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Human serum albumin (HSA) is a very well-characterized protein, which has already been used for many biocompatible coatings. We hypothesized binding between HSA and magnetic iron oxide nanoparticles (MNPs) as well as HSA coating stability to be pH- and ionic strength-dependent. The impact of phosphate buffer on protein coating was studied at varying pH (6.0, 6.6, and 7.5) and ionic strengths (0.15 and 0.30 M NaCl) using different physicochemical methods. In addition, the stability of HSA coatings on MNPs was studied by means of UV/visible spectrophotometry, dynamic light scattering, and electron magnetic resonance. We used differential scanning calorimetry (DSC) to determine the differences in the change of enthalpies and denaturation temperatures of HSA in various buffer conditions and on the surface of the particles. The binding thermodynamics of HSA and MNPs were determined by isothermal titration calorimetry (ITC), and it was also dependent on pH and ionic strength. The stability of adsorbed layer on MNPs decreases with increasing pH [from weakly acidic (pH 6.0-6.6) to slightly alkaline (pH 7.5)], as well as with an increase of ionic strength. This study develops stable HSA coating on MNPs which might be applied to a wide range of biomedical applications.

A new type of magnetic chitosan nanocomposites modified with graphene oxide and polyethyleneimine (MCS/GO-PEI) was synthesized, which was used as an adsorbent to remove the toxic heavy metals of As and Hg as well as anionic azo dyes of congo red and amaranth in environmental water. In this experiment, MCS/GO-PEI was first synthesized and the structure and morphology characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier-transform infrared spectrometry (FT-IR), X-ray diffractometer (XRD), vibrating sample magnetometry (VSM) and X-ray photoelectron spectroscopy (XPS). The adsorption performance of the material for four analytes was investigated through adsorption experiments. The kinetic and isothermal results showed that the adsorption process was well described by pseudo-second-order kinetic and Langmuir isotherm model. Besides, the important parameter pH in the adsorption process was investigated and optimized. The maximum adsorption capacities of the nanocomposites for arsenic, mercury ions, congo red, amaranth were 220.26, 124.84, 162.07, 93.81 mg g−1 under optimum adsorption conditions, respectively. The adsorption-desorption showed that the adsorbents were presented adequate reusability. The as-prepared MCS/GO-PEI nanocomposite could serve as promising adsorbent for arsenic, mercury, congo red and amaranth in environmental water samples treatment technology.

Iron oxide nanoparticles (IONPs) have gained increasing attention in various biomedical and industrial sectors due to their physicochemical and magnetic properties. In the biomedical field, IONPs are being developed for enzyme/protein immobilization, magnetofection, cell labeling, DNA detection, and tissue engineering. However, in some established areas, such as magnetic resonance imaging (MRI), magnetic drug targeting (MDT), magnetic fluid hyperthermia (MFH), immunomagnetic separation (IMS), and magnetic particle imaging (MPI), IONPs have crossed from the research bench, received clinical approval, and have been commercialized. Additionally, in industrial sectors IONP-based fluids (ferrofluids) have been marketed in electronic and mechanical devices for some time. This review explores the historical evolution of IONPs to their current state in biomedical and industrial applications.

The magnetic particles modified with silicon dioxide (SiO2) and amino groups (-NH2), as well as the magnetic particles modified with human serum albumin (HSA) were synthesized using the approaches we developed before and characterized by physico-chemical methods in this study. Plasminogen was chosen as a model protein since plasminogen plays a major role in the fibrinolytic system and plasminogen level correlates with different pathologies and conditions. For the first time it has been carried out qualitative and quantitative assessment of plasminogen nonspecific binding (noncovalent adsorption) by the particles in buffer and plasma solutions. The fibrinolytic activity of plasminogen on the surface of the particles has been measured by the aid of commercially available kits and appeared to be 28-30% of its initial value. Plasminogen desorption from the surface of particles was studied in phosphate buffer with NaCl and e-aminocaproic acid. Despite nonspecific plasminogen binding is an undesirable process, the data obtained is valuable for further modification of particles for high-specific proteins extraction from biological fluids or transport of plasminogen by the particles. The perspectives of particles modified with SiO2 and -NH2, and particles modified with HSA for isolation of protein analytes and their quantitative assessment thereafter have been discussed.

One of the most severe diseases threatening the ageing population is Alzheimer’s disease (AD). Recent studies found that the cellular uptake of extracellular amyloid beta (Aβ) peptides can lead to a build-up of intracellular Aβ in certain neuronal cells, which consequently lead to the onset of AD pathogenesis. It is therefore hypothesized that the detection of cells that are involved in such Aβ uptake could facilitate the early diagnosis of AD. In this work, a magnetofluorescent nanoprobe was prepared conjugating dye-labeled Aβ42 peptides with iron oxide nanoparticles (IONPs). When incubated with SH-SY5Y cells, the cellular uptake of Aβ42-IONPs was enhanced, compared to that of bare IONPs. Further, by labelling SH-SY5Y and HCT-116 cells, it was found that the Aβ42-IONPs are selectively targeting the neuronal cells. This enhanced and specific neuronal targeting is attributed to the cellular uptake of extracellular amyloid by SH-SY5Y cells. In addition, the MR relaxivities of the Aβ42-IONPs are preserved after the peptides functionalization. The results suggest that the Aβ42 functionalized magnetofluorescent IONPs can be used as a bimodal probe to interrogate the cellular uptake of amyloid peptides.

The limited durability of dentin bonding harshly shortens the lifespan of resin composites restorations. The controlled, dynamic movement of materials through non-contacting forces provides exciting opportunities in adhesive dentistry. We, herein, describe comprehensive investigations of a new dental adhesive with superparamagnetic iron oxide nanoparticles (SPIONs) sensitive to magnetic fields for bonding optimization. This contribution outlines a roadmap of (1) designing and tuning of an adhesive formulation containing SPIONs to enhance penetrability into etched dentin guided by magnetic-field; (2) employing a clinically relevant model of simulated hydrostatic pulpal pressure on the microtensile bond to dentin; and (3) investigating a potential antibacterial effect of the formulated adhesives, and their biocompatibility. SPION-concentration-dependency chemical and mechanical behavior was shown via the degree of conversion, ultimate tensile strength, and micro shear bond strength to dentin. The effects of SPIONs carried on a dental adhesive on the bonding strength to dentin are studied in depth by combining experiments with in vitro simulated model. The results show that under the guided magnetic field, 0.07 wt.% of SPIONs-doped adhesive increased the bond strength that surpasses the reduction caused by hydrostatic pulpal pressure. Using a magnetic guide workflow during the bonding procedures, SPIONs-doped adhesives improved dentin's adhesion without changing adhesives’ physicochemical properties. This outcome addresses the key challenge of poor resin infiltration of dentin's conventional total etching during the bonding procedure. The real-time magnetic motion of dental adhesives may open new paths to enhance resin-based restorations’ longevity. Statement of significance In this study, dental adhesives containing superparamagnetic iron oxide nanoparticles (SPIONs) were developed to enhance penetrability into dentin guided by a magnetic field. The adhesives were screened for physical, chemical, antibacterial properties, and cytotoxicity. For the first time, simulated pulpal pressure was used concurrently with the magnetic field to simulate a clinical setting. This approach showed that it is feasible to overcome pulpal pressure jeopardization on bond strength when SPIONs and a magnetic field are applied. The magnetic-responsive adhesives had great potential to improve bond strength, opening new paths to enhance resin-based restorations' longevity without affecting adhesives' biological properties. The use of magnetic-responsive particles and magnetically assisted motion is a promising strategy to improve the sealing ability of dental adhesives.

