Nano-SAR Modeling for Predicting the Cytotoxicity of Metal Oxide Nanoparticles to PaCa2.

Nowadays, the impact of engineered nanoparticles (NPs) on human health and environment has aroused widespread attention. It is essential to assess and predict the biological activity, toxicity, and physicochemical properties of NPs. Computation-based methods have been developed to be efficient alternatives for understanding the negative effects of nanoparticles on the environment and human health. Here, a classification-based structure-activity relationship model for nanoparticles (nano-SAR) was developed to predict the cellular uptake of 109 functionalized magneto-fluorescent nanoparticles to pancreatic cancer cells (PaCa2). The norm index descriptors were employed for describing the structure characteristics of the involved nanoparticles. The Random forest algorithm (RF), combining with the Recursive Feature Elimination (RFE) was employed to develop the nano-SAR model. The resulted model showed satisfactory statistical performance, with the accuracy (ACC) of the test set and the training set of 0.950 and 0.966, respectively, demonstrating that the model had satisfactory classification effect. The model was rigorously verified and further extensively compared with models in the literature. The proposed model could be reasonably expected to predict the cellular uptakes of nanoparticles and provide some guidance for the design and manufacture of safer nanomaterials.

Evaluating genotoxicity of metal oxide nanoparticles: Application of advanced supervised and unsupervised machine learning techniques.

Presence of missing data points in datasets is among main challenges in handling the toxicological data for nanomaterials. As the processing of missing data is an important part of data analysis, we have introduced a read-across approach that uses a combination of supervised and unsupervised machine learning techniques to fill the missing values. A series of classification models (supervised learning) was developed to predict class label, and self-organizing map approach (unsupervised learning) was used to estimate relative distances between nanoparticles and refine results obtained during supervised learning. In this study, genotoxicity of 49 silicon and metal oxide nanoparticles in Ames and Comet tests. Collected literature data did not demonstrate significant variations related to the change of size including selected bulk materials. Genotoxicity-related features of nanomaterials were represented by ionic characteristics. General tendencies found in the current study were convincingly linked to known theories of genotoxic action at nano-level. Mechanisms of primary and secondary genotoxic effects were discussed in the context of developed models.

Comparison of hyperspectral classification methods for the analysis of cerium oxide nanoparticles in histological and aqueous samples.

Hyperspectral imaging (HSI) and classification are established methods that are being applied in new ways to the analysis of nanoscale materials in a variety of matrices. Typically, enhanced darkfield microscopy (EDFM)-based HSI data (also known as image datacubes) are collected in the wavelength range of 400-1000 nm for each pixel in a datacube. Utilising different spectral library (SL) creation methods, spectra from pixels in the datacube corresponding to known materials can be collected into reference spectral libraries (RSLs), which can be used to classify materials in datacubes of experimental samples using existing classification algorithms. In this study, EDFM-HSI was used to visualise and analyse industrial cerium oxide (CeO2 ; ceria) nanoparticles (NPs) in rat lung tissues and in aqueous suspension. Rats were exposed to ceria NPs via inhalation, mimicking potential real-world occupational exposures. The lung tissues were histologically prepared: some tissues were stained with hematoxylin and eosin (H&E) and some were left unstained. The goal of this study was to determine how HSI and classification results for ceria NPs were influenced by (1) the use of different RSL creation and classification methods and (2) the application of those methods to samples in different matrices (stained tissue, unstained tissue, or aqueous solution). Three different RSL creation methods - particle filtering (PF), manual selection, and spectral hourglass wizard (SHW) - were utilised to create the RSLs of known materials in unstained and stained tissue, and aqueous suspensions, which were then used to classify the NPs in the different matrices. Two classification algorithms - spectral angle mapper (SAM) and spectral feature fitting (SFF) - were utilised to determine the presence or absence of ceria NPs in each sample. The results from the classification algorithms were compared to determine how each influenced the classification results for samples in different matrices. The results showed that sample matrix and sample preparation significantly influenced the NP classification thresholds in the complex matrices. Moreover, considerable differences were observed in the classification results when utilising each RSL creation and classification method for each type of sample. Results from this study illustrate the importance of appropriately selecting HSI algorithms based on