The Cytotoxicity of Metal Nanoparticles Depends on Their Synergistic Interactions

With a steady growth in use of engineered nanoparticles (NPs) in consumer products the unintended exposure to humans has increased. The risks associated with introduction of NPs in the environment have been widely investigated, but mostly for single type of NPs. Herein, a single NP and NP co-exposure study is reported: the cellular effects of silver and platinum NPs on the main components of the blood–brain barrier, human cerebral microvascular endothelial cells, and human primary astrocytes. The synergy is quantitatively evaluated as per the Chou–Talalay method. NP co-exposure synergistically inhibits proliferation of both cell types, to a greater extent for endothelial cells. In addition, astrocytes are more tolerant to NPs. The mechanism of synergy with short-duration incubation time points (up to 30 min) is further explored. Although intracellular trafficking studies and quantitative assessments of NP uptake does not explain the mechanisms of synergistic cytotoxicity, a proteomics analysis suggests that it arises from activation of an immune modulating response and deregulation of the extracellular matrix organization. The substantial synergetic effects in the co-exposure studies highlight the importance of this work in relation to assessment of the health risks associated with nanomaterials.     

The Cellular Interactions of PEGylated Gold Nanoparticles: Effect of PEGylation on Cellular Uptake and Cytotoxicity

Poly(ethylene glycol) (PEG) is frequently used to coat various medical nanoparticles (NPs). As PEG is known to minimize NP interactions with biological specimens, the question remains whether PEGylated NPs are intrinsically less toxic or whether this is caused by reduced NP uptake. In the present work, the effect of gold NP PEGylation on uptake by three cell types is compared and evaluated the effect on cell viability, oxidative stress, cell morphology, and functionality using a multiparametric methodology. The data reveal that PEGylation affects cellular NP uptake in a cell‐type‐dependent manner and influences toxicity by different mechanisms. At similar intracellular NP numbers, PEGylated NPs are found to yield higher levels of cell death, mostly by induction of oxidative stress. These findings reveal that PEGylation significantly reduces NP uptake, but that at similar functional (= cell‐associated) NP levels, non‐PEGylated NPs are better tolerated by the cells.     

Encapsulation of a proteasome inhibitor with gold-polysaccharide nanocarriers

Groundwater remediation using iron oxide and zero-valent iron nanoparticles (NPs) can be effective, but is limited in many applications due to the NP strong retention in groundwater-saturated porous media after injection, the passivation of the porous surface, and the high cost of nanomaterials versus macro scale iron. In this study, we investigated transport of bare and polymer-coated 2-line ferrihydrite NPs (30–300 nm) in saturated aquifer sediments. The influence of poly(acrylic acid) (PAA) polymer coatings was studied on the colloidal stability and transport in sediments packed column tests simulating groundwater flow in saturated sediments. In addition, the influence of calcium cations was investigated by transport measurements using sediments with calcium concentrations in the aqueous phase ranging from 0.5 (typical for most sediments) to 2 mM. Measurements were also made of zeta potential, hydrodynamic diameter, polymer adsorption and desorption properties, and bio-availability of PAA-coated NPs. We found that NP transport through the saturated aquifer sediments was improved by PAA coating and that the transport properties could be tuned by adjusting the polymer concentration. We further discovered that PAA coatings enhanced NP transport, compared to bare NPs, in all calcium-containing experiments tested, however, the presence of calcium always exhibited a negative effect on NP transport. In tests of bioavailability, the iron reduction rate of the coated and bare NPs by Geobacter sulfurreducens was the same, which shows that the PAA coating does not significantly reduce NP Fe(III) bioavailability. Our results demonstrate that much improved transport of iron oxide NP can be achieved in saturated aquifer sediments by introducing negatively charged polyelectrolytes and optimizing polymer concentrations, and furthermore, these coated NPs retain their bioavailability that is needed for applications in bio-environmental remediation.     