Jinman Zhong,1,* Jianke Ding,2,* Lei Deng,1 Ying Xiang,1 Duoduo Liu,1 Yanyan Zhang,1 Xin Chen,1 Quanxin Yang1 1Department of Radiology, The Second Affiliated Hospital, Xi’ an Jiaotong University, Xi’an, Shaanxi Province, 710004, People’s Republic of China; 2Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, 710032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Quanxin Yang; Xin ChenDepartment of Radiology, The Second Affiliated Hospital, Xi’ an Jiaotong University, 157 Xiwu Road, Xi’an, Shaanxi Province, 710004, People’s Republic of ChinaEmail quanxin1962@163.com; chen_x129@163.comBackground: The sensitive and specific detection of pathogenic cells is important in tumor diagnosis at an early stage. Aptamers are short single-stranded oligonucleotides evolved from systematic evolution of ligands by exponential enrichment (SELEX). It has been proved that aptamers can interact with cognate target molecules with high affinity and specificity and have great potential in the development of medical imaging at molecular level.Purpose: To select epithelial cell adhesion molecule (EpCAM) specific aptamers targeting prostate cancer and further to conjugate aptamers with GoldMag nanoparticles (a typical iron oxide core/gold shell structure) to construct magnetic molecular probes for medical imaging.Methods: EpCAM-specific aptamers were selected by Cell-SELEX. The enrichment of specific aptamer candidates was monitored by flow cytometric analysis. Aptamers were further conjugated with GoldMag nanoparticles to construct magnetic molecular probes. The affinity and specificity of aptamer candidates and aptamer-conjugated GoldMag nanoparticles were evaluated. The MR imaging of aptamer-conjugated GoldMag nanoparticles to prostate cancer was further explored in vitro and in vivo.Results: After 12 rounds of selection, aptamer candidates Eppc6 and Eppc14 could specifically target three types of prostate cancer cells, revealing a high affinity of Eppc6 and Eppc14. Moreover, aptamer-conjugated GoldMag nanoparticles not only exhibited good affinity to different prostate cancer cells but also produced strong T2WI signal intensity reduction distinguished from peritumoral tissue in MRI, indicating that the molecular probes possess both the affinity properties of EpCAM-specific aptamer and the superparamagnetic features of iron oxide.Conclusion: Our study indicates that aptamer Eppc6 and Eppc14 can recognize prostate cancer cells and tissues. The aptamer-conjugated GoldMag nanoparticles constructed in the study can be used as a molecular imaging agent for detection of PCa in MRI.Keywords: EpCAM, aptamer, Cell-SELEX, prostate cancer

Samer Hasan Hussein-Al-Ali,1,2 Mohd Zobir Hussein,3 Saifullah Bullo,3 Palanisamy Arulselvan4 1Faculty of Pharmacy, Isra University, Amman, 11622, Jordan; 2Department of Chemistry, Faculty of Science, Isra University, Amman, 11622, Jordan; 3Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia, Selangor, 43400, Malaysia; 4Laboratory of Vaccines and Immunotherapeutic, Institute of Bioscience, Universiti Putra Malyasia, Serdange, Selangor, 43400 UPM, MalaysiaCorrespondence: Mohd Zobir HusseinMaterials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Malaysia Universiti Putra Malaysia, UPM, Serdang, Selangor, 43400, MalaysiaTel +603 89466801Fax +603 89435380Email mzobir@upm.edu.mySamer Hasan Hussein-Al-AliDepartment of Chemistry, Faculty of Science, Isra University, P.O. Box 22, Amman, 11622, JordanTel +962 4711710Fax +962 4711505Email samer.alali@iu.edu.joIntroduction: Traditional cancer therapies may have incomplete eradication of cancer or destroy the normal cells. Nanotechnology solves the demerit by a guide in surgical resection of tumors, targeted chemotherapies, selective to cancerous cells, etc. This new technology can reduce the risk to the patient and automatically increased the probability of survival. Toward this goal, novel iron oxide nanoparticles (IONPs) coupled with leukemia anti-cancer drug were prepared and assessed.Methods: The IONPs were prepared by the co-precipitation method using Fe+3/Fe+2ratio of 2:1. These IONPs were used as a carrier for chlorambucil (Chloramb), where the IONPs serve as the cores and chitosan (CS) as a polymeric shell to form Chloramb-CS-IONPs. The products were characterized using transmission electron microscopy (TEM), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) analysis, Fourier transform infrared spectroscopy (FTIR), vibrating sample magnetometry (VSM) analyses, and thermal gravimetric analysis (TGA).Results: The as-prepared IONPs were found to be magnetite (Fe3O4) and were coated by the CS polymer/Chloramb drug for the formation of the Chloramb-CS-IONPs. The average size for CS-IONPs and Chloramb-CS-IONPs nanocomposite was found to be 15 nm, with a drug loading of 19% for the letter. The release of the drug from the nanocomposite was found to be of a controlled-release manner with around 89.9% of the drug was released within about 5000 min and governed by the pseudo-second order. The in vitro cytotoxicity studies of CS-IONPs and Chloramb-CS-IONPs nanocomposite were tested on the normal fibroblast cell lines (3T3) and leukemia cancer cell lines (WEHI). Chloramb in Chloramb-CS-IONPs nanocomposite was found to be more efficient compared to its free form.Conclusion: This work shows that Chloramb-CS-IONPs nanocomposite is a promising candidate for magnetically targeted drug delivery for leukemia anti-cancer agents.Keywords: chlorambucil, anticancer, leukemia cell lines, magnetic nanoparticles, sustained release

Chlorin e6 (Ce6) is a promising photosensitizer for tumor photodynamic therapy (PDT). However, the efficacy of Ce6 PDT is limited by Ce6's poor water solubility, rapid blood clearance, and inadequate accumulation in the tumor tissue. This problem is tackled in this work, wherein functionalized superparamagnetic iron oxide nanoparticles (IO-NPs) were used as carriers to deliver Ce6 to melanoma. The IO-NPs were coated with polyglycerol (PG) to afford good aqueous solubility. The chemotherapeutic agent doxorubicin (DOX) was attached to the PG coating via the hydrazone bond to afford affinity to the cell membrane and thereby promote the cell uptake. The hydrophobic nature of DOX also induced the aggregation of IO-NPs to form nanoclusters. Ce6 was then loaded onto the IO nanoclusters through physical adsorption and coordination with surface iron atoms, yielding the final composites IO-PG-DOX-Ce6. In vitro experiments showed that IO-PG-DOX-Ce6 markedly increased Ce6 uptake in mouse melanoma cells, leading to much-enhanced photocytotoxicity characterized by intensified reactive oxygen species production, loss of viability, DNA damage, and stimulation of tumor cell immunogenicity. In vivo experiments corroborated the in vitro findings and demonstrated prolonged blood clearance of IO-PG-DOX-Ce6. Importantly, IO-PG-DOX-Ce6 markedly increased the Ce6 distribution and retention in mouse subcutaneous melanoma grafts and significantly improved the efficacy of Ce6-mediated PDT. No apparent vital organ damage was observed at the same time. In conclusion, the IO-PG-DOX NPs provide a simple and safe delivery platform for efficient tumor enrichment of Ce6, thereby enhancing antimelanoma PDT.

Yana Toropova,1 Dmitry Korolev,1 Maria Istomina,1,2 Galina Shulmeyster,1 Alexey Petukhov,1,3 Vladimir Mishanin,1 Andrey Gorshkov,4 Ekaterina Podyacheva,1 Kamil Gareev,2 Alexei Bagrov,5 Oleg Demidov6,7 1Almazov National Medical Research Centre, Ministry of Health of the Russian Federation, Saint-Petersburg, 197341, Russian Federation; 2Saint Petersburg Electrotechnical University “LETI”, Saint-Petersburg, 197376, Russian Federation; 3Personalised Medicine Center, Almazov National Medical Research Centre, Ministry of Health of the Russian Federation, Saint-Petersburg, 197341, Russian Federation; 4FSBI “Research Institute of Influenza named after A.A. Smorodintsev “ Ministry of Health of Russian Federation, Saint-Petersburg, Russian Federation; 5Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Saint-Petersburg, Russian Federation; 6Institute of Cytology RAS, Saint-Petersburg, 194064, Russian Federation; 7INSERM U1231, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche Comté, Dijon, FranceCorrespondence: Yana ToropovaAlmazov National Medical Research Centre, Ministry of Health of the Russian Federation, Saint-Petersburg, 197341, Russian FederationTel +7 981 9564800Fax +7 812 4997069Email yana.toropova@mail.ruBackground: A promising approach to solve the problem of cytostatic toxicity is targeted drug transport using magnetic nanoparticles (MNPs).Purpose: To use calculation to determine the optimal characteristics of the magnetic field for controlling MNPs in the body, and to evaluate the efficiency of magnetically controlled delivery of MNPs in vitro and in vivo to a tumour site in mice.Material and Methods: For the in vitro study, reference MNPs were used, while for in vivo studies, MNPs coated in polylactide including fluorescent indocyanine (MNPs-ICG) were used. The in vivo luminescence intensity study was performed in mice with tumours, with and without of a magnetic field at the sites of interest. The studies were performed on a hydrodynamic stand developed at the Institute of Experimental Medicine of the Almazov National Medical Research Centre of the Ministry of Health of Russia.Results: The use of neodymium magnets facilitated selective accumulation of MNPs. One minute after the administration of MNPs-ICG to mice with a tumour, MNPs-ICG predominantly accumulated in the liver, in the absence and presence of a magnetic field, which indicates its metabolic pathway. The intensity of the fluorescence in the animals’ livers did not change over time, although an increase in fluorescence in the tumour was observed in the presence of a magnetic field.Conclusion: This type of MNP, used in combination with a magnetic field of calculated strength, can form the basis for the development of magnetically controlled transport of cytostatic drugs into tumour tissue.Keywords: fluorescence analysis, indocyanine, iron oxide nanoparticles, magnetically controlled delivery of cytostatics, tumor targeting

