in-one platform for cancer therapy. Additionally, in vivo animal experiments verified the significant suppression of malignant tumor growth with negligible side effects, which were attributed to the consecutive 13 day synergistic therapy of magnetic hyperthermia and chemotherapy in one. To be specific, Fe3O4@C-PVP@DOX significantly decreases the volume (2.5 to 0.44 of tumor volume ratio) and weight (0.49 g to 0.10 g) of tumors after magnetic-triggered hyperthermia and chemotherapy treatments. Moreover, no big difference of body weight and associated damage was observed among all major organs. Therefore, owing to its high-efficiency combined therapy of magnetic-triggered hyperthermia and chemotherapy, this smart nanoplatform holds great potential application in the precise treatments of clinical cancer.

In this manuscript, biological durability, cytotoxicity and MRI image contrast effect of chitosan modified magnetic nanoparticles were investigated. The result of durability study shows that the asprepared sample with average size of about 30 nm had a high stability under pH conditions in range of from 2 to 12 and at salt concentration in range of from 0 to 300 mM. The cytotoxicity testing indicates that the obtained Fe₃O₄@CS ferrofluid revealed a low cytotoxicity. After 48 h of test on the line of prostate tumor cells of Sarcoma 180, collected IC 50 value was 178.5±22 ( μ g/ml), 7.5 to 27.9 times less cytotoxicity than that of reported ferromagnetic fluids. MRI data shows that the transverse relaxation rate ( r 2) of the ferrite nanoparticles was 130.32 (mM -1 s -1 ), 2 and 1.44 times larger than that of the commercial products of Sinerem (AMI-227) and Ferumoxytol products, respectively. Invivo test in rabbit shows that the picture of body parts was clearly observed after the injection of the Fe₃O₄@CS ferrofluid. With these outstanding properties, this magnetic fluid based on the chitosan modified Fe₃O₄ nanoparticles had great potential for enhancing the image contrast in image diagnosis by MRI magnetic resonance imaging technique.

Nanoparticles (NPs) are increasingly exploited as diagnostic and therapeutic devices in medicine. Among them, superparamagnetic nanoparticles (SPIONs) represent very promising tools for magnetic resonance imaging, local heaters for hyperthermia, and nanoplatforms for multimodal imaging and theranostics. However, the use of NPs, including SPIONs, in medicine presents several issues: first, the encounter with the biological world and proteins in particular. Indeed, nanoparticles can suffer from protein adsorption, which can affect NP functionality and biocompatibility. In this respect, we have investigated the interaction of small SPIONs covered by an amphiphilic double layer of oleic acid/oleylamine and 1-octadecanoyl- sn -glycero-3-phosphocholine with two abundant human plasma proteins, human serum albumin (HSA) and human transferrin. By means of spectroscopic and scattering techniques, we analyzed the effect of SPIONs on protein structure and the binding affinities, and only found strong binding in the case of HSA. In no case did SPIONs alter the protein structure significantly. We structurally characterized HSA/SPIONs complexes by means of light and neutron scattering, highlighting the formation of a monolayer of protein molecules on the NP surface. Their interaction with lipid bilayers mimicking biological membranes was investigated by means of neutron reflectivity. We show that HSA/SPIONs do not affect lipid bilayer features and could be further exploited as a nanoplatform for future applications. Overall, our findings point toward a high biocompatibility of phosphocholine-decorated SPIONs and support their use in nanomedicine.

The noteworthy intensification in the development of nanotechnology has led to the development of various types of nanoparticles. The diverse applications of these nanoparticles make them desirable candidate for areas such as drug delivery, coasmetics, medicine, electronics, and contrast agents for magnetic resonance imaging (MRI) and so on. Iron oxide magnetic nanoparticles are a branch of nanoparticles which is specifically being considered as a contrast agent for MRI as well as targeted drug delivery vehicles, angiogenic therapy and chemotherapy as small size gives them advantage to travel intravascular or intracavity actively for drug delivery. Besides the mentioned advantages, the toxicity of the iron oxide magnetic nanoparticles is still less explored. For in vivo applications magnetic nanoparticles should be nontoxic and compatible with the body fluids. These particles tend to degrade in the body hence there is a need to understand the toxicity of the particles as whole and degraded products interacting within the body. Some nanoparticles have demonstrated toxic effects such inflammation, ulceration, and decreases in growth rate, decline in viability and triggering of neurobehavioral alterations in plants and cell lines as well as in animal models. The cause of nanoparticles' toxicity is attributed to their specific characteristics of great surface to volume ratio, chemical composition, size, and dosage, retention in body, immunogenicity, organ specific toxicity, breakdown and elimination from the body. In the current review paper, we aim to sum up the current knowledge on the toxic effects of different magnetic nanoparticles on cell lines, marine organisms and rodents. We believe that the comprehensive data can provide significant study parameters and recent developments in the field. Thereafter, collecting profound knowledge on the background of the subject matter, will contribute to drive research in this field in a new sustainable direction.

Nanoparticles are recently employed as a new strategy to directly kill pathogens (e.g., bacteria and fungus) and acted as nanofertilizers. However, the influences of this foliar deposition of nanoparticles on plant physiology particularly plant immunity are poorly understood. The uptake and physiological effects of Fe 3 O 4 nanoparticles (Fe 3 O 4 NPs), and plant resistance response against Tobacco mosaic virus (TMV) after foliar spraying were studied. Specifically, Fe 3 O 4 NPs entered leaf cells and were transported and accumulated throughout the whole Nicotiana benthamiana plant, and increased plant dry and fresh weights, activated plant antioxidants, and upregulated SA synthesis and the expression of SA-responsive PR genes (i.e., PR1 and PR2), thereby enhancing plant resistance against TMV. Conversely, the viral infection was not inhibited in the NahG transgenic plants treated by Fe 3 O 4 NPs, suggesting the involvement of salicylic acid (SA) induced by Fe 3 O 4 NPs in the production of plant resistance. Moreover, no inhibition was observed of the infection after inoculating with the pretreated TMV mixtures. Thus, the deposition of Fe 3 O 4 NPs induced the accumulation of endogenous SA, which was correlated with the plant resistance against TMV infection. Such information is vital for valuing the risk of Fe 3 O 4 NPs products and broadens the researching and applying nanoparticles in the fight against plant diseases meantime., 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 © 2020 Elsevier B.V. All rights reserved.)