Uptake of silver nanoparticles by monocytic THP-1 cells depends on particle size and presence of serum proteins

Human health risks by silver nanoparticle (AgNP) exposure are likely to increase due to the increasing number of NP-containing products and demonstrated adverse effects in various cell lines. Unfortunately, results from (toxicity) studies are often based on exposure dose and are often measured only at a fixed time point. NP uptake kinetics and the time-dependent internal cellular concentration are often not considered. Macrophages are the first line of defense against invading foreign agents including NPs. How macrophages deal with the particles is essential for potential toxicity of the NPs. However, there is a considerable lack of uptake studies of particles in the nanometer range and macrophage-like cells. Therefore, uptake rates were determined over 24 h for three different AgNPs sizes (20, 50 and 75 nm) in medium with and without fetal calf serum. Non-toxic concentrations of 10 ng Ag/mL for monocytic THP-1 cells, representing realistic exposure concentration for short-term exposures, were chosen. The uptake of Ag was higher in medium without fetal calf serum and showed increasing uptake for decreasing NP sizes, both on NP mass and on number basis. Internal cellular concentrations reached roughly 32/10 %, 25/18 % and 21/15 % of the nominal concentration in the absence of fetal calf serum/with fetal calf serum for 20-, 50- and 75-nm NPs, respectively. Our research shows that uptake kinetics in macrophages differ for various NP sizes. To increase the understanding of the mechanism of NP toxicity in cells, the process of uptake (timing) should be considered.     

Selective Targeting of Lymphoma Cells by Monoclonal Antibody Grafted onto Zwitterionic-Functionalized Nanoparticles

Nanomedicine is considered a promising alternative to improve cancer diagnosis and treatment. Particularly, the use of nanoparticles (NPs) has enabled the encapsulation of highly toxic anticancer drugs, facilitated ultimate targeting, and allowed tailoring of drug delivery. However, when in biological fluids, these NPs are coated by proteins which hide the targeting moieties and suppress the engineered biological outcome. Herein, how the Ki-1 monoclonal antibody (mAb) can preserve its targetability through grafting on the surface of zwitterionic-functionalized nanoparticles, is unveiled. Zwitterions, known for their stealth ability, are used to minimize unspecific NPs protein adsorption and consequently maintain mAb functionality. In this work, Ki-1 mAb is used as it recognizes TNFRSF8 (CD30⁺) transmembrane protein overexpressed on CD30⁺ lymphoma cells such as L540 cells. While nonfunctionalized NPs show negligible toxic effects toward L540 cells, the Ki-1-functionalized structure demonstrates cytotoxicity, since they undergo cellular uptake, suggesting a receptor-mediated internalization. This dual-functionalization strategy provides a promising multifunctional nanoplatform toward future personalized medicine applications, minimizing unspecific protein adsorption on NPs and ensuring selective cancer cell targeting.     

Uptake and Intracellular Fate of Peptide Surface‐Functionalized Silica Hybrid Magnetic Nanoparticles In Vitro

Recently, the use of nanomaterials as intracellular targeting tools for theranostics has gained heightened interest. Despite the clear advantages posed by surface‐functionalized nanoparticles (NPs) in this regard, limited understanding currently exists due to difficulties in reliably synthesizing NPs with surface functionalizations adequate for use in such applications, as well as the manner of analytics used to assess the cellular uptake and intracellular localization of these NPs. In the present study, two key surface functionalities (a nuclear localization sequence (NLS) and integrin‐ligand (cRGD)) are attached to the surface of multifunctional, silica hybrid magnetic nanoparticles (SHMNPs) containing a polyethylene glycol (PEG) polymer coating using a well‐described, reliable, and reproducible microreactor set‐up. Subsequent analytical interpretation, via laser scanning confocal, transmission electron and dark‐field microscopy, as well as flow cytometry, of the interaction of SHMNPs‐PEG‐cRGD‐NLS with macrophage (J774A.1) and epithelial (HeLa) cells shows internalization of the SHMNPs‐PEG‐cRGD‐NLS in both cell types up to 24 h after 20 μg mL^?1 exposure, as well as increasing aggregation inside of vesicles over this time period. The findings of this study show that by incorporating a variety of state‐of‐the‐art analytical and imaging approaches, it is possible to determine the specific effectiveness of surface peptide and ligand sequences upon multifunctional SHMNPs.     