In the current biosensor, the signal generation is limited to single virus detection in the reaction chamber. An adaptive strategy is required to enable the recognition of multiple viruses for diagnostics and surveillance. In this work, a nanocarrier is deployed to bring specific signal amplification into the biosensor, depending on the target viruses. The nanocarrier is designed using pH-sensitive polymeric nanoparticle-laden nanocarriers (PNLNs) prepared by sequential nanoprecipitation. The nanoprecipitation of two chromogens, phenolphthalein (PP) and thymolphthalein (TP), is investigated in three different solvent systems in which PNLNs demonstrate a high loading of the chromogen up to 59.75% in dimethylformamide (DMF)/dimethyl sulfoxide (DMSO)/ethanol attributing to the coprecipitation degree of the chromogens and the polymer. The PP-encapsulated PNLNs (PP@PNLNs) and TP-encapsulated PNLNs (TP@PNLNs) are conjugated to antibodies specific to target viruses, influenza virus A subtype H1N1 (IV/A/H1N1) and H3N2 (IV/A/H3N2), respectively. After the addition of anti-IV/A antibody-conjugated magnetic nanoparticles (MNPs) and magnetic separation, the enriched PNLNs/virus/MNPs sandwich structure is treated in an alkaline solution. It demonstrates a synergy reaction in which the degradation of the polymeric boundary and the pH-induced colorimetric development of the chromogen occurred. The derivative binary biosensor shows feasible detection on IV/A with excellent specificities of PP@PNLNs on IV/A/H1N1 and TP@PNLNs on IV/A/H3N2 with LODs of 27.56 and 28.38 fg mL-1, respectively. It intrigues the distinguished analytical signal in human serum with a variance coefficient of 25.8% and a recovery of 93.6-110.6% for one-step subtype influenza virus detection.

For the purpose of improving the quality of life and minimizing the psychological morbidity of a mastectomy, breast-conserving treatment (BCT) has become the more preferable choice in breast cancer patients. Meanwhile, tumor hypoxia has been increasingly recognized as a major deleterious factor in cancer therapies. In the current study, a novel, effective, and noninvasive magnetothermodynamic strategy based on an oxygen-independent free-radical burst for hypoxia-overcoming BCT is proposed. Radical precursor (AIPH) and iron oxide nanoparticles (IONPs) are coincorporated within the alginate (ALG) hydrogel, which is formed in situ within the tumor tissue by leveraging the cross-linking effect induced by the local physiological Ca2+ with ALG solution. Inductive heating is mediated by IONPs under AMF exposure, and consequently, regardless of the tumor hypoxia condition, a local free-radical burst is achieved by thermal decomposition of AIPH via AMF responsivity. The combination of magnetic hyperthermia and oxygen-irrelevant free-radical production effectively enhances the in vitro cytotoxic effect and also remarkably inhibits tumor proliferation. This study provides a valuable protocol for an hypoxia-overcoming strategy and also an alternative formulation candidate for noninvasive BCT.

Background Nasopharyngeal carcinoma (NPC) is a type of head and neck malignant tumor with a high incidence in specific regional distribution, and its traditional therapies face some challenges. It has become an urgent need to seek new therapeutic strategies without or with low toxicity and side effects. At present, more and more researchers has been attracting attention by nanotheranostic platform. Therefore, our team synthesized the polyethylene glycol-coated ultrasmall superparamagnetic iron oxide nanoparticles-coupled sialyl Lewis X (USPIO-PEG-sLex) nanotheranostic platform with high temperature pyrolysis. Results The USPIO-PEG-sLex nanoparticles had excellent photothermal conversion property, and the temperature of USPIO-PEG-sLex nanoparticles solution increased with its concentration and power density of near-infrared (NIR) on 808 nm wavelengths. Five USPIO-PEG-sLex nanoparticles with different concentrations of 0 mg/ml, 0.025 mg/ml, 0.05 mg/ml, 0.1 mg/ml and 0.2 mg/ml were prepared. The biological toxicity results showed that the viability of NPC 5-8F cells is related to the concentration of USPIO-PEG-sLex nanoparticles and the culture time (P x nanoparticles increases (P x nanoparticles could target the tumor area, and reduce the T2* value of tumor tissue. The T2* values of tumor pre- and post-injection were 30.870 ± 5.604 and 18.335 ± 4.351, respectively (P x nanoparticles as a photothermal agent for PTT could effectively inhibit tumor progression. The ratio of volume change between tail vein injection group, control group, nanoparticles without laser irradiation group and blank group after 5 treatments were 3.04 ± 0.57, 5.80 ± 1.06, 8.09 ± 1.96, 7.89 ± 2.20, respectively (P < 0.001). Conclusions Our synthesized USPIO-PEG-sLex nanotheranostic platform, and it may be become a new strategy for the treatment of NPC. Graphic Abstract

Gray level co-occurrence matrix (GLCM) analysis is a contemporary and innovative computer-based algorithm that can be used for the quantification of subtle changes in a cellular structure. In this work, we use this method for the detection of discrete alterations in hepatocyte chromatin distribution after in vivo exposure to iron oxide nanoparticles (IONPs). The study was performed on 40 male, healthy C57BL/6 mice divided into four groups: three experimental groups that received different doses of IONPs and 1 control group. We describe the dose-dependent reduction of chromatin textural uniformity measured as GLCM angular second moment. Similar changes were detected for chromatin textural uniformity expressed as the value of inverse difference moment. To the best of our knowledge, this is the first study to investigate the impact of iron-based nanomaterials on hepatocyte GLCM parameters. Also, this is the first study to apply discrete wavelet transform analysis, as a supplementary method to GLCM, for the assessment of hepatocyte chromatin structure in these conditions. The results may present the useful basis for future research on the application of GLCM and DWT methods in pathology and other medical research areas.

Nonalcoholic fatty liver disease (NAFLD) is the leading hepatic manifestation of metabolic syndrome worldwide, and is clinically accompanied by iron overload. As the increasing application of iron oxide nanoparticles (IONPs) on the imaging and diagnosis in NAFLD, the potential hepatic effect and mechanism of IONPs on NAFLD should be well studied. Here, we demonstrate that carboxyl-modified (COOH-IONPs) and amino-coated IONPs (NH2-IONPs) exhibit no significant hepatic toxicity in normal mice at the clinical injection dose, but aggravate SREBP-1c-mediated de novo lipogenesis (DNL) in the livers of mice with NAFLD induced by high-fat diet (HFD) and in HepG2 cells incubated with oleic acid (OA), especially in those treated by the positive NH2-IONPs. In the present study, mice receiving IONPs for 7 day show mild iron overload in the liver and exhibit enhanced hepatic inflammation in NAFLD. The BMP-SMAD pathway is initiated by hepatic iron overload and is aggravated in NAFLD. In conclusion, BMP-SMAD-mediated hepatic iron overload aggravated lipid accumulation in the liver and hepatic inflammatory responses, implying that effective measures in addition to hepatic iron overload are needed for individuals at the risk of IONPs in NAFLD.