Superparamagnetic cobalt ferrite nanoparticles (CoFe 2 O 4 ) possess favourite advantages for theranostic applications. Most of previous studies reported that CoFe 2 O 4 magnetic nanoparticles (MNPs) are suitable candidates for induction of hyperthermia and transfection agents for drug delivery. The present study synthesized and investigated the potential use of CoFe 2 O 4 as a contrast agent in magnetic resonance imaging (MRI) by using a conventional MRI system. The CoFe 2 O 4 were synthesized using co-precipitation method and characterized by TEM, XRD, FTIR, EDX and VSM techniques. Relaxivities r 1 and r 2 of CoFe 2 O 4 were then calculated using a 1.5 Tesla clinical magnetic field. The cytotoxicity of CoFe 2 O 4 was evaluated by the MTT assay. Finally, the optimal concentrations of MNPs for MRI uses were calculated through the analysis of T 2 weighted imaging cell phantoms. The superparamagnetic CoFe2O4 NPs with an average stable size of 10.45 nm were synthesized. Relaxivity r 1 , 2 calculations resulted in suitable r 2 and r 2 / r 1 with values of 58.6 and 51 that confirmed the size dependency on relaxivity values. The optimal concentration of MNPs for MR image acquisition was calculated as 0.154 mM. Conclusion: CoFe 2 O 4 synthesized in this study could be considered as a suitable T 2 weighted contrast agent because of its high r 2 / r 1 value.

Effective delivery of chemotherapeutics with minimal toxicity and maximal outcome is clinically important but technically challenging. Here, we synthesize a complex of doxorubicin (DOX)-loaded magneto-liposome (DOX-ML) microbubbles (DOX-ML-MBs) for magnetically responsive and ultrasonically sensitive delivery of anticancer therapies with enhanced efficiency. Citrate-stabilized iron oxide nanoparticles (MNs) of 6.8 ± 1.36 nm were synthesized, loaded with DOX in the core of oligolamellar vesicles of 172 ± 9.2 nm, and covalently conjugated with perfluorocarbon (PFC)-gas-loaded microbubbles to form DOX-ML-MBs of ∼4 μm. DOX-ML-MBs exhibited significant magnetism and were able to release chemotherapeutics and DOX-MLs instantly upon exposure to ultrasound (US) pulses. In vitro studies showed that DOX-ML-MBs in the presence of US pulses promoted apoptosis and were highly effective in killing both BxPc-3 and Panc02 pancreatic cancer cells even at a low dose. Significant reduction in the tumor volume was observed after intravenous administration of DOX-ML-MBs in comparison to the control group in a pancreatic cancer xenograft model of nude mice. Deeply penetrated iron oxide nanoparticles throughout the magnetically targeted tumor tissues in the presence of US stimulation were clearly observed. Our study demonstrated the potential of using DOX-ML-MBs for site-specific targeting and controlled drug release. It opens a new avenue for the treatment of pancreatic cancer and other tissue malignancies where precise delivery of therapeutics is necessary.

Purpose: Osteonecrosis of the femoral head (ONFH) is a chronic and irreversible disease that eventually develops into a joint collapse and results in joint dysfunction. Early intervention and treatment are essential for preserving the joints and avoiding hip replacement. In this study, a system of human umbilical mesenchymal stem cells-supermagnetic iron oxide nanoparticles (NPs) @polydopamine (SCIOPs) was constructed. The magnetic targeting system gathers in the lesion area, inhibits the apoptosis of bone cells, enhances osteogenic effect, and effectively treats ONFH under external magnetic field., Materials and Methods: The supermagnetic iron oxide NPs @polydopamine (SPION@PDA NPs) were characterized by transmission electron microscopy and zeta potential, respectively. The effects of SPION@PDA NPs on the viability, proliferation, and differentiation of stem cells were detected by the CCK8 method, flow cytometry, and staining, respectively. The serum inflammatory indicators were detected by Luminex method. The bone mass of the femoral head was analyzed by micro computed tomography. The expression of apoptosis and osteoblast-related cytokines was detected by Western blotting. The osteogenesis of the femoral head was detected by histological and immunohistochemical sections., Results: The SCIOPs decreased the pro-inflammatory factors, and the micro CT showed that the bone repair of the femoral head was enhanced after treatment. The hematoxylin and eosin sections also showed an increase in the osteogenesis in the femoral head. Western blotting results showed and increased expression of anti-apoptotic proteins Akt and Bcl-2, decreased expression of apoptotic proteins caspase-3 and Bad, and increased expression of osteogenic proteins Runx-2 and Osterix in the femoral head., Conclusion: Under the effect of magnetic field and homing ability of stem cells, SCIOPs inhibited the apoptosis of osteoblasts, improved the proliferation ability of osteoblasts, and promoted bone repair in the femoral head through the Akt/Bcl-2/Bad/caspase-3 signaling pathway, thereby optimizing the tissue repair ability., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Duan et al.)

The combination of reactive oxygen species (ROS)-induced chemodynamic therapy (CDT) and photothermal therapy (PTT) holds a promising application prospect for their superb anticancer efficiency. Herein, we created a novel Fe 3 O 4 @polydopamine (PDA)@bovine serum albumin (BSA)-Bi 2 S 3 composite as a theranostic agent, by chemically linking the Fe 3 O 4 @PDA with BSA-Bi 2 S 3 via the amidation between the carboxyl groups of BSA and the amino groups of PDA. In this formulation, the Fe 3 O 4 NPs could not only work as a mimetic peroxidase to trigger Fenton reactions of the innate H 2 O 2 in the tumor and generate highly cytotoxic hydroxyl radicals (•OH) to induce tumor apoptosis but also serve as the magnetic resonance imaging (MRI) contrast agent to afford the precise cancer diagnosis. Meanwhile, the PDA could prevent the oxidization of Fe 3 O 4 , thus supporting the long-term Fenton reactions and the tumor apoptosis in the tumor. The Bi 2 S 3 component exhibits excellent photothermal transducing performance and computed tomography (CT) imaging capacity. In addition, the PDA and Bi 2 S 3 endow the Fe 3 O 4 @PDA@BSA-Bi 2 S 3 composite with an excellent photothermal transforming ability which could lead to tumor hyperthermia. All of these merits play the synergism with the tumor microenvironment and qualify the Fe 3 O 4 @PDA@BSA-Bi 2 S 3 NPs for a competent agent in the MRI/CT-monitored enhanced PTT/CDT synergistic therapy. Findings in this research will evoke new interests in future cancer therapeutic strategies based on biocompatible nanomaterials.