Dye-sensitized solar cells based on ZnO nanowire array/TiO2 nanoparticle composite photoelectrodes with controllable nanowire aspect ratio

The ZnO nanowire (NW) array/TiO₂ nanoparticle (NP) composite photoelectrode with controllable NW aspect ratio has been grown from aqueous solutions for the fabrication of dye-sensitized solar cells (DSSCs), which combines the advantages of the rapid electron transport in ZnO NW array and the high surface area of TiO₂ NPs. The results indicate that the composite photoelectrode achieves higher overall photoelectrical conversion efficiency (η) than the ZnO NW alone. As a result, DSSCs based on the ZnO NW array/TiO₂ NP composite photoelectrodes get the enhanced photoelectrical conversion efficiency, and the highest η is also achieved by rational tuning the aspect ratio of ZnO NWs. With the proper aspect ratio (ca. 6) of ZnO NW, the ZnO NW array/TiO₂ NP composite DSSC exhibits the highest conversion efficiency (5.5 %). It is elucidated by the dye adsorption amount and interfacial electron transport of DSSCs with the ZnO NW array/TiO₂ NP composite photoelectrode, which is quantitatively characterized using the UV-Vis absorption spectra and electrochemical impedance spectra. It is evident that the DSSC with the proper aspect ratio of ZnO NW displays the high dye adsorption amount and fastest interfacial electron transfer.     

Monosaccharide-Directed Selective Internalization of Gold and Silver Nanoparticles in Hepatic Cancer Cells

The therapeutic success of nanomedicines requires nanomaterials to either adhere to the surface or internalize within the cytoplasm. The endocytosis phenomenon is controlled by the nanomaterial's shape, size, composition, charge, and capping molecules. The membrane potential-based non-specific internalization of therapeutic nanomedicines offers limited benefits than receptor-based specific delivery. Glut receptor-based internalization of glucose molecules is a well-known process in cancerous cells, which is one of the most exploited strategies to target cancer cells using nanoparticles. However, the internalization process of other structurally similar monosaccharides (D-Galactose, Mannose, and D-Fructose) conjugated nanoparticles remains to be unexplored. Herein, D-Glucose, D-Galactose, Mannose, and D-Fructose-coated AuNPs and AgNPs have been synthesized and studied the role of Glut receptors in their internalization in liver cancer cells, and compared them with non-cancerous cells. Results revealed that almost all monosaccharide-coated NPs exhibited high uptake in liver cancer cells than non-cancerous cells. Glut-1 receptor is observed to play a key role in the uptake and inhibition of Glut-1 receptors by genistein lead to a significant decrease in nanoparticle uptake. In conclusion, monosaccharide-conjugated nanoparticles can be used to direct the selective internalization of AuNPs and AgNPs in hepatic cancer cells to realize therapeutic and imaging applications.     

Tribological properties of magnetite nanoparticles with various morphologies as lubricating additives

The manipulation of matter at the nanoscale has unleashed a great potential for engineering biomedical drug carriers, but the transport of nanoparticles (NPs) under nanoscale confinement is still poorly understood. Using colloidal physics to describe NP interactions, we have computationally studied the passive transport of NPs using experimentally relevant conditions from bulk into a nanochannel of 60–90 nm height. NP size, channel height, and the Debye length are comparable so that changes in nanoscale dimensions may induce substantial changes in NP transport kinetics. We show that subtle changes in nanochannel dimensions may alter the energy barrier by about six orders of magnitude resulting in different NP penetration depths and diffusion mechanisms: ballistic, first-order and quasi zero-order transport regimes. The analysis of NP diffusion by continuum methods reveals that apparent diffusivity is reduced by decreasing channel size. The continuum finite element (FE) numerical method reproduced the colloidal model results only when surface interactions were accounted for. These results give a new insight into NP passive transport at the boundaries of nanoconfined domains, and have implications on the design of nanoscale fluidics and NP systems for biomedical and engineering applications.     