Krzysztof Marycz,1,2 Agnieszka Smieszek,1 Klaudia Marcinkowska,1 Mateusz Sikora,1 Eliza Turlej,1 Paulina Sobierajska,3 Adrian Patej,3 Alina Bienko,4 Rafal J Wiglusz3 1The Department of Experimental Biology, The Faculty of Biology and Animal Science, University of Environmental and Life Sciences, Wroclaw, Poland; 2International Institute of Translational Medicine, Malin, Poland; 3Institute of Low Temperature and Structure Research, PAS, Wroclaw, Poland; 4Faculty of Chemistry, University of Wroclaw, Wroclaw, PolandCorrespondence: Krzysztof MaryczThe Department of Experimental Biology, The Faculty of Biology and Animal Science, University of Environmental and Life Sciences Wroclaw, Norwida 27B St, Wroclaw, 50– 375, PolandTel +48 71 320 5201Email krzysztof.marycz@upwr.edu.plPurpose: Osteoporosis results in a severe decrease in the life quality of many people worldwide. The latest data shows that the number of osteoporotic fractures is becoming an increasing international health service problem. Therefore, a new kind of controllable treatment methods for osteoporotic fractures is extensively desired. For that reason, we have manufactured and evaluated nanohydroxyapatite (nHAp)-based composite co-doped with iron oxide (IO) nanoparticles. The biomaterial was used as a matrix for the controlled delivery of miR-21-5p and miR-124-3p, which have a proven impact on bone cell metabolism.Methods: The nanocomposite Ca5(PO4)3OH/Fe3O4 (later called nHAp/IO) was obtained by the wet chemistry method and functionalised with microRNAs (nHAp/IO@miR-21/124). Its physicochemical characterization was performed using XRPD, FT-IR, SEM-EDS and HRTEM and SAED methods. The modulatory effect of the composite was tested in vitro using murine pre-osteoblasts MC3T3-E1 and pre-osteoclasts 4B12. Moreover, the anti-inflammatory effects of biomaterial were analysed using a model of LPS-treated murine macrophages RAW 264.7. We have analysed the cells’ viability, mitochondria membrane potential and oxidative stress under magnetic field (MF+) and without (MF-). Moreover, the results were supplemented with RT-qPCR and Western blot assays to evaluate the expression profile for master regulators of bone metabolism.Results: The results indicated pro-osteogenic effects of nHAp/IO@miR-21/124 composite enhanced by exposure to MF. The enhanced osteogenesis guided by nHAp/IO@miR-21/124 presence was associated with increased metabolism of progenitor cells and activation of osteogenic markers (Runx-2, Opn, Coll-1). Simultaneously, nanocomposite decreased metabolism and differentiation of pre-osteoclastic 4B12 cells accompanied by reduced expression of CaII and Ctsk. Obtained composite regulated viability of bone progenitor cells and showed immunomodulatory properties inhibiting the expression of inflammatory markers, ie, TNF-α, iNOs or IL-1β, in LPS-stimulated RAW 264.7 cells.Conclusion: We have described for the first time a new concept of osteoporosis treatment based on nHAp/IO@miR-21/124 application. Obtained results indicated that fabricated nanocomposite might impact proper regeneration of osteoporotic bone, restoring the balance between osteoblasts and osteoclast.Keywords: nanocomposites, hydroxyapatite, osteoblasts, osteoclasts, osteoporosis

Aim: Superparamagnetic cubic iron oxide nanoparticles (IONPs) were synthesized and functionalized with meso-2,3-dimercaptosuccinic acid (DMSA) as a potential agent for cancer treatment. Methods: Monodisperse cubic IONPs with a high value of saturation magnetization were synthesized by thermal decomposition method and functionalized with DMSA via ligand exchange reaction, and their cytotoxic effects on HeLa cells were investigated. Results: DMSA functionalized cubic IONPs with an edge length of 24.5 ± 1.9 nm had a specific absorption rate value of 197.4 W/gFe (15.95 kA/m and 488 kHz) and showed slight cytotoxicity on HeLa cells when incubated with 3.3 × 1010, 6.6 × 1010 and 9.9 × 1010 NP/mL for 24, 48 and 72 h. Conclusion: To the best of our knowledge, this is the first study to investigate both the cytotoxic effects of DMSA-coated cubic IONPs on HeLa cells and hyperthermia performance of these nanoparticles.

This study aims at controlling excess nutrients, including nitrogen and phosphorus, and harmful algae that pollute the marine environment using biosynthesized iron oxide nanoparticles. Aqueous extracts of brown seaweeds named

Overuse of antibiotics has led to the development of multi drug resistant strains. Antibiotic resistance is a major drawback in the biomedical field since medical implants are prone to infection by biofilms of antibiotic resistant strains of bacteria. With increasing prevalence of antibiotic resistant pathogenic bacteria, the search for alternative method is utmost importance. In this regard, magnetic nanoparticles are commonly used as a substitute for antibiotics that can circumvent the problem of biofilms growth on the surface of biomedical implants. Iron oxide nanoparticles (IONPs) have unique magnetic properties that can be exploited in various ways in the biomedical applications. IONPs are engineered employing different methods to induce surface functionalization that include the use of polyethyleneimine and oleic acid. IONPs have a mechanical effect on biofilms when in presence of an external magnet. In this review, a detailed description of surface engineered magnetic nanoparticles as ideal antibacterial agents is provided, accompanied by various methods of literature review. This article is protected by copyright. All rights reserved.

Ferroptosis is a form of cell death associated with iron-dependent lipid peroxidation. We used a chicken embryo model to investigate if ferroptosis was implicated in the molecular mechanism underlying the potential effects of maternal exposure to iron oxide nanoparticles (IONPs) on the developing brain. One hundred and eighty fertilized eggs were randomly divided into six groups (30 eggs/group; 10 eggs/replicate). Groups I and II received maghemite (γ-Fe2 O3 ) NPs (MGMNPs), while groups III and IV received magnetite (Fe3 O4 ) NPs (MGTNPs). Both MGMNP and MGTNP were administrated at the concentrations of 100 and 250 ppm. One group (placebo) received saline, and the other remained untreated (control). The compounds were given by in ovo method (0.3 ml/egg) only once on the first day of the embryonic period. Samples from cerebral tissue were collected on day 20 for histopathological, biochemical and gene expression analyses. Total antioxidant capacity (TAC) and malondialdehyde (MDA) increased; glutathione peroxidase (GPX) expression and activity decreased in IONPs-treated groups. Ferroptotic cells appeared in the cerebral tissue following exposure to the low dose of MGMNP and MGTNP. Oxidative stress and ferroptotic cells were more evident for MGMNP compared to MGTNP. The low dose of MGMNP and MGTNP induced more severe oxidative stress in the cerebral tissue. According to the results, maternal exposure to IONPs is associated with ferroptosis in the brain. This work could encourage future researches to investigate inhibitors of ferroptosis as a protective strategy against iron-induced cell injuries and cell death.

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 IC50 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 IC50 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.

Gang Gui,1,* Ziqi Fan,1,* Yihuan Ning,1 Cancan Yuan,2 Baolin Zhang,3 Qin Xu1 1College of Pharmacy, Guilin Medical University, Guilin, 541004, People’s Republic of China; 2Department of Pharmacy, Luohe City People’s Hospital, Luohe, 462000, People’s Republic of China; 3College of Materials Science and Engineering, Guilin University of Technology, Guilin, 541004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qin XuCollege of Pharmacy, Guilin Medical University, Guilin, 541004, People’s Republic of ChinaEmail xuqincpu@126.comBaolin ZhangCollege of Materials Science and Engineering, Guilin University of Technology, Guilin, 541004, People’s Republic of ChinaEmail zhangbaolin@glut.edu.cnBackground: Paclitaxel (PTX) has interesting anticancer activity. However, it is insoluble in water, which seriously hinders its use in clinical. Superparamagnetic iron oxide nanoparticles (SPIONs) are used as an ideal drug delivery system. Therefore, we proposed a folic acid (FA) targeting drug-loaded SPIONs to reduce its adverse reaction.Methods: To improve the hydrophilicity of PTX, the structure of PTX was modified by succinic anhydride to obtain 2ʹ-succinate paclitaxel (SPTX). FA conjugated Polyethylene glycol (PEG)/polyethyleneimine (PEI)-SPIONs SPTX-loaded nanoparticles (SPTX@FA@PEG/PEI-SPIONs) were prepared by solvent volatilization and hydrogen bond adsorption, and the nano-formulation was optimized by response surface methodology (RSM). The characteristics, antitumor effect in vitro, pharmacokinetics, and biodistribution of SPTX@FA@PEG/PEI-SPIONs were evaluated.Results: SPTX was successfully loaded on the surface of FA@PEG/PEI-SPIONs. The formation of SPTX@FA@PEG/PEI-SPIONs was exhibited water-dispersive monodispersity with high stability by RSM, and dynamic light scattering (DLS) was 178.1± 3.12 nm, particle size observed in the transmission electron microscope (TEM) was 13.01± 1.10 nm, and the encapsulation efficiency (EE) and loading efficiency (LE) were 81.1± 1.66% and 14.8± 1.46%, respectively. It enhanced the stability in normal physiological condition, accelerated drug release at tumorous pH, and preferentially prolonged the circulation time. In vitro, the SPTX@FA@PEG/PEI-SPIONs significantly targeted to folate receptor (FR) positive cancers cell (HNE-1) via the receptor-ligand mediated pathway, resulting in effective cytotoxic activity. Pharmacokinetic results demonstrated that SPTX@FA@PEG/PEI-SPIONs (t1/2=3.41 h) had longer than free SPTX or PTX (t1/2=1.67 h) in rats in vivo. Tissue distribution studies showed that SPTX@FA@PEG/PEI-SPIONs were present at high levels in the liver and help in targeting the folate receptors present on the kidneys.Conclusion: These results suggest that SPTX@FA@PEG/PEI-SPIONs offer a highly promising approach to control drug release, improve drug pharmacokinetics and actively target the nasopharyngeal carcinoma.Keywords: paclitaxel, folic acid, superparamagnetic iron oxide nanoparticles, targeted drug delivery, response surface methodology, anti-nasopharyngeal carcinoma

The efficient entry of nanotechnology-based pharmaceuticals into target cells is highly desired to reach high therapeutic efficiencywhile minimizing the side effects. Despite intensive research, the impact of the surface coating on the mechanism of nanoparticleuptake is not sufficiently understood yet. Herein, we present a mechanistic study of cellular internalization pathways of two magneticiron oxide nanoparticles (MNPs) differing in surface chemistry into A549 cells. The MNP uptake was investigated in the presenceof different inhibitors of endocytosis and monitored by spectroscopic and imaging techniques. The results revealed that theroute of MNP entry into cells strongly depends on the surface chemistry of the MNPs. While serum bovine albumin-coated MNPsentered the cells via clathrin-mediated endocytosis (CME), caveolin-mediated endocytosis (CavME) or lipid rafts were preferentiallyinvolved in the internalization of polyethylene glycol-coated MNPs. Our data indicate that surface engineering can contribute toan enhanced delivery efficiency of nanoparticles.

