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Cerium oxide nanoparticles (CeO 2 NPs, NM-212) are well-known for their catalytic properties and antioxidant potential, and have many applications in various industries, drug delivery, and cosmetic formulations. CeO 2 NPs exhibit strong antimicrobial activity and can be used to efficiently remove pathogens from different environments. However, knowledge of the toxicological evaluation of CeO 2 NPs is too limited to support their safe use. In this study, CeO 2 NPs were orally administered to Sprague Dawley rats for 13 weeks at the doses of 0, 10, 100, and 1000 mg/kg bw/day, followed by a four week recovery period. The hematology values for the absolute and relative reticulocyte counts in male rats treated with 1000 mg/kg bw/day CeO 2 NPs were lower than those in control rats. The clinical chemistry values for sodium and chloride in the treated male rat groups (100 and 1000 mg/kg/day) and total protein and calcium in the treated female rat groups (100 mg/kg/day) were higher than those in the control groups. However, these changes were not consistent in both sexes, and no abnormalities were found in the corresponding pathological findings. The results showed no adverse effects on any of the parameters assessed. CeO 2 NPs accumulated in the jejunum, colon, and stomach wall of rats administered 1000 mg/kg CeO 2 NPs for 90 days. However, these changes were not abnormal in the corresponding histopathological and immunohistochemical examinations. Therefore, 1000 mg/kg bw/day may be considered the "no observed adverse effect level" of CeO 2 NPs (NM-212) in male and female SD rats under the present experimental conditions., (© 2024. The Author(s).)

To prevent the ongoing spread of the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accurate and early detection based on a rapid, ultrasensitive, and highly reliable sensing method is crucially important. Here, we present a bumpy core-shell surface-enhanced Raman spectroscopy (SERS) nanoprobe-based sensing platform with single-nanoparticle (SNP)-based digital SERS analysis. The tailorable bumpy core-shell SERS nanoprobe with an internal self-assembled monolayer of 4-nitrobenzenethiol Raman reporters, synthesized using HEPES biological buffer, generates a strong, uniform, and reproducible SERS signal with an SNP-level sensitive and narrowly distributed enhancement factor (2.1 × 10 8 to 2.2 × 10 9 ). We also propose an SNP-based digital SERS analysis method that provides direct visualization of SNP detection at ultralow concentrations and reliable quantification over a wide range of concentrations. The bumpy core-shell SERS nanoprobe-based sensing platform with SNP-based digital SERS analysis achieves the ultrasensitive and quantitative detection of the SARS-CoV-2 spike protein with a limit of detection of 7.1 × 10 -16 M over a wide dynamic range from 3.7 × 10 -15 to 3.7 × 10 -8 M, far outperforming the conventional enzyme-linked immunosorbent assay method for the target protein. Furthermore, it can detect mutated spike proteins from the SARS-CoV-2 variants, representing the key mutations of Alpha, Beta, Gamma, Delta, and Omicron variants. Therefore, this sensing platform can be effectively and efficiently used for the accurate and early detection of SARS-CoV-2 and be adapted for the ultrasensitive and reliable detection of other highly infectious diseases.

Biomolecule detection based on surface-enhanced Raman scattering (SERS) for application to biosensors and bio-imaging requires the fabrication of SERS nanoprobes that can generate strong Raman signals as well as surface modifications for analyte-specific recognition and binding. Such requirements lead to disadvantages in terms of reproducibility and practicality, and thus, it has been difficult to apply biomolecule detection utilizing the advantages of the SERS phenomenon to actual clinically relevant analysis. To achieve reproducible and practical SERS signal generation in a biomolecule-specific manner without requiring the synthesis of nanostructures and their related surface modification to introduce molecules for specific recognition, we developed a new type of SERS probe formed by enzyme reactions in the presence of Raman reporters. By forming unique plasmonic structures, our method achieves the detection of biomolecules on chips with uniform and stable signals over long periods. To test the proposed approach, we applied it to a SERS-based immunohistochemistry assay and found successful multiplexed protein detection in brain tissue from transgenic mice.