The Toxicity of Silver Nanoparticles Depends on Their Uptake by Cells and Thus on Their Surface Chemistry

A set of three types of silver nanoparticles (Ag NPs) are prepared, which have the same Ag cores, but different surface chemistry. Ag cores are stabilized with mercaptoundecanoic acid (MUA) or with a polymer shell [poly(isobutylene‐alt‐maleic anhydride) (PMA)]. In order to reduce cellular uptake, the polymer‐coated Ag NPs are additionally modified with polyethylene glycol (PEG). Corrosion (oxidation) of the NPs is quantified and their colloidal stability is investigated. MUA‐coated NPs have a much lower colloidal stability than PMA‐coated NPs and are largely agglomerated. All Ag NPs corrode faster in an acidic environment and thus more Ag(I) ions are released inside endosomal/lysosomal compartments. PMA coating does not reduce leaching of Ag(I) ions compared with MUA coating. PEGylation reduces NP cellular uptake and also the toxicity. PMA‐coated NPs have reduced toxicity compared with MUA‐coated NPs. All studied Ag NPs were less toxic than free Ag(I) ions. All in all, the cytotoxicity of Ag NPs is correlated on their uptake by cells and agglomeration behavior.     

Prominin‐1‐Specific Binding Peptide‐Modified Apoferritin Nanoparticle Carrying Irinotecan as a Novel Radiosensitizer for Colorectal Cancer Stem‐Like Cells

Resistance of cancer stem cells to radiotherapy remains a major obstacle to successful cancer management. Prominin‐1 (PROM1) is a cancer stem cell marker. Nanoparticle (NP) chemotherapeutics preferentially accumulate in tumors and are able to target cancer and cancer stem‐like cells through cancer cell‐specific ligands, making them uniquely suited as radiosensitizers for chemoradiation therapy. Using a biocompatible apoferritin NP, a PROM1‐targeted NP carrying irinotecan (PROM1‐NP) is engineered. The synergistic effect of the NP and irradiation is evaluated in PROM1‐overexpressing HCT‐116 colorectal cancer cell lines in vitro and in vivo. PROM1‐NP has a size of 17.2 ± 0.2 nm and surface charge of ?13.5 ± 0.2 mV. It demonstrates higher intracellular uptake than nontargeted NP or irinotecan alone. Treatment with PROM1‐NPs decreases HCT‐116 cell proliferation in a dose‐ and time‐dependent manner. In vitro radiosensitization reveals that PROM1‐NP is significantly more effective as a radiosensitizer than nontargeted NP or irinotecan. HCT‐116 tumor xenograft growth is markedly slower following treatment with PROM1‐NP plus irradiation, suggesting that PROM1‐NP is more effective as a radiosensitizer than irinotecan and nontargeted NP in vivo. This study provides the first preclinical evidence of the effectiveness of PROM1‐targeted NP formulation of irinotecan as a radiosensitizer.     

Direct Visualization of Vesicle Maturation and Plasma Membrane Protein Trafficking

Internalization and intracellular trafficking of membrane proteins are now recognized as essential mechanisms that contribute to a number of cellular processes. Current methods lack the ability to specifically label the plasma membrane of a live cell, follow internalization of labeled membrane molecules, and conclusively differentiate newly formed membrane-derived vesicles from pre-existing endocytic or secretory structures in the cytoplasm. Here, we detail a visualization method for surface biotinylation of plasma membrane-derived vesicles that allows us to follow their progress from membrane to cytosol at specific time points. Using the transmembrane receptor RET as a model, we demonstrate how this method can be applied to identify plasma membrane-derived vesicle maturation, determine RET’s presence within these structures, and monitor RET’s recycling to the cell surface. This method improves on static and less discriminatory methods, providing a tool for analysis of real-time vesicle trafficking that is applicable to many systems.     

The surface science of nanoparticles for catalysis: electronic and steric effects of organic ligands

Recent studies demonstrate the important roles of surface ligands in creating metal-organic interfaces that can significantly improve both catalytic activity as well as selectivity of chemically synthetized nanoparticle (NP) catalysts. Both steric and electronic effects can be efficiently used to tune catalytic properties of the NPs. Here, we overview the recent advancements in the field of the surface science of NPs for their catalytic applications and discuss the steric and electronic effects of ligands immobilized at the NP surface on the activity and selectivity of catalytically active NPs in different catalytic reactions.     