Iron oxide nanoparticles have attracted much attention because of their superparamagnetic properties and their potential applications in many fields such as magnetic storage devices, catalysis, sensors, superparamagnetic relaxometry (SPMR), and high‐sensitivity biomolecule magnetic resonance imaging (MRI) for medical diagnosis and therapeutics. In this study, iron oxide nanoparticles (Fe2O3 NPs) have been synthesized using a taranjabin (camelthorn or persian manna) aqueous solution. The synthesized Fe2O3 NPs were identified through powder X‐ray diffraction (PXRD), X‐ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT‐IR), field energy scanning electron microscopy (FESEM), transmission electron microscopy (TEM), energy‐dispersive spectroscopy (EDX), vibrating‐sample magnetometer (VSM) and Raman technics. The results show that the nanoparticles have a hexagonal structure with 20 to 60 nm in size. The cytotoxic effect of the synthesized nanoparticles has been tested upon application against lung cancer cell (A549) lines. It was found that there is no cytotoxic activity at lower concentrations of 200 μg/mL. The ability of the synthesized nanoparticles for lead removal in wastewaters was tested. Results show that highest concentration of adsorbent (50 mg/L) has maximum removal efficiency (96.73 %). So, synthesized Fe2O3 NPs can be a good candidate to use as heavy metals cleaner from contaminated waters., Iron oxide nanoparticles have been synthesized using persian manna in aqueous solution. The nanoparticles have been tested for cytotoxic activity and for their lead removal properties in wastewaters.

Iron oxide nanoparticles gain increasing attention due to their broad industrial use. However, safety concerns exist since their effects on human cells are still under investigation. The presence of iron oxide nanoparticles in the food pigment E172 has been shown recently. Here, we studied four iron oxide nanoparticles, one food pigment E172 and the ionic control FeSO4 regarding dissolution in biological media, uptake and transport, and cellular effects in vitro in human intestinal Caco-2 and HepaRG hepatocarcinoma cells. The iron oxide nanoparticles passed the gastrointestinal passage without dissolution and reached the intestine in the form of particles. Minor uptake was seen into Caco-2 cells but almost no transport to the basolateral site was detected for any of the tested particles. HepaRG cells showed higher particle uptake. Caco-2 cells showed no alterations in reactive oxygen species production, apoptosis, or mitochondrial membrane potential, whereas two particles induced apoptosis in HepaRG cells, and one altered mitochondrial membrane potential at non-cytotoxic concentrations. No correlation between physicochemical particle characteristics and cellular effects was observed, thus emphasizing the need for case-by-case assessment of iron oxide nanoparticles. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-020-02960-7.

Cardiovascular disease is one of the major contributors to global disease burden. Atherosclerosis is an inflammatory process that involves the accumulation of lipids and fibrous elements in the large arteries, forming an atherosclerotic plaque. Rupture of unstable plaques leads to thrombosis that triggers life-threatening complications such as myocardial infarction. Current diagnostic methods are invasive as they require insertion of a catheter into the coronary artery. Molecular imaging techniques, such as magnetic resonance imaging, have been developed to image atherosclerotic plaques and thrombosis due to its high spatial resolution and safety. The sensitivity of magnetic resonance imaging can be improved with contrast agents, such as iron oxide nanoparticles. This review presents the most recent advances in atherosclerosis, thrombosis, and myocardial infarction molecular imaging using iron oxide-based nanoparticles. While some studies have shown their effectiveness, many are yet to undertake comprehensive testing of biocompatibility. There are still potential hazards to address and complications to diagnosis, therefore strategies for overcoming these challenges are required.

The structural, physicochemical, morphological, and magnetic properties of magnetic drug nanoparticles prepared using polymer, layered double hydroxide (LDHs) and drug as the coating agent and magnetic iron oxide nanoparticles (MNPs) as the core were systematically studied. Firstly, a co-precipitation method was employed to synthesize the Fe3O4 nanoparticles. Then, the surface was coated with polyvinyl alcohol, Zn/Al-LDH and sorafenib (SO). XRD and FTIR studies indicate that the core has the crystal structure of the iron oxide. The TGA results supported the existence of both the core and the shell. The saturation magnetization of the as-synthesized Fe3O4 nanoparticles was found to be reduced from 80 to57 emu/g when the nanoparticles were coated with polyvinyl alcohol, Zn/Al-LDH and the drug sorafenib. HRTEM images revealed that the mean dimension of the naked Fe3O4 nanoparticles is around 30 nm. Further structural characterizations showed that the addition of the shell led to the formation of uniform particles with a particle size distribution of about 95 nm. The kinetics of drug release from the nanoparticles was found to be governed by the pseudo-second-order equation. Cell viability assays clearly showed that the magnetic iron oxide nanoparticles coated with polyvinyl alcohol-sorafenib-Zn/Al-layered double hydroxide were found to be more potent than sorafenib alone against HepG2 liver cancer cells, while displayed no cytotoxicity against 3T3 fibroblasts. These results show that the coated Fe3O4 magnetite nanoparticles are a good candidate as a drug delivery carrier to be further explored for biomedical applications.

Recently the applications of engineered nanoparticles in the agricultural sector is increased as nano-pesticides, nano-fertilizers, nanocarrier for macro- or micronutrients, nano-sensors, etc. In this study, biocompatible iron oxide nanoparticles (FeO NPs) have been synthesized through an environment-friendly route using Cassia occidentalis L. flower extract to act as nano-priming agent for promoting germination of Pusa basmati rice seeds. Different characterization methods, viz. X-ray diffraction, particle size analyser, zeta potential and scanning electron microscopy, were used to show efficacious synthesis of FeO NPs capped with phytochemicals. Rice seeds primed with FeO NPs at 20 and 40 mg/L efficiently enhanced germination and seedling vigour compared to ferrous sulphate (FeSO4) priming and hydro-primed control. The seeds primed with 20 mg/L FeO NPs showed up to 50% stimulation in biophysical parameters such as root length and dry weight. Substantial stimulation of sugar and amylase content was also reported at the same concentration. The antioxidant enzyme activity was significantly increased as compared to FeSO4 priming and control. Inductively coupled plasma mass spectroscopy (ICP-MS) study was also done for analysis of Fe, Zn, K, Ca, and Mn concentration in seeds. The seed priming technique signifies a comprehensible and innovative approach that could enhance α-amylase activity, iron acquisition, and ROS production, ensuing elevated soluble sugar levels for supporting seedling growth and enhancing seed germination rate, respectively. In this report, phytochemical-capped FeO NPs are presented as a capable nano-priming agent for stimulating the germination of naturally aged rice seeds.

Salicylic acid and iron-oxide nanoparticles alleviated salt toxicity and improved plant growth by stimulating the activities of H+-ATPase and H+-PPase and preventing nutrient imbalance. Two factorial experiments were undertaken in a greenhouse during 2018 and 2019, to evaluate the impacts of SA (1 mM) and nano-Fe2O3 (3 mM) sprays at 7 leaves and flowering stages on vacuolar H+-pumps, growth and essential oil of salt-subjected (0, 4, 8 and 12 dS m−1 NaCl) ajowan plants. Measurements of plant traits were started at about 12 days after the last foliar spray and continued up to maturity. The H+-ATPase and H+-PPase activities and root ATP content were enhanced under low salinity, but higher salinities reduced these parameters. Rising salinity enhanced Na uptake and translocation, endogenous SA and DPPH activity, while reduced K+/Na+ ratio and nutrients uptake, leading to a reduction in plant biomass. Treatment with SA, nano-Fe2O3 and their combination improved H+-pumps activities and ATP content in roots and leaves. The SA-related treatments caused the highest activities of H+-pumps in roots, but Fe-related treatments resulted in the highest activities of these pumps in leaves. Increasing H+-pumps activities reduced sodium uptake and translocation and enhanced nutrients uptake. Foliar treatments, especially SA + nano-Fe2O3 augmented endogenous SA, DPPH activity, and plant growth in salt-stressed plants. Essential oil contents of vegetative and inflorescence organs under severe salinity and seeds under moderate and severe salinities were enhanced. Maximum essential oil was obtained from seeds of SA + nano-Fe2O3-treated plants, which was strongly correlated with endogenous SA and DPPH. Nevertheless, the SA + nano-Fe2O3 was the best treatment for diminishing salt toxicity and improving ajowan plant growth and essential oil production.