Recently, magnetic nanoparticles (MNPs) have gained much attention in the field of biomedical engineering for therapeutic as well as diagnostic purposes. Carbon magnetic nanoparticles (C-MNPs) are a class of MNPs categorized as organic nanoparticles. C-MNPs have been under considerable interest in studying in various applications such as magnetic resonance imaging, photothermal therapy, and intracellular transportof drugs. Research work is still largely in progress for testing the efficacy of C-MNPs on the theranostics platform in cellular studies and animal models. In this study, we evaluated the neurobehavioral toxicity parameters on the adult zebrafish ( Danio rerio ) at either low (1 ppm) or high (10 ppm) concentration level of C-MNPs over a period of two weeks by waterborne exposure. The physical properties of the synthesized C-MNPs were characterized by transmission electron microscopy, Raman, and XRD spectrum characterization. Multiple behavior tests for the novel tank, mirror biting, predator avoidance, conspecific social interaction, shoaling, and analysis of biochemical markers were also conducted to elucidate the corresponding mechanism. Our data demonstrate the waterborne exposure of C-MNPs is less toxic than the uncoated MNPs since neither low nor high concentration C-MNPs elicit toxicity response in behavioral and biochemical tests in adult zebrafish. The approach combining biochemical and neurobehavioral approaches would be helpful for understanding C-MNPs association affecting the bioavailability, biosafety, interaction, and uptake of these C-MNPs in the living organism.

Engineered Nanomaterials (NMs), such as Superparamagnetic Iron Oxide Nanoparticles (SPIONs), offer significant benefits in a wide range of applications, including cancer diagnostic and therapeutic strategies. However, the use of NMs in biomedicine raises safety concerns due to lack of knowledge on possible biological interactions and effects. The initial basis for using SPIONs as biomedical MRI contrast enhancement agents was the idea that they are selectively taken up by macrophage cells, and not by the surrounding cancer cells. To investigate this claim, we analyzed the uptake of SPIONs into well-established cancer cell models and benchmarked this against a common macrophage cell model. In combination with fluorescent labeling of compartments and siRNA silencing of various proteins involved in common endocytic pathways, the mechanisms of internalization of SPIONs in these cell types has been ascertained utilizing reflectance confocal microscopy. Caveolar mediated endocytosis and macropinocytosis are both implicated in SPION uptake into cancer cells, whereas in macrophage cells, a clathrin-dependant route appears to predominate. Colocalization studies confirmed the eventual fate of SPIONs as accumulation in the degradative lysosomes. Dissolution of the SPIONs within the lysosomal environment has also been determined, allowing a fuller understanding of the cellular interactions, uptake, trafficking and effects of SPIONs within a variety of cancer cells and macrophages. Overall, the behavior of SPIONS in non-phagocytotic cell lines is broadly similar to that in the specialist macrophage cells, although some differences in the uptake patterns are apparent.

This paper presents sols of uncoated and citric acid-coated Fe 3 O 4 nanoparticles obtained by a combination of coprecipitation and sonochemistry methods. A stable concentrated CA-Fe 3 O 4 sol synthesized by a combination of coprecipitation with an inconvenient Fe 2+ /Fe 3+ ratio, modification with citric acid and US treatment was obtained for the first time. A comparative analysis of the composition and morphology of nanoparticles was performed. The sols are oppositely charged and behave as a typical ferrofluid. The citric acid-modified sol is aggregatively stable over wider ranges of pH and electrolyte concentration, but it becomes less stable with the temperature increase. DLVO calculations showed that steric repulsion forces are a vital factor contributing to increased aggregative stability in a modified Fe 3 O 4 sol. The experiments have revealed the magneto-optical effect in a modified Fe 3 O 4 sol with an electrolyte concentration of 0.025-0.075 M caused by a high potential barrier and a deep secondary minimum in pairwise interaction curves. The "p K spectroscopy" mathematical model to describe the potentiometric curves of synthesized magnetite sols was used for the first time. According to potentiometric titration, the ions of the electrolyte practically do not contribute to formation of a surface charge in modified Fe 3 O 4 with a change in pH due to blocking the magnetite surface by citric acid molecules. Drosophila melanogaster was used as a model to show that Fe 3 O 4 in chronic exposure has a low toxic effect.

Background: The primary strategy to repair peripheral nerve injuries is to bridge the lesions by promoting axon regeneration. Thus, the ability to direct and manipulate neuronal cell axon regeneration has been one of the top priorities in the field of neuroscience. A recent innovative approach for remotely guiding neuronal regeneration is to incorporate magnetic nanoparticles (MNPs) into cells and transfer the resulting MNP-loaded cells into a magnetically sensitive environment to respond to an external magnetic field. To realize this intention, the synthesis and preparation of ideal MNPs is an important challenge to overcome., Results: In this study, we designed and prepared novel fluorescent-magnetic bifunctional Fe 3 O 4 ·Rhodamine 6G@polydopamine superparticles (FMSPs) as neural regeneration therapeutics. With the help of their excellent biocompatibility and ability to interact with neural cells, our in-house fabricated FMSPs can be endocytosed into cells, transported along the axons, and then aggregated in the growth cones. As a result, the mechanical forces generated by FMSPs can promote the growth and elongation of axons and stimulate gene expression associated with neuron growth under external magnetic fields., Conclusions: Our work demonstrates that FMSPs can be used as a novel stimulator to promote noninvasive neural regeneration through cell magnetic actuation.