This year, France banned the application of titanium dioxide nanoparticles as a food additive (hereafter, E171) based on the insufficient oral toxicity data. Here, we investigated the subchronic toxic responses of E171 (0, 10, 100, and 1,000 mg/kg) and tried to elucidate the possible toxic mechanism using AGS cells, a human stomach epithelial cell line. There were no dose-related changes in the Organisation for Economic Cooperation and Development test guideline-related endpoints. Meanwhile, E171 deeply penetrated cells lining the stomach tissues of rats, and the IgM and granulocyte-macrophage colony-stimulating factor levels were significantly lower in the blood from rats exposed to E171 compared with the control. The colonic antioxidant protein level decreased with increasing Ti accumulation. Additionally, after 24-h exposure, E171 located in the perinuclear region of AGS cells and affected expression of endoplasmic reticulum stress-related proteins. However, cell death was not observed up to the used maximum concentration. A gene profile analysis also showed that immune response-related microRNAs were most strongly affected by E171 exposure. Collectively, we concluded that the NOAEL of E171 for 90 days repeated oral administration is between 100 and 1,000 mg/kg for both male and female rats. Additionally, further study is needed to clarify the possible carcinogenesis following the chronic accumulation in the colon., (© 2020 John Wiley & Sons, Ltd.)

Nanoparticles (NPs) are substances between 1 and 100 nm in size. They have been the subject of numerous studies because of their potential applications in a wide range of fields such as cosmetics, electronics, medicine, and food. For biological applications of nanoparticles, they are usually coated with a substance capable of preventing agglomeration of the nanoparticles and nonspecific binding and exhibiting water-solubility characteristics with specific immobilized (bio)molecules. In order to evaluate the chemical properties of the surface-modified nanoparticles for bioapplications, including drug delivery, a simple and reliable method for the analysis of the presence of the surface chemicals and the ligand states of the nanoparticles is necessary. In this study, the authors numerically evaluated the extent of polyethylene glycol (PEG) ligand conjugation on AuNPs by concurrently adopting a microliquid inkjet printing system for sampling of the PEGylated AuNPs solution and ToF-SIMS imaging together with statistical analysis. The statistical correlation values calculated from the signals of PEG and Au measured by ToF-SIMS imaging on the sample spots made by a microliquid inkjet printing system showed better reproducibility and improved correlation values compared to the pipet spotting. Their improved method will be useful to evaluate ligand-conjugated nanoparticles for quality control of each conjugation process.

Because of their nutritional value, zinc oxide (ZnO) nanoparticles (NPs) are applied as a dietary source of zinc, by direct addition to complex, multiple-component food matrices. The thereby occurring interactions of NPs with food matrices may have biological or toxic effects. In particular, NP interactions with food protein can lead to structural deformation of the latter, potentially changing its digestive efficiency and gastrointestinal absorption. In this study, interactions between ZnO NPs and a representative complex protein food matrix, skim milk, were compared with those between NPs and individual components of this food matrix (i.e., protein, saccharide, and mineral). The effects of the interactions on biological responses were investigated in terms of cytotoxicity, cellular uptake, intestinal transport, structural deformation for proteins, and digestive efficiency. The results demonstrated that the physicochemical properties of ZnO NPs were strongly influenced by the protein matrix type, leading to an increased dispersion stability in the complex protein matrix. However, these interactions did not affect cell proliferation, membrane damage, cellular uptake, intestinal transportation, or protein digestive efficiency, although a slight conformational change of proteins was observed in the presence of ZnO NPs. In conclusion, no toxic effects were observed, suggesting the safety of NPs when added to complex food matrices.