Bimodal sub-5 nm superparamagnetic iron oxide nanoparticles (SPIO-5) coated with polyethylene glycol of different chain lengths (i.e. PEG-800, -2000 and -5000) have been prepared and characterized. Fluorescence properties have been obtained by mean of the grafting of a near-infrared-emitting dye (NIR-dye) onto the surface of the oxide, thanks to the carboxylic acid functions introduced towards an organosilane coating. Such modification allowed us to follow in vivo their biodistribution and elimination pathways by T1-w and T2-w high-field magnetic resonance imaging (MRI), as well as by optical and optoacoustic imaging. Interestingly, it has been highlighted that for a given composition, the thickness of the coating strongly influences the pharmacokinetic properties of the administrated SPIO-5.

Magnetic resonance imaging (MRI) is a widely used non-invasive methodology for both preclinical and clinical studies. However, MRI lacks molecular specificity. Molecular contrast agents for MRI would be highly beneficial for detecting specific pathological lesions and quantitatively evaluating therapeutic efficacy in vivo. In this study, an optimized Magnetization Prepared—RApid Gradient Echo (MP-RAGE) with 2 inversion times called MP2RAGE combined with advanced image co-registration is presented as an effective non-invasive methodology to quantitatively detect T1 MR contrast agents. The optimized MP2RAGE produced high quality in vivo mouse brain T1 (or R1 = 1/T1) map with high spatial resolution, 160 × 160 × 160 µm3 voxel at 9.4 T. Test–retest signal to noise was > 20 for most voxels. Extremely small iron oxide nanoparticles (ESIONPs) having 3 nm core size and 11 nm hydrodynamic radius after polyethylene glycol (PEG) coating were intracranially injected into mouse brain and detected as a proof-of-concept. Two independent MP2RAGE MR scans were performed pre- and post-injection of ESIONPs followed by advanced image co-registration. The comparison of two T1 (or R1) maps after image co-registration provided precise and quantitative assessment of the effects of the injected ESIONPs at each voxel. The proposed MR protocol has potential for future use in the detection of T1 molecular contrast agents.

Local delivery of drugs, proteins and living cells with on demand release manner using porous scaffolds has been widely used in the field of tissue engineering and cancer therapies. Drugs directly loaded in the porous scaffolds, are generally prone to free diffuse especially for long term incubation. Herein, in this study, hollow fiber alginate/iron oxide nanoparticles scaffolds were prepared by coaxial 3D printing with drugs, protein or living cells encapsulating in the core part (low concentration of alginate gels). Magnetically-driven on demand release was realized by extruding the loaded drugs, proteins and cells from the core part of the hollow fibers due to the deformation of the scaffolds under magnetic field. Additionally, the hollow fibers could sever as diffusion barriers to reduce uncontrolled diffusion of drugs, proteins and cells from scaffolds in the conditions of no required stimulation. The factors influencing the deformation of the scaffolds, as well as the release behavior were investigated. The data indicated that the scaffolds prepared by 10 wt% of alginate with 13% of iron oxide nanoparticles after crosslinking using 0.1 M CaCl2 solution for 10 s showed repeated on demand release capability in vitro and in vivo under intermittently magnetic stimulation. Thus, this 3D printed alginate/iron oxide nanoparticles hollow scaffolds with on demand controlled delivery capability may prove useful for tissue engineering and disease therapies.

The CXCR4 chemokine receptor is an important biomolecular target in cancer diagnostics and therapeutics. In a new multivalent approach, iron oxide nanoparticles were conjugated with multiple binding units of a low affinity azamacrocylic CXCR4 antagonist. The silica coated nanostructure has good suspension stability, a mode size of 72 nm and high affinity for CXCR4, showing >98% inhibition of anti-CXCR4 mAb binding in a receptor binding competition assay on Jurkat cells.

Yunhan Zhang,1,* Meihui Xia,2,* Zizhen Zhou,3 Xiaoqing Hu,1 Jiabin Wang,1 Meiyu Zhang,3 Yi Li,4 Liankun Sun,1 Fangfang Chen,4,5 Huimei Yu1,6 1Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People’s Republic of China; 2Department of Obstetrics & Gynecology, The First Hospital of Jilin University, Changchun, Jilin 130021, People’s Republic of China; 3Clinical Medical College, Jilin University, Changchun 130021, People’s Republic of China; 4State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun, Jilin 130012, People’s Republic of China; 5Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, People’s Republic of China; 6Animal Experiment Center, College of Basic Medical Sciences, Jilin University, Changchun 130021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huimei YuKey Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, People’s Republic of ChinaTel +86 431 85619485Email yuhuimei@jlu.edu.cnFangfang ChenDepartment of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, People’s Republic of ChinaTel +86 431 84995312Email cff@jlu.edu.cnMethods: In this study, we used MTT assays to demonstrate that a combination of SPIO-Serum and wild-type p53 overexpression can reduce ovarian cancer cell viability in vitro. Prussian blue staining and iron assays were used to determine changes in intracellular iron concentration following SPIO-Serum treatment. TEM was used to evaluate any mitochondrial damage induced by SPIO-Serum treatment, and Western blot was used to evaluate the expression of the iron transporter and lipid peroxidation regulator proteins. JC-1 was used to measure mitochondrial membrane potential, and ROS levels were estimated by flow cytometry. Finally, xCT protein expression and mitochondrial ROS levels were confirmed using fluorescence microscopy.Results: SPIO-Serum effectively induced lipid peroxidation and generated abundant toxic ROS. It also facilitated the downregulation of GPX4 and xCT, ultimately resulting in iron-dependent oxidative death. These effects could be reversed by iron chelator DFO and lipid peroxidation inhibitor Fer-1. SPIO-Serum treatment disrupted intracellular iron homeostasis by regulating iron uptake and the cells presented with missing mitochondrial cristae and ruptured outer mitochondrial membranes. Moreover, we were able to show that p53 contributed to SPIO-Serum-induced ferroptosis in ovarian cancer cells.Conclusion: SPIO-Serum induced ferroptosis and overexpressed p53 contributed to ferroptosis in ovarian cancer cells. Our data provide a theoretical basis for ferroptosis as a novel cell death phenotype induced by nanomaterials.Keywords: ferroptosis, SPIO, p53, TF, xCT, iron-based nanomaterials

Cancer immunotherapy is a novel approach to cancer treatment that leverages components of the immune system as opposed to chemotherapeutics or radiation. Cell migration is an integral process in a therapeutic immune response, and the ability to track and image the migration of immune cells in vivo allows for better characterization of the disease and monitoring of the therapeutic outcomes. Iron oxide nanoparticles (IONPs) are promising candidates for use in immunotherapy as they are biocompatible, have flexible surface chemistry, and display magnetic properties that may be used in contrast-enhanced magnetic resonance imaging (MRI). In this review, advances in application of IONPs in cell tracking and cancer immunotherapy are presented. Following a brief overview of the cancer immunity cycle, developments in labeling and tracking various immune cells using IONPs are highlighted. We also discuss factors that influence the effectiveness of IONPs as MRI contrast agents. Finally, we outline different approaches for cancer immunotherapy and highlight current efforts that utilize IONPs to stimulate immune cells to enhance their activity and response to cancer.

To overcome the shortcoming of conventional transarterial chemoembolization (cTACE) like high systemic release, a novel droplet-based flow-focusing microfluidic device was fabricated and the biocompatible poly(lactic-co-glycolic acid) (PLGA) magnetic drug-eluting beads transarterial chemoembolization (TACE) microspheres with tunable size and shell thickness were prepared via this device. Paclitaxel, as a model active, was loaded through O/O/W emulsion method with high efficiency. The size and the shell thickness vary when adjusting the flow velocity and/or solution concentration, which caters for different clinical requirements to have different drug loading and release behavior. Under the designed experimental conditions, the average diameter of the microspheres is 60 ± 2 μm and the drug loading efficiency has reached 6%. The drug release behavior of the microspheres shows the combination of delayed release and smoothly sustained release profiles and the release kinetics differ within different shell thickness. The microspheres also own the potential of magnetic resonance imaging (MRI) visuality because of the loaded magnetic nanoparticles. The microsphere preparation method and device we proposed are simple, feasible, and effective, which have a good application prospect.