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are central microdomains of the ER that interact with mitochondria. MAMs provide an essential platform for crosstalk between the ER and mitochondria and play a critical role in the local transfer of calcium (Ca 2+ ) to maintain cellular functions. Despite the potential uses of superparamagnetic iron oxide nanoparticles (SPIO-NPs) in biomedical applications, the hepatotoxicity of these nanoparticles (NPs) is not well characterized and little is known about the involvement of MAMs in ER-mitochondria crosstalk. We studied SPIO-NPs-associated hepatotoxicity in vitro and in vivo . In vitro , human normal hepatic L02 cells were exposed to SPIO-NPs (2.5, 7.5, and 12.5 μg/mL) for 6 h and SPIO-NPs (12.5 μg/mL) was found to induce apoptosis. In vivo , SPIO-NPs induced liver injury when mice were intravenously injected with 20 mg/kg body weight SPIO-NPs for 24 h. Based on both in vitro and in vivo studies, we found that the structure and Ca 2+ transport function of MAMs were perturbated and an accumulation of cyclooxygenase-2 (COX-2) in MAMs fractions was increased upon treatment of SPIO-NPs. The interaction between COX-2 and the components of MAMs, in terms of IP3R-GRP75-VDAC1 complex, was also revealed. Furthermore, the role of COX-2 in SPIO-NPs-associated hepatotoxicity was investigated by modifying the expression of COX-2. We demonstrated that COX-2 increases the structural and functional ER-mitochondria coupling and enhances the efficacy of ER-mitochondria Ca 2+ transfer through the MAMs, thus sensitizing hepatocytes to a mitochondrial Ca 2+ overload-dependent apoptosis. Taken together, our findings link SPIO-NPs-triggered hepatotoxicity with ER-mitochondria Ca 2+ crosstalk which is mediated by COX-2 and provide mechanistic insight into the impact of interorganelle ER-mitochondria communication on hepatic nanotoxicity.

Significant ROS production capability of bare iron oxide nanoparticles in safe doses for healthy cells offers an interesting therapeutic window for cancer. In this context, the aim of the current study is to investigate therapeutic potential of the synthesized magnetite (Fe₃O₄) nanoparticles (~80 nm) as attractive vehicles for biomedical applications on hepatocellular carcinoma cells (HepG2). To investigate their time (0-72 h) and dose (0-100 μ g/ml) dependent effect on physiological state (proliferation/ cytotoxicity) and mitochondrial activity of the tumor cells, xCELLigence system and MTT assay were used, respectively. Both 50 and 100 μ g/ml of nanoparticle treatment induced significant (p < 0.01) increases in ROS production in HepG2 cells; however, ~4-day real-time cell analysis illustrated that all concentrations of the nanoparticles caused significant ( p < 0.01) increases in proliferation of the tumor cells from 4 h after the treatment to the end of the analysis. While 50 and 100 μ g/ml of nanoparticles caused significant deteriorations in the mitochondrial activity of the tumor cells in the case of 24 h-( p < 0.05 and p < 0.01, respectively) and 72 h-treatment ( p < 0.01); 24 h-treatment of 100 μ g/ml of nanoparticles and 72 h-treatment of 50 and 100 μ g/ml of nanoparticles caused significant increases in the mitochondrial activity of the tumor cells ( p < 0.01) under static magnetic field (1.35 T). Although the synthesized magnetite nanoparticles have not therapeutic potential alone on HepG2 cells in doses safe for healthy cells, the results of the current study are illuminating for future magnetite nanoparticle-based biomedical applications and combination cancer therapy containing magnetite nanoparticles.

Among pollutants, nanoparticles (NPs) consist a potential environmental hazard, as they could possibly harm the aquatic and terrestrial ecosystems while having unpredictable repercussions on human health. Since monitoring the impact of NPs on aquatic and terrestrial life is challenging, due to the differential sensitivities of organisms to a given nanomaterial, the present study examines magnetite nanoparticles' mediated toxicity in different animal models, representing distinctive environments (terrestrial and aquatic). Oxidative, proteolytic and genotoxic effects were evaluated on the hemocytes of the snail Cornu aspersum; in addition to those, apoptotic effects were measured in gills and liver of the zebrafish Danio rerio, and the prussian carp Carassius gibelio. All biochemical parameters studied increased significantly in animals after 8 days exposure to NPs. Inter-species and inter-tissues differences in responses were evident. Our results suggest a common toxicity response mechanism functioning in the tissues of the three animals studied that is triggered by magnetite NPs. The simultaneous use of these parameters could be established after further investigation as a reliable multi-parameter approach for biomonitoring of terrestrial and aquatic ecosystems against magnetite nanoparticles. Additionally, the results of our study could contribute to the design of studies for the production and rational utilization of nanoparticles., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Magnetic resonance imaging (MRI) is the most powerful technique for non-invasive diagnosis of human diseases and disorders. Properly designed contrast agents can be accumulated in the damaged zone and be internalized by cells, becoming interesting cellular MRI probes for disease tracking and monitoring. However, this approach is sometimes limited by the relaxation rates of contrast agents currently in clinical use, which show neither optimal pharmacokinetic parameters nor toxicity. In this work, a suitable contrast agent candidate, based on iron oxide nanoparticles (IONPs) coated with polyethyleneglycol, was finely designed, prepared and fully characterized under a physical, chemical and biological point of view. To stand out the real potential of our study, all the experiments were performed in comparison with Ferumoxytol, a FDA approved IONPs. IONPs with a core size of 15 nm and coated with polyethyleneglycol of 5 kDa (OD15-P5) resulted the best ones, being able to be uptaken by both tumoral cells and macrophages and showing no toxicity for in vitro and in vivo experiments. In vitro and in vivo MRI results for OD15-P5 showed r 2 relaxivity values higher than Ferumoxitol. Furthermore, the injected OD15-P5 were completely retained at the tumor site for up to 24 h showing high potential as MRI contrast agents for real time long-lasting monitoring of the tumor evolution., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this paper we report about the preparation, physicochemical and biological characterization of a magneto responsive nanostructured material based on magnetite nanoparticles (NP) coated with hyaluronic acid (HA). A synthetic approach, based on a Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition "click" reaction between azido-functionalized magnetite NP and a derivative of hyaluronic acid bearing propargylated ferulic acid groups (HA-FA-Pg), was developed to link covalently the polymer layer to the magnetite NP. The functionalization steps of the magnetite NP and their coating with the HA-FA-Pg layer were monitored by Fourier Transform Infrared (FTIR) spectroscopy and Thermal Gravimetric Analysis (TGA) while Dynamic Light Scattering (DLS) and ζ-potential measurements were performed to characterize the aqueous dispersions of the HA-coated magnetite NP. Aggregation and sedimentation processes were investigated also by UV-visible spectroscopy and the dispersions of HA-coated magnetite NP were found significantly more stable than those of bare NP. Magnetization and zero field cooled/field cooled curves revealed that both bare and HA-coated magnetite NP are superparamagnetic at room temperature. Moreover, cytotoxicity studies showed that the coating with HA-FA-Pg significantly reduces the cytotoxicity of the magnetite NP providing the rational basis for the application of the HA-coated magnetite NP as healthcare material., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Superparamagnetic iron oxide nanoparticles (SPION) require stable surface modifications to render safe nanocapsules for biomedical applications. Herein, two types of surface modified poly(lactic-co-glycolic acid)-encapsulated SPION were synthesized using either α-tocopheryl-polyetheleneglycol-succinate (TPGS) or didodecyl-dimethyl-ammonium-bromide (DMAB) as surfactants by emulsification. SPION-TPGS (180 nm) was larger than SPION-DMAB (25 nm) and uncoated SPION (10 nm). Both formulations were positively charged and induced lower cyto-genotoxicity and ROS generation than uncoated SPION in human lymphocytes. SPION-DMAB was least cyto-genotoxic among the three. Based on these results, mice were gavaged with the formulations for 5 consecutive days and biocompatibility studies were performed on the 7th and 21st days. ICP-AES and Prussian blue staining revealed the internalization of SPION-DMAB in brain and spleen, and SPION-TPGS in liver and kidney on day 7. This was correlated with high DNA damage and oxidative stress in the same organs. Substantial clearance of Fe was accompanied by reduced genotoxicity and oxidative stress on day 21. Therefore, SPION-DMAB can be further studied for oral drug delivery to the brain and imaging of cerebral tissue without any functional ligand or external magnetic field., 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 Ltd. All rights reserved.)