Bare gold nanospheres have been shown to have anti-angiogenic effects but are optically unfavorable because their resonant wavelength lies in the visible spectrum. Here, we design gold nanodisks with a higher scattering capability than gold nanorods and with a resonant wavelength at near-infrared region - the area where the source of light utilized by optical coherence tomography (OCT) lies. With a physical synthesis system, we then fabricate 160-nm-sized gold nanodisks exhibiting resonant wavelength at 830 nm. The synthesized nanoparticles were successfully visualized in in vivo OCT at concentrations as low as 1 pM. After demonstrating their binding ability to vascular endothelial growth factor (VEGF), we show that they suppress VEGF-induced migration of endothelial cells. Finally, we demonstrate that intravitreally injected gold nanodisks attenuate neovascularization of oxygen-induced retinopathy in mice, in a dose dependent manner, such that they are cleared from the vitreous within 2 weeks without histologic or electrophysiologic toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Red ginseng, a steamed and sun-dried ginseng, is a popular health-promoting food in Korea and other Asian countries. We introduced nanofertilizer technology using gold nanoparticles in an effort to develop red ginseng with an elevated level of ginsenosides, the main active compounds of ginseng. Shoots of 6-year-old ginseng plants were fertilized three times with colloidal gold nanoparticle sprays. Red ginseng extract was prepared from the main roots. The concentrations of gold and ginsenosides were measured following gold nanoparticle treatment. To evaluate the anti-inflammatory effects, mouse peritoneal macrophages of male BALB/c mouse were stimulated with lipopolysaccharide plus interferon-γ in the presence of extracts from red ginseng with or without gold nanoparticle treatment. The content of ginsenosides, such as Rg1, Re, Rf, and Rb1, increased in ginseng treated with gold nanofertilizer whereas the steaming process increased only the levels of Rd and Rg3. The levels of nitric oxide, inducible nitric oxide synthase, and interleukin-6, but not tumor necrosis factor-α, were more suppressed in macrophages treated with extract from gold nanoparticle-treated red ginseng. Our results show that the use of a colloidal gold nanoparticle fertilizer improved the synthesis of ginsenosides in ginseng and enhanced the anti-inflammatory effects of red ginseng. Further research is required to elucidate the causal factors for the gold-induced change in ginsenoside synthesis and to determine the in vivo effect of gold nanoparticle-treated ginseng.

Bio-conjugated nanoparticles have emerged as novel molecular probes in nano-biotechnology and nanomedicine and chemical analyses of their surfaces have become challenges. The time-of-flight (TOF) secondary ion mass spectrometry (SIMS) has been one of the most powerful surface characterization techniques for both nanoparticles and biomolecules. When combined with various nanoparticle-based signal enhancing strategies, TOF-SIMS can probe the functionalization of nanoparticles as well as their locations and interactions in biological systems. Especially, nanoparticle-based SIMS is an attractive approach for label-free drug screening because signal-enhancing nanoparticles can be designed to directly measure the enzyme activity. The chemical-specific imaging analysis using SIMS is also well suited to screen nanoparticles and nanoparticle-biomolecule conjugates in complex environments. This review presents some recent applications of nanoparticle-based TOF-SIMS to the chemical analysis of complex biological systems., (© 2014 Wiley Periodicals, Inc.)

A high surface coverage of gold nanoparticles (AuNPs) is a prerequisite for enhancing the peptide signal intensity in time-of-flight secondary ion mass spectrometry (TOF-SIMS). Here, we demonstrate the TOF-SIMS signal amplification of peptides on a surface by enlarging surface-confined AuNPs using the NH(2)OH/Au(3+) seeding method. Because of the increased surface area and spherical structure of the Au, the SIMS intensity of the peptides became significantly enhanced on the enlarged-AuNPs surface, especially at high concentrations of peptide solution (>10 μM), compared to that of the bare gold surface or submonolyer of AuNPs. We are confident that this will be a useful method for diagnosis and bioassay with high sensitivity in a label-free manner.