Transport and abatement of fluorescent silica nanoparticle (SiO<Subscript>2</Subscript> NP) in granular filtration: effect of porous media and ionic strength

The extensive production and application of engineered silica nanoparticles (SiO₂ NPs) will inevitably lead to their release into the environment. Granular media filtration, a widely used process in water and wastewater treatment plants, has the potential for NP abatement. In this work, laboratory-scale column experiments were performed to study the transport and retention of SiO₂ NPs on three widely used porous materials, i.e., sand, anthracite, and granular activated carbon (GAC). Synthetic fluorescent core-shell SiO₂ NPs (83 nm) were used to facilitate NP detection. Sand showed very low capacity for SiO₂ filtration as this material had a surface with limited surface area and a high concentration of negative charge. Also, we found that the stability and transport of SiO₂ NP were strongly dependent on the ionic strength of the solution. Increasing ionic strength led to NP agglomeration and facilitated SiO₂ NP retention, while low ionic strength resulted in release of captured NPs from the sand bed. Compared to sand, anthracite and GAC showed higher affinity for SiO₂ NP capture. The superior capacity of GAC was primarily due to its porous structure and high surface area. A process model was developed to simulate NP capture in the packed bed columns and determine fundamental filtration parameters. This model provided an excellent fit to the experimental data. Taken together, the results obtained indicate that GAC is an interesting material for SiO₂ NP filtration.     

Preparation, characterization and properties of novel covalently surface-functionalized zinc oxide nanoparticles

Novel covalently surface-modified zinc oxide (ZnO) nanoparticles (NP) (ZHIE) were successfully prepared, which have organic chains composed of hydrophilic amide and urethane linkages, and terminal amino groups on the surfaces, using zinc acetate monohydrate. FTIR spectroscopy, X-ray analysis and TEM observation suggested that the resultant ZHIE NPs have the mean sizes of about 10 nm in diameters, the organic chains linking the amino groups in the terminals and wurtzite crystal structure. UV-vis absorption spectrum of the ZHIE NPs in methanol showed maximum absorption band at 348 nm, supporting the TEM observations. Photoluminescent spectrum measurements depicted that the ZHIE NPs show broad visible emission band on the basis of trapped-electron emission. Cytotoxicity and phagocytosis assays suggested that the ZHIE NPs are noncytotoxic, and the ZHIE-labeled zymosan particles derived by conjugation of the ZHIE NPs with zymosan are internalized into the cells and generate fluorescence based on the ZHIE NPs.     

Phenol adsorption on surface-functionalized iron oxide nanoparticles: modeling of the kinetics,isotherm, and mechanism

Phenol adsorption from aqueous solution was carried out using uncoated and methyl acrylic acid (MAA)-coated iron oxide nanoparticles (NPs), having size <10 nm, as adsorbents. Batch adsorption studies revealed that the phenol removal efficiency of MAA-coated NPs (950 mg g^?1) is significantly higher than that of uncoated NPs (550 mg g^?1) under neutral to acidic conditions. However, this improvement disappears above pH 9. The adsorption data under optimized conditions (pH 7) were modeled with pseudo-first- and pseudo-second-order kinetics and subjected to Freundlich and Langmuir isotherms. The analysis determined that pseudo-second-order kinetics and the Freundlich model are appropriate for both uncoated and MAA-coated NPs (all R ² > 0.98). X-ray photoelectron spectroscopy analysis of pristine and phenol-adsorbed NPs revealed core-level binding energy and charge for Fe(2s) and O(1s) on the NP surfaces. The calculations suggest that phenol adsorption onto MAA-coated NPs is a charge transfer process, where the adsorbate (phenol) acts as an electron donor and the NP surface (Fe, O) as an electron acceptor. However, a physisorption process appears to be the relevant mechanism for uncoated NPs.     