Background: In orthopedics, the treatment of implant-associated infections represents a high challenge. Especially, potent antibacterial effects at implant surfaces can only be achieved by the use of high doses of antibiotics, and still often fail. Drug-loaded magnetic nanoparticles are very promising for local selective therapy, enabling lower systemic antibiotic doses and reducing adverse side effects. The idea of the following study was the local accumulation of such nanoparticles by an externally applied magnetic field combined with a magnetizable implant. The examination of the biodistribution of the nanoparticles, their effective accumulation at the implant and possible adverse side effects were the focus. In a BALB/c mouse model (n = 50) ferritic steel 1.4521 and Ti90Al6V4 (control) implants were inserted subcutaneously at the hindlimbs. Afterwards, magnetic nanoporous silica nanoparticles (MNPSNPs), modified with rhodamine B isothiocyanate and polyethylene glycol-silane (PEG), were administered intravenously. Directly/1/7/21/42 day(s) after subsequent application of a magnetic field gradient produced by an electromagnet, the nanoparticle biodistribution was evaluated by smear samples, histology and multiphoton microscopy of organs. Additionally, a pathohistological examination was performed. Accumulation on and around implants was evaluated by droplet samples and histology., Results: Clinical and histological examinations showed no MNPSNP-associated changes in mice at all investigated time points. Although PEGylated, MNPSNPs were mainly trapped in lung, liver, and spleen. Over time, they showed two distributional patterns: early significant drops in blood, lung, and kidney and slow decreases in liver and spleen. The accumulation of MNPSNPs on the magnetizable implant and in its area was very low with no significant differences towards the control., Conclusion: Despite massive nanoparticle capture by the mononuclear phagocyte system, no significant pathomorphological alterations were found in affected organs. This shows good biocompatibility of MNPSNPs after intravenous administration. The organ uptake led to insufficient availability of MNPSNPs in the implant region. For that reason, among others, the nanoparticles did not achieve targeted accumulation in the desired way, manifesting future research need. However, with different conditions and dimensions in humans and further modifications of the nanoparticles, this principle should enable reaching magnetizable implant surfaces at any time in any body region for a therapeutic reason.

Superparamagnetic iron oxide nanoparticles (SPIOn) are widely used as a contrast agent for cell labeling. Macrophages are the first line of defense of organisms in contact with nanoparticles after their administration. In this study we investigated the effect of silica-coated nanoparticles (γ-Fe 2 O 3 -SiO 2 ) with or without modification by an ascorbic acid (γ-Fe 2 O 3 -SiO 2 -ASA), which is meant to act as an antioxidative agent on rat peritoneal macrophages. Both types of nanoparticles were phagocytosed by macrophages in large amounts as confirmed by transmission electron microscopy and Prusian blue staining, however they did not substantially affect the viability of exposed cells in monitored intervals. We further explored cytotoxic effects related to oxidative stress, which is frequently documented in cells exposed to nanoparticles. Our analysis of double strand breaks (DSBs) marker γH2AX showed an increased number of DSBs in cells treated with nanoparticles. Nanoparticle exposure further revealed only slight changes in the expression of genes involved in oxidative stress response. Lipid peroxidation, another marker of oxidative stress, was not significantly affirmed after nanoparticle exposure. Our data indicate that the effect of both types of nanoparticles on cell viability, or biomolecules such as DNA or lipids, was similar; however the presence of ascorbic acid, either bound to the nanoparticles or added to the cultivation medium, worsened the negative effect of nanoparticles in various tests performed. The attachment of ascorbic acid on the surface of nanoparticles did not have a protective effect against induced cytotoxicity, as expected.