The pathological angiogenesis in the retina is the major cause of vision loss at all ages. In particular, retinopathy of prematurity (ROP) is a leading cause of blindness in children. This study investigated whether gold nanoparticle (GNP) could inhibit retinal neovascularization in the animal model of ROP. Intravitreal injection of GNP significantly inhibited retinal neovascularization in the mouse model of ROP. In addition, GNP effectively suppressed VEGF-induced in vitro angiogenesis of retinal microvascular endothelial cells including proliferation, migration and capillary-like networks formation. GNP blocked VEGF-induced auto-phosphorylation of VEGFR-2 to inhibit consequently ERK 1/2 activation. GNP never affected on the cellular viability of retinal microvascular endothelial cells and induced no retinal toxicity. Our data suggest that GNP could be a potent inhibitor to retinal neovascularization without retinal toxicity. Furthermore, GNP could be extensively applied to variable vaso-proliferative retinopathies mediated by VEGF., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging analysis was performed on murine macrophage cells treated with various concentrations of iron oxide (Fe3O4) nanoparticles, which are used as MRI contrast agents. First, murine macrophage cells were seeded on a slide glass for 24 hrs and treated with varying concentrations of Fe3O4 nanoparticles for 24 hrs. To expose a cross section of each cell and obtain a distribution of the nanoparticles inside the cells, the cells were sputtered using Bi ions after which the cross section of each cell was scanned and imaged using the focused cluster ion beam with a spatial resolution of 300 nm. Fe3O4 nanoparticles were found mainly in the cytoplasm region of the cells, not in the nucleus region of cells, suggesting that the uptake of the Fe3O4 nanoparticles were into the cytoplasm of cell, not into the nucleus of cell. Based on these observations, our protocol using mass imaging analysis would be a useful addition to the study of in vitro nanoparticle cytotoxicity.

We propose a new scheme of matrix-free laser desorption/ionization with cation assistance for surface mass spectrometry of self-assembled monolayers (SAMs) of alkanethiolates on gold substrates and gold nanoparticles (NPs). In a proof-of-concept experiment, a simple treatment using an aqueous salt solution such as NaI(aq) was shown to lead to a significant laser desorption/ionization, producing the characteristic (disulfide) ions of alkanethiolate molecules from the monolayers. Further efforts to understand the mechanism were also given, including laser power and salt concentration dependence studies. In the power dependence study, the characteristic ions were found to be produced at low laser power where no gold substrate species was seen. At high laser power, the generation of gold species, Au(+)-Au5(+), resulted in a saturation behavior in the characteristic mass peak for alkanethiolate molecules. In addition, characteristic ions with gold adducts were not observed at any laser power. With increasing salt concentration, the characteristic mass peak was gradually increased. The results suggest that the adduct formation of a cation with alkanethiolates in the monolayers provide a facile pathway to supply a charge to UV laser-desorbed secondary neutrals for mass spectrometric detection. This cation-assisted laser desorption/ionization (CALDI) mass spectrometry was further examined with the SAMs and mixed SAMs with various terminals such as -OH, -OCH3, -NH2, -ethylene (-CH=CH2), and -acetylene (-C[triple bond]CH). The CALDI method was also successfully applied to surface mass spectrometry of monolayer-protected gold NPs (approximately 16 nm diameter) with OH- and COOH-terminated SAMs. The unique advantages of the matrix-free CALDI method may extend our capability in investigations of interfacial chemistry at SAMs as well as mass spectrometric applications using biochips and nanoparticles.

Micropatterns of silica on a gold substrate were generated by a biomimetic approach, namely, the biosilicification of silicic acids. The procedure consists of three simple steps: pattern generation of a polymerization initiator, (BrC(CH(3))(2)COO(CH(2))(11)S)(2), by microcontact printing; surface-initiated, atom-transfer radical polymerization of 2-(dimethylamino)ethyl methacrylate (DMAEMA) from the patterned area; and polycondensation of silicic acids. The tertiary amine-containing polymer, pDMAEMA, aided in the spatially controlled polycondensation of silicic acids on surfaces in the presence of phosphate ions, and micropatterns of silica on a gold substrate were successfully generated in combination with the technique of microcontact printing. The procedure could be extended to the controlled fabrication of silica patterns with any size, shape, or thickness.