Thermally evaporated Ag nanoparticle films for plasmonic enhancement in organic solar cells: effects of particle geometry

We report on the simple fabrication of Ag NP films via thermal evaporation and subsequent annealing. The NPs are formed on indium tin oxide electrodes, coated with PEDOT:PSS and implemented into PCPDTBT:PC70BM solar cells. Scanning electron microscopy and atomic force microscopy are used to determine the size distributions and surface coverage of the NP film. We apply finite‐difference time‐domain techniques to model the optical properties of different nanoparticle films and compare this with the absorption properties of the organic active layer. The simulations demonstrate that the absorption and scattering efficiency of the particles are very sensitive to particle geometry. Solar cells prepared with window electrodes containing NP layers with less surface coverage, show a 14.8% improvement in efficiency. We discuss variations in the external quantum efficiency of the devices in terms of forward scattering and parasitic absorption losses induced by the NP layer. (© 2015 WILEY‐VCH Verlag GmbH &Co. KGaA, Weinheim)     

SERS study of Ag nanoparticles electrodeposited on patterned TiO2 nanotube films

In this work, Ag nanoparticles (NPs) were deposited on patterned TiO₂ nanotube films through pulse‐current (PC) electrodeposition, and as a result patterned Ag NPs films were achieved. Scanning electron microscopy (SEM), electron probe microanalysis (EPMA), and X‐ray diffraction (XRD) were used, respectively, to study the morphology, uniformity, and phase structure of the patterned Ag NP films. The size and density of the as‐deposited Ag NPs could be controlled by changing the deposition charge density, and it was found that the patterned Ag NP films produced under a charge density of 2.0 C cm⁻² gave intense UV–vis and Raman peaks. Two‐dimensional surface‐enhanced Raman scattering (SERS) mapping of rhodamine 6G (R6G) on the patterned Ag NP films demonstrated a high‐throughput, localized molecular adsorption and micropatterned SERS effect. Copyright © 2010 John Wiley & Sons, Ltd.     

Analysis of the toxicity of gold nano particles on the immune system: effect on dendritic cell functions

The effect of manufactured gold nanoparticles (NPs) on the immune system was analysed through their ability to perturb the functions of dendritic cells (DCs), a major actor of both innate and acquired immune responses. For this purpose, DCs were produced in culture from mouse bone marrow progenitors. The analysis of the viability of the cells after their incubation in the presence of gold NPs shows that these NPs are not cytotoxics even at high concentration. Furthermore, the phenotype of the DC is unchanged after the addition of NPs, indicating that there is no activation of the DC. However, the analysis of the cells at the intracellular level reveals important amounts of gold NPs amassing in endocytic compartments. Furthermore, the secretion of cytokines is significantly modified after such internalisation indicating a potential perturbation of the immune response.     

Influence of the Morphology of Lysozyme‐Shelled Microparticles on the Cellular Association,Uptake, and Degradation in Human Breast Adenocarcinoma Cells

The ultrasound‐assisted self‐assembly and cross‐linking of lysozyme at the water–air and water–perfluorohexane interfaces are shown to produce lysozyme‐shelled hollow microbubbles (LSMBs) and microcapsules (LSMC), respectively. The arrangement of lysozyme at the air–liquid or oil–liquid interfaces is accompanied by changes in the bioactivity and conformational state of the protein. The interaction of LSMB and LSMC with human breast adenocarcinoma cells (SKBR3) is studied. LSMB and LSMC are phagocyted by cells within 2 h without exerting a cytotoxic activity. The cellular internalization kinetics of LSMB and LSMC and the effects on cell cycle are evaluated using flow cytometry. Evidence for the internalization of microparticles and degradation within the cell are also monitored by confocal and scanning electron microscopic analyses. The integrity of cell membrane and cell cycle is not affected by LSMBs and LSMCs uptake. These studies show that the positively charged LSMB and LSMC are not cytotoxic and can be readily internalized and degraded by the SKBR3 cells. LSMBs and LSMCs show a different uptake kinetics and intracellular degradation pattern due to differences in the arrangement of the protein at the air–liquid or oil–liquid interfaces.