Fe 3 O 4 magnetic nanoparticles (MNPs), as one of the most intensively researched NPs, have a range of applications in cancer treatments. In current research, we have focused on the influences of MNPs on cancer cells. We chose polyethyleneimine (PEI) coated MNPs (PEI-MNPs) as a model and they are colloidally stable in biological media. It can be proved that PEI-MNPs result in autophagy induction via mTOR-Akt-p70S6 K and ATG7 signaling pathways. For the first time, we have reported that PEI-MNPs activate both NF-κB and TGF-β signaling, two key pro-inflammatory pathways, in cancer cells. More significantly, we have found that autophagy induction and NF-κB and TGF-β activation can be efficiently suppressed through the inhibition of PEI-MNP dependent reactive oxygen species (ROS) over-production. ROS are deemed as a 'double edge sword' for cancer cells, owing to the cancer-suppressing and cancer-promoting actions. Our findings would be useful for designing MNPs induced ROS anti-cancer strategies or diminishing long-term toxic effects.

This work was aimed at defining the suitable test for evaluating Fe 3 O 4 NPs cytotoxicity after short-term exposure in human mesenchymal stem cells (hMSCs) using different viability tests, namely NRU, MTT and TB assays, paralleled by cell morphology analyses for cross checking. MTT and NRU data (culture medium with/without hMSCs plus Fe 3 O 4 NPs) indicated artificial/false increments in cell viability after Fe 3 O 4 NPs. These observations did not fit with the morphological analyses showing reduced cell density, loss of monolayer features, and morphological alterations at Fe 3 O 4 NPs ≥50 μg/ml. Fe 3 O 4 NPs alone induced a substantial increased absorbance at the wavelength required for MTT and NRU. A significant death (25%) of hMSC at Fe 3 O 4 NPs ≥10 μg/ml, with a maximum effect (45%) at 300 μg/ml after 24 h, exacerbated after 48 h, was observed when applying TB test. These results paralleled the effects on cell morphology. The optical properties and stability of Fe 3 O 4 NP suspension (tendency to agglomerate in a specific culture medium) represent factors that limit in vitro result interpretation. These findings suggest the non applicability of the spectrophotometric assays for hMSC culture conditions, while TB is an accurate method for determining cell viability after Fe 3 O 4 NP exposure in this model. In relation to NPs safety assessment: cell-based assays must be considered on case-by-case basis; selection of relevant cell models is also important for predictive toxicological studies; application of a testing strategy is fundamental for understanding the toxicity pathways driving cellular responses.

Though anesthetic drug delivery system and drug vehicles is generally applied for pain relief, there are have many difficulties and issues due to its short duration carrier and low biocompatibility, effectiveness at the conditions of inflammation at acidic pH. To resolve this issue, we have designed and developed the dual (pH and temperature) responsive bio-nanomaterial to improve the efficiency anesthetic drug delivery system. Chitosan is a unique class of biomaterials that is widely used in medical devices. The surface engineering of ZnFe 2 O 4 nanoparticles was performed by coating with chitosan using simple precipitation method. Then, multi-active anesthetic drug (Lidocaine) was loaded into nano-ferrite to form a drug delivery vehicle. The prepared drug-vesicle was characterized by using XRD, FTIR, SEM, XPS and TGA analysis. XRD analysis proved the face center cubic structure of zinc nanoferrite. The sustained delivery of Lidocaine (LDC) from CS coated nanoferrite (CS/ZnFe 2 O 4 ) was stimulated by pH and temperature responsive characteristics of vesicles. The in vitro cytotoxicity of the CS/ZnFe 2 O 4 particles towards fibroblast cells was analyzed by using MTT assay. The drug loaded CS/ZnFe 2 O 4 particles exhibit high biocompatibility and sustained drug release in the physiological pH environment (4.8, 5.5 and 7.4) and temperature responsive (25 and 37 °C) of normal tissues and also drug loading efficiency was measured., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Superparamagnetic iron oxide nanoparticles (SPION) have been widely studied for different biomedical and environmental applications. In this study we evaluated the toxicity and potential alterations of relevant physiological parameters caused to the microalga Chlamydomonas reinhardtii (C. reinhardtii) upon exposure to SPION. The results showed dose-dependent toxicity. A mechanistic study combining flow cytometry and physiological endpoints showed a toxic response consisting of a decrease in metabolic activity, increased oxidative stress and alterations in the mitochondrial membrane potential. Additionally, and due to the light absorption of SPION suspensions, we observed a significant shading effect, causing a marked decrease in photosynthetic activity. In this work, we demonstrated for the first time, the internalization of SPION by endocytosis in C. reinhardtii. These results demonstrated that SPION pose a potential risk for the environment if not managed properly., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cancer treatment by magnetic hyperthermia offers numerous advantages, but for practical applications many variables still need to be adjusted before developing a controlled and reproducible cancer treatment that is bio-compatible (non-damaging) to healthy cells. In this work, Fe 3 O 4 and CoFe 2 O 4 were synthesized and systematically studied for the development of efficient therapeutic agents for applications in hyperthermia. The biocompatibility of the materials was further evaluated using HepG2 cells as biological model. Colorimetric and microscopic techniques were used to evaluate the interaction of magnetic nano-materials (MNMs) and HepG2 cells. Finally, the behavior of MNMs was evaluated under the influence of an alternating magnetic field (AMF), observing a more efficient temperature increment for CoFe 2 O 4 , a desirable behavior for biomedical applications since lower doses and shorter expositions to alternating magnetic field might be required.