Among conventional cancer therapies, radio-frequency magnetic hyperthermia (MHT) has widely been investigated for use with magnetic nanoparticles (MNPs). However, the majority of in vivo biodistribution studies have tested very low MNP dosages (equivalent to magnetic resonance imaging (MRI) applications) to check for clearance rate; which is far below the clinical dose of MHT. Due to this poor validation in preclinical scenarios, quite a few MNPs already in clinical use were later discontinued, on grounds of unexpected clinical outcomes in terms of inflammation, and prolonged clearance in vivo. By exploiting an economical method of synthesis, we have developed chitosan-coated Fe3O4 nanoparticles with high heating efficiency performance. Their anti-tumor response was evaluated in an ectopic tumor model of C6 glioblastoma by MHT. The intratumoral injection of MNPs on days 1 and 7 resulted in rapid tumor inhibition rate of 69.4% within 8 days, with complete inhibition within 32 days, and no recurrence recorded over a 5-month follow-up. Notably, the MNP-mediated MHT therapy achieved the highest degree of therapeutic efficacy required for complete tumor ablation by combining controlled temperature range (

Hydrogels that respond to non-invasive, external stimuli such as a magnetic field are of exceptional interest for the development of adaptive soft materials. To date magneto tuneable gels are predominantly based on macromolecular building blocks, while comparable low molecular weight systems are rarely found in the literature. Herein, we report a highly efficient peptide-based gelator (Nap GFYE), which can form hydrogels and incorporate Fe3O4 superparamagnetic nanoparticles in the gel matrix. The magnetic nanoparticles act as a physical crosslinker for the self-assembled peptide nanostructures and thus give rise to a fortified hybrid gel with distinctively improved mechanical properties. Furthermore, the particles provide the material with magnetic susceptibility and a gel to sol transition is observed upon application of a weak magnetic field. Magnetization of the inorganic-organic hybrid nanomaterial leads to on-demand release of an incorporated fluorescent dye into the supernatant.

Microbial inhibition of carboxymethyl dextran (CMD) magnetic nanoparticles (MNPs) was investigated on two different bacterial cultures, Escherichia coli and Staphylococcus aureus, where inhibition properties of CMD-MNPs were confirmed, while uncoated MNPs exhibited no inhibition properties. To such CMD-MNPs, enzyme alcohol dehydrogenase (ADH) from Saccharomyces cerevisiae was immobilized. Later on, CMD-MNPs were functionalized, using an epoxide cross-linker epiclorohydrin (EClH) for another option of ADH immobilization. Residual activities of immobilized ADH onto epoxy functionalized and non-functionalized CMD-MNPs were determined. Effect of cross-linker concentration, temperature of immobilization and enzyme concentration on residual activities of immobilized ADH were determined, as well. With optimal process conditions (4% (v/v) EClH, 4 °C and 0.02 mg/mL of ADH), residual activity of immobilized ADH was 90%. Such immobilized ADH was characterized using FT-IR, SEM and DLS analysis.

In this study, hematite nanoparticles (HNPs) were used as the persulfate (PS) activator for the sonocatalytic degradation of bisphenol A (BPA). The physicochemical properties of the synthesized HNPs were investigated using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM). The effect of different operational parameters (pH, nanoparticle dosage, persulfate concentration, and ultrasonic power) on catalytic activity were evaluated. The BPA degradation rate was improved when ultrasonic (US) irradiation was used simultaneously with HNPs for activating PS. According to the results, 98.94% of BPA (10 mg/L) was degraded within 15 min of reaction time at 4 mM persulfate and 0.01 g/L HNPs under ultrasonic irradiation of 250 W. The degree of mineralization of BPA was measured using chemical oxygen demand (COD), and 36.98% was achieved under optimum conditions. Quenching tests were done using different scavenger compounds; these showed that both hydroxyl and sulfate radicals were reactive species in BPA degradation. According to the results of reusability tests, the degradation efficiency decreased to 86.34%, indicating that HNPs can be recycled several times. All of the anions tested, but mainly hydrogen phosphate, had an inhibitory effect on BPA degradation. The results showed that the US/HNPs/PS process is effective for the degradation of the organic pollutants.

The knowledge of protein-nanoparticle interplay is of crucial importance to predict the fate of nanomaterials in biological environments. Indeed, protein corona on nanomaterials is responsible for the physiological response of the organism, influencing cell processes, from transport to accumulation and toxicity. Herein, a comparison using four different proteins reveals the existence of patterned regions of carboxylic groups acting as recognition sites for naked iron oxide nanoparticles. Readily interacting proteins display a distinctive surface distribution of carboxylic groups, recalling the geometric shape of an ellipse. This is morphologically complementary to nanoparticles curvature and compatible with the topography of exposed FeIII sites laying on the nanomaterial surface. The recognition site, absent in non-interacting proteins, promotes the nanoparticle harboring and allows the formation of functional protein coronas. The present work envisages the possibility of predicting the composition and the biological properties of protein corona on metal oxide nanoparticles.

The use of nanocarriers composed of polyethylene glycol- and polyvinyl alcohol-coated vesicles encapsulating active molecules in place of conventional chemotherapy drugs can reduce many of the chemotherapy-associated challenges because of the increased drug concentration at the diseased area in the body. The present study investigated the structure and magnetic properties of iron oxide nanoparticles in the presence of polyvinyl alcohol and polyethylene glycol as the basic surface coating agents. We used superparamagnetic iron oxide nanoparticles (FNPs) as the core and studied their effectiveness when two polymers, namely polyvinyl alcohol (PVA) and polyethylene glycol (PEG), were used as the coating agents together with magnesium–aluminum-layered double hydroxide (MLDH) as the nanocarrier. In addition, the anticancer drug sorafenib (SO), was loaded on MLDH and coated onto the surface of the nanoparticles, to best exploit this nano-drug delivery system for biomedical applications. Samples were prepared by the co-precipitation method, and the resulting formation of the nanoparticles was confirmed by X-ray, FTIR, TEM, SEM, DLS, HPLC, UV–Vis, TGA and VSM. The X-ray diffraction results indicated that all the as-synthesized samples contained highly crystalline and pure Fe3O4. Transmission electron microscopy analysis showed that the shape of FPEGSO-MLDH nanoparticles was generally spherical, with a mean diameter of 17 nm, compared to 19 nm for FPVASO-MLDH. Fourier transform infrared spectroscopy confirmed the presence of nanocarriers with polymer-coating on the surface of iron oxide nanoparticles and the existence of loaded active drug consisting of sorafenib. Thermogravimetric analyses demonstrated the thermal stability of the nanoparticles, which displayed enhanced anticancer effect after coating. Vibrating sample magnetometer (VSM) curves of both produced samples showed superparamagnetic behavior with the high saturation magnetization of 57 emu/g for FPEGSO-MLDH and 49 emu/g for FPVASO-MLDH. The scanning electron microscopy (SEM) images showed a narrow size distribution of both final samples. The SO drug loading and the release behavior from FPEGSO-MLDH and FPVASO-MLDH were assessed by ultraviolet–visible spectroscopy. This evaluation showed around 85% drug release within 72 h, while 74% of sorafenib was released in phosphate buffer solution at pH 4.8. The release profiles of sorafenib from the two designed samples were found to be sustained according to pseudo-second-order kinetics. The cytotoxicity studies confirmed the anti-cancer activity of the coated nanoparticles loaded with SO against liver cancer cells, HepG2. Conversely, the drug delivery system was less toxic than the pure drug towards fibroblast-type 3T3 cells.

BackgroundNon-viral gene carriers because of their limited side effects, biocompatibility, simplicity and taking the advantages of electrostatic interactions have shown noticeable potential in gene delivery. The low transfection rate of non-viral vectors under physiological conditions is a significant issue. MethodsWe investigated the efficacy of hydrophilic and hydrophobic groups on gene carriers such as two synthesized amphiphilic polymer of dextran-stearic acid-spermine (DSASP) with verified lipid and amine conjugations that associated with Fe3O4 superparamagnetic nanoparticles to promote the target delivery and decrease the transfection time using static magnetic field.ResultsOur findings illustrate that magnetic nanoparticles are spherical with positive surface charges and superparamagnetic behaviors. The DSASP–pDNA/MNPs offered a strong pDNA condensation, protection against DNase degradation, significant cell viability in HEK 293T cells. Although conjugations of spermine play a critical role in transfection efficiency, amphiphilic polymer with more derivatives of stearic acid showed better transfection yields. ConclusionDSASP amphiphilic magnetic carriers offer new insights for gene delivery due to the amine contents and ameliorate the uptake of complexes via cell membrane based on its hydrophilic surface.