Nanoparticles (NPs) production is increasing worldwide. These products are likely to end up in aquatic environments. However, few studies evaluated the chronic toxicity of iron-based NPs (Fe-NPs) to cladocerans and their potential ecotoxicological hazards. In this study we aimed to investigate the effects of iron oxide nanoparticles (Fe 3 O 4 -NPs) to Ceriodaphnia silvestrii Daday, 1902, assessing acute (48 h) and chronic toxicity (up to 14 d). Besides traditional endpoints (immobility and lethality), we also evaluated physiological responses (respiration rates) in a 48 h-exposure. No immobility was observed (EC 50  > 100 mg L -1 ) after 48 h, whereas respiration rates at the highest concentration were 400% of that in control, indicating that this endpoint was more sensitive during acute toxicity. In chronic assays, Fe 3 O 4 -NPs affected body length (8.24% growth inhibition in 7 d-exposure) and number of eggs (7-d IC 10 : 3.53, IC 20 : 6.69 mg Fe L -1 ) and neonates (7-d IC 10 : 1.25, IC 20 : 3.75 mg Fe L -1 ). Based on species sensitivity distribution (SSD), C. silvestrii was a sensitive organism, suggesting Fe-NPs as a possible threat for this species. Our results also indicate that the NPs caused a physical barrier, impairing food absorption, since we observed NPs agglomerations into cladocerans' gut. We demonstrate that Fe 3 O 4 -NPs affects C. silvestrii metabolism and reproduction and our results support the use of sublethal endpoints to assess environmental safety. The release of these NPs into freshwater environments should be carefully evaluated, since disturbances on cladoceran population dynamics could cause strong impacts on the entire food web structure and ultimately on ecosystem functioning., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Understanding the in vivo size-dependent pharmacokinetics and toxicity of nanoparticles is crucial to determine their successful development. Systematic studies on the size-dependent biological effects of nanoparticles not only help to unravel unknown toxicological mechanism but also contribute to the possible biological applications of nanomaterial., Methods: In this study, the biodistribution and the size-dependent biological effects of Fe 3 O 4 @SiO 2 -NH 2 nanoparticles (Fe@Si-NPs) in three diameters (10, 20 and 40 nm) were investigated by ICP-AES, serum biochemistry analysis and NMR-based metabolomic analysis after intravenous administration in a rat model., Results: Our findings indicated that biodistribution and biological activities of Fe@Si-NPs demonstrated the obvious size-dependent and tissue-specific effects. Spleen and liver are the target tissues of Fe@Si-NPs, and 20 nm of Fe@Si-NPs showed a possible longer blood circulation time. Quantitative biochemical analysis showed that the alterations of lactate dehydrogenase (LDH) and uric acid (UA) were correlated to some extent with the sizes of Fe@Si-NPs. The untargeted metabolomic analyses of tissue metabolomes (kidney, liver, lung, and spleen) indicated that different sizes of Fe@Si-NPs were involved in the different biochemical mechanisms. LDH, formate, uric acid, and GSH related metabolites were suggested as sensitive indicators for the size-dependent toxic effects of Fe@Si-NPs. The findings from serum biochemical analysis and metabolomic analysis corroborate each other. Thus we proposed a toxicity hypothesis that size-dependent NAD depletion may occur in vivo in response to nanoparticle exposure. To our knowledge, this is the first report that links size-dependent biological effects of nanoparticles with in vivo NAD depletion in rats., Conclusion: The integrated metabolomic approach is an effective tool to understand physiological responses to the size-specific properties of nanoparticles. Our results can provide a direction for the future biological applications of Fe@Si-NPs.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been recently recognized as highly efficient photothermal therapy (PTT) agents. Here, we demonstrate, for the first time to our knowledge, dose and laser intensity dependent PTT potential of small, spherical, 3-aminopropyltrimethoxysilane coated cationic superparamagnetic iron oxide nanoparticles (APTMS@SPIONs) in aqueous solutions upon irradiation at 795 nm. Indocyanine green (ICG) which has been recently used for photodynamic therapy (PDT), was loaded to APTMS@SPIONs to improve the stability of ICG and to achieve an effective mild PTT and PDT (dual therapy) combination for synergistic therapeutic effect on cancer cells via a single laser treatment in the near infrared (NIR). Neither APTMS@SPIONs nor ICG-APTMS@SPIONs showed dark toxicity on MCF7 breast and HT29 colon cancer cell lines. A safe laser procedure was determined as 10 min irradiation at 795 nm with 1.8 W/cm 2 of laser intensity, at which APTMS@SPION did not cause a significant cell death. However, free ICG reduced cell viability at and above 10 μg/ml under these conditions along with generation of reactive oxygen species (ROS), more effectively in MCF7. ICG-APTMS@SPION treated cells showed 2-fold increase in ROS generation and near complete cell death at and below 5 μg/ml ICG dose, even in less sensitive HT29 cells after a single laser treatment at NIR, which would be safe for the healthy tissue and provide a longer penetration depth. Besides, both components can be utilized for diagnosis and the overall composition may be used for optical-image guided phototherapy in the NIR region., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction . The objective of this study was to evaluate the feasibility and toxicity of superparamagnetic iron oxide nanoparticles (SPIONs) administered into the cochlea through the round window (RW) by an external magnetic field. Materials and Methods . In 5 Wistar rats, the left RW was punctured. SPIONs suspended in hyaluronic gel (5 mg/mL) were applied in the RW niche and covered by a muscle graft. The nanoparticles were mobilized using a rare earth magnet (0.54 T) held in 4 consecutive positions around the head. The right ear served as control. Hearing function was monitored by auditory brainstem responses (4-32 kHz tone bursts). Results . The auditory thresholds remained unchanged 1 month after the administration. The histological study of the cochleae showed that SPIONs were driven into the scala tympani in the basal turn, the second turn, and the apex. Conclusion . Superparamagnetic nanoparticles can be driven inside the cochlea toward the apex with a preserved hearing up to 1 month in rats.

Due to the abuse of antibiotics and the tendency of bacteria to form protective biofilms, the design and development of new efficient agents that can eliminate bacteria and biofilms are still highly desired but remain a great challenge; on the other hand, natural enzymes with unique catalytic characteristics can cause an irreversible damage to the bacteria without inducing drug-resistance in the bacteria. However, the intrinsic drawbacks, such as insufficient stability and high purification cost, of enzymes significantly limit their antimicrobial applications. Therefore, significant research efforts have been devoted towards the development of quality-equivalent or even superior enzyme substitutes with low cost and high stability. In this regard, nanomaterials with extraordinary enzyme-mimetic catalytic activities (termed as nanozymes) are considered as suitable candidates. To date, nanozymes have been proved to be promising materials for combating bacteria and biofilms under mild conditions. In this review, we have summarized the recent progress of nanozymes in this highly active field. The antibacterial mechanisms of nanozymes and the roles of their sizes, morphologies, compositions, surface modifications and microenvironment on their overall performance have been discussed. Moreover, the current challenges and prospects in this research area have been discussed. We believe that nanozymes with unique features and functions can provide a wealth of opportunities via their clinical and industrial applications.

Being crucial under several pathological conditions, tumors, and tissue engineering, the MRI tracing of hypoxia within cells and tissues would be improved by the use of nanosystems allowing for direct recognition of low oxygenation and further treatment-oriented development. In the present study, we functionalized dendron-coated iron oxide nanoparticles (dendronized IONPs) with a bioreductive compound, a metronidazole-based ligand, to specifically detect the hypoxic tissues. Spherical IONPs with an average size of 10 nm were obtained and then decorated with the new metronidazole-conjugated dendron. The resulting nanoparticles (metro-NPs) displayed negligible effects on cell viability, proliferation, and metabolism, in both monolayer and 3D cell culture models, and a good colloidal stability in bio-mimicking media, as shown by DLS. Overtime quantitative monitoring of the IONP cell content revealed an enhanced intracellular retention of metro-NPs under anoxic conditions, confirmed by the in vitro MRI of cell pellets where a stronger negative contrast generation was observed in hypoxic primary stem cells and tumor cells after labeling with metro-NPs. Overall, these results suggest desirable properties in terms of interactions with the biological environment and capability of selective accumulation into the hypoxic tissue, and indicate that metro-NPs have considerable potential for the development of new nano-platforms especially in the field of anoxia-related diseases and tissue engineered models.

Rapid, accurate, and safe screening of foodborne pathogenic bacteria is essential to effectively control and prevent outbreaks of foodborne illness. Fluorescent sensors constructed from carbon dots (CDs) and nanomaterial-based quenchers have provided an innovative method for screening of pathogenic bacteria. Herein, an ultrasensitive magnetic fluorescence aptasensor was designed for separation and detection of Staphylococcus aureus ( S. aureus ). Multicolor fluorescent CDs with a long fluorescent lifetime (6.73 ns) and high fluorescence stability were synthesized using a facile hydrothermal approach and modified cDNA as a highly sensitive fluorescent probe. CD fluorescence was quenched by Fe 3 O 4 + aptamer via fluorescence resonance energy transfer (FRET). Under optimal conditions, the FRET-based aptasensor can detect S. aureus accompanied by a wide linear range of 50-10 7 CFU·mL -1 and a detection limit of 8 CFU·mL -1 . Compared with other standard methods, this method was faster and more convenient, and the entire test was finished within 30 min. The capability of the aptasensor was simultaneously investigated on food samples. Additionally, the developed CDs exhibited excellent biocompatibility and were thus applied as fluorescent probes for bioimaging both in vitro and in vivo. This new platform provided an excellent application of the CDs for detecting and bioimaging pathogenic bacteria.

Magnetic resonance imaging (MRI) is widely applied in medical research and diagnosis, and a MRI contrast medium plays a crucial role in improving the sensitivity of detection. Ultrasmall superparamagnetic iron oxides (USPIOs) exhibit the potential as a T 2 enhancement contrast medium for MRI due to their excellent magnetic response performance; however, to endow them with specific tumor targetability, long-term circulation performance has always been a hot topic in this field. In this study, a well-designed procedure of chemical coprecipitation, surface modification, and peptide grafting was applied to prepare the active tumor-targeting USPIOs@F127-WSG, in which Pluronic F127 (F127) and the peptide WSGPGVWGASVK (peptide-WSG) were selected as the template agent and the ovarian tumor-targeting ligand, respectively. The results showed that single USPIOs@F127-WSG particles were Fe 3 O 4 nanoparticles regulated by the confinement effect of F127 micelles with a uniform globular morphology and size (∼9 nm), and peptide-WSG was grafted for their tumor targetability. USPIOs@F127-WSG particles presented superparamagnetic behavior with high T 2 relaxivity ( r 2 = 278.15 mM -1 s -1 ) and in vitro targetability for SKOV-3 cells due to the special binding between peptide-WSG and specific receptors of SKOV-3. The test results in vivo verified the targetability of USPIOs@F127-WSG by their specific aggregation in the tumor regions, leading to the T 2 -weighted MRI contrast enhancement. These outstanding properties indicate that USPIOs@F127-WSG have great potential to be applied as the active tumor-targeting contrast agent for MRI.

Upconversion nanoparticles (UCNPs) are prospective platforms for bioimaging and phototherapy, but a critical bottleneck is the limited brightness due to the faint absorptivity of lanthanide ions and the low quantum yield. To circumvent this problem, we herein propose our strategy to reconstruct the energy cascade of UCNPs using semiconductor quantum dots (QDs) as light sensitizer of Nd 3+ /Yb 3+ codoped UCNPs. Ag 2 Se QDs with strong absorption at 808 nm acted as efficient antenna and transferred their energy to Yb 3+ via a resonance energy transfer process, significantly enhancing the luminescence of UCNPs. This nanocomposite was then combined with Rose Bengal and applied for photodynamic therapy. Both in vitro and in vivo studies revealed the introduction of QDs improved the therapeutic performance remarkably. Our study suggests Ag 2 Se QDs with excellent photophysical properties can be promising agents to overcome the shortcomings of UCNPs and further strengthen their applications.

The problems associated with hydrophobic anticancer drugs are among the most important challenges to achieve efficient therapeutics for cancer treatment. In this study, PEGylated curcumin was used as the surface modification of magnetic nanoparticles (MNP@PEG-Cur) in order to simultaneously take advantage of magnetic targeting characteristic of nanoparticles and PEG conjugated drug. Curcumin was conjugated through EDC/NHS chemistry to the PEG hydroxyl functional groups, and then physically decorated on the surface of magnetic nanoparticles (MNP). The analysis of the conjugate and nanoparticles by FT-IR, 1 HNMR, FE-SEM, TEM, EDX, TGA and VSM confirmed the successful synthesis and proper physicochemical properties of MNP@PEG-Cur nanoparticles. The carrier showed pH dependent drug release profile with higher drug release at acidic media (pH = 5.4) compared to neural condition (pH = 7.4). In addition, LD 50 and hemolysis assay confirmed the biocompatibility of MNP@PEG-Cur. The cell viability assay also revealed that neither carrier, nor curcumin-loaded nanoparticles are cytotoxic at physiologic pH (7.4)., (Copyright © 2019 Elsevier B.V. All rights reserved.)