Although incorporating proteases into sperm medium is considered the most effective procedure to eliminate camel semen viscosity, it drastically affects viability, morpho-functional properties and, hence, fertilization potential of spermatozoa. The present work aimed at evaluating adequacy of employing magnetic nanoparticles-based sperm purification technique for eluting impaired and apoptotic camel spermatozoa from cryopreserved semen doses following protease-based semen liquefaction. Thirty cryopreserved semen doses (50 x 106 sperm/straw) representing the following liquefaction treatments: control (untreated), 0.1 mg/ml papain or 5 U/ml bromelain were used (n = 10 straws per treatment). Immediately after thawing (38°C for 40 s), sperm concentration of each straw within treatment was readjusted to 15 x 106 sperm/mL by dilution in PBS (37°C). Sperm physical and cytological properties were then assessed (non-purified semen). Thereafter, each specimen was subjected to lectin-functionalized DNA-defrag magnetic nanoparticles sperm purification, and the same sperm traits were re-evaluated after undergoing purification (purified semen). Sperm DNA fragmentation level within each group, prior to and after magnetic nano-purification, was also determined by fluorescent imaging. The results showed a dramatic improvement (p < .05) in post-thaw motility (%), viability (%), normal sperm (%), intact acrosome (%) and HOST-reacted (%) spermatozoa in protease-liquefied semen following sperm magnetic nano-purification. Additionally, the highest (p < .05) DNA fragmentation level was recorded in all cryopreserved semen groups prior to purification, whereas the lowest (p < .05) was observed in the protease-treated specimens after magnetic nano-purification. These results indicate that protease-based semen liquefaction prior to cryopreservation in conjunction with magnetic nano-purification post-thawing holds potential for reducing the proportion of damaged and dead spermatozoa, hence improving camel sperm fertilization competence.

Biomineralization is mediated by specialized proteins that guide and control mineral sedimentation. In many cases, the active regions of these biomineralization proteins are intrinsically disordered. High-resolution structures of these proteins while they interact with minerals are essential for understanding biomineralization processes and the function of intrinsically disordered proteins (IDPs). Here we used the cavity of ferritin as a nanoreactor where the interaction between M6A, an intrinsically disordered iron-binding domain, and an iron oxide particle was visualized at high resolution by cryo-EM. Taking advantage of the differences in the electron-dose sensitivity of the protein and the iron oxide particles, we developed a method to determine the irregular shape of the particles found in our density maps. We found that the folding of M6A correlates with the detection of mineral particles in its vicinity. M6A interacts with the iron oxide particles through its C-terminal side, resulting in the stabilization of a helix at its N-terminal side. The stabilization of the helix at a region that is not in direct contact with the iron oxide particle demonstrates the ability of IDPs to respond to signals from their surroundings by conformational changes. These findings provide the first glimpse toward the long-suspected mechanism for biomineralization protein control over mineral microstructure, where unstructured regions of these proteins become more ordered in response to their interaction with the nascent mineral particles.

We investigated whether polyethylene glycol-coated Fe(3)O(4) nanoparticles (IONs), acute stress and their combination modifies vascular functions, nitric oxide synthase (NOS) activity, mean arterial pressure (MAP) as well as hepcidin and ferritin H gene expressions in Wistar-Kyoto rats. Rats were divided into control, ION-treated rats (1 mg Fe/kg i.v.), repeated acute air-jet stress-exposed rats and IONs-and-stress co-exposed rats. Maximal acetylcholine (ACh)-induced and sodium nitroprusside (SNP)-induced relaxations in the femoral arteries did not differ among the groups. IONs alone significantly elevated the Nω-nitro-L-arginine methyl ester (L-NAME)-sensitive component of ACh-induced relaxation and reduced the sensitivity of vascular smooth muscle cells to SNP. IONs alone also elevated NOS activity in the brainstem and hypothalamus, reduced NOS activity in the kidneys and had no effect in the liver. Acute stress alone failed to affect vascular function and NOS activities in all the tissues investigated but it elevated ferritin H expression in the liver. In the ION-and-stress group, NOS activity was elevated in the kidneys and liver, but reduced in the brainstem and hypothalamus vs. IONs alone. IONs also accentuated air-jet stress-induced MAP responses vs. stress alone. Interestingly, stress reduced ION-originated iron content in blood and liver while it was elevated in the kidneys. In conclusion, the results showed that 1) acute administration of IONs altered vascular function, increased L-NAME-sensitive component of ACh-induced relaxation and had tissue-dependent effects on NOS activity, 2) ION effects were considerably reduced by co-exposure to repeated acute stress, likely related to decrease of ION-originated iron in blood due to elevated decomposition and/or excretion.

We report the preparation of both control chitosan and magnetic chitosan beads as biosorbents using chitosan as matrix and magnetite (Fe3O4) nanoparticles as reinforcement followed by detailed advanced characterization. The batch trials were performed to study the adsorption kinetics of biosorbents by removing As(III) and As(V) species from water systems. The experimental data was inserted into Langmuir and Freundlich's isotherms to undertake the mechanism and adsorption capacity of the test biosorbents. Under Langmuir's isotherm, maximum monolayer adsorption capacity (qmax) of the biosorbent was observed to be 73.69 and 79.49 mg/g for As(III) and As(V) species, respectively, under specified conditions. The optimum doses of 1.5 and 2 g/L of MCBB at pH 6.7 showed 99.5 and 99% removal of As(V) and As(III), respectively. The analysis demonstrated that the biosorption process obeyed pseudo 2nd order kinetics with linear regression coefficient (R2) of >0.999. The regeneration and reusability of biosorbents were also assessed.

The technology of directing nanoparticles to specific locations in the body continues to be an area of great interest in a myriad of research fields. In the present study, we have developed nanoparticles and a method that allows the nanoparticles to move to specific sites by simultaneously utilizing the homing ability and magnetism of stem cells. Polymeric clustered SPIO (PCS) nanoparticles are composed of a superparamagnetic iron oxide nanoparticle (SPION) cluster core coated with poly lactic-co-glycolic acid (PLGA) and labeled with the fluorescent dye Cy5.5 for tracking. PCS is designed to be internalized by stem cells via endocytosis and then moved to the desired subcellular location through magnetism. Here, we investigated the interactions between SPIONs and mesenchymal stem cells (MSCs), including their absorption mechanism and subcellular localization. Exposure to the nanoparticles at 40 μg/mL for over 96 h did not affect cell survival or differentiation. We used a variety of endocytosis inhibitors and identified the potential cellular internalization pathway of SPIONs to be clathrin-mediated endocytosis. Antibodies to organelles were used to accumulate lysosomes through early and late endosomes. PCS at 40 μg/mL was internalized and stored without significant deleterious effects on stem cells, indicating that MSCs can act as an effective nanoparticle carrier. These findings also demonstrate the successful localization of the novel particles using magnetic attraction.

Researches have proved that increasing level of prostate-specific antigen (PSA) is an indicator for the progression of prostate cancer. The present study was focused to determine the PSA level by using anti-PSA antibody conjugated iron oxide nanoparticles, as the probe immobilized on the gap-fingered electrode sensing surface. The detection limit and sensitivity were found at the level of 1.9 pg/mL on the linear regression curve (y = 1.6939x - 0.5671; R² = 0.9878). A dose-dependent liner range was found from 1.9 until 60 pg/mL. Further, PSA was spiked in human serum and did not affect the interaction of PSA and its antibody. This method of detection quantifies the level of PSA, which helps to diagnose prostate cancer at its earlier stage.

Iron oxide nanoparticles are used in various industrial fields, as a tool in biomedicine as well as in food colorants, and can therefore reach human metabolism via oral uptake or injection. However, their effects on the human body, especially the liver as one of the first target organs is still under elucidation. Here, we studied the influence of different representative iron oxide materials on xenobiotic metabolism of HepaRG cells. These included four iron oxide nanoparticles, one commercially available yellow food pigment (E172), and non-particulate ionic control FeSO4. The nanoparticles had different chemical and crystalline structures and differed in size and shape and were used at a concentration of 50 µg Fe/mL. We found that various CYP enzymes were downregulated by some but not all iron oxide nanoparticles, with the Fe3O4-particle, both γ-Fe2O3-particles, and FeSO4 exhibiting the strongest effects, the yellow food pigment E172 showing a minor effect and an α-Fe2O3 nanoparticle leading to almost no inhibition of phase I machinery. The downregulation was seen at the mRNA, protein expression, and activity levels. Thereby, no dependency on the size or chemical structure was found. This underlines the difficulty of the grouping of nanomaterials regarding their physiological impact, suggesting that every iron oxide nanoparticle species needs to be evaluated in a case-by-case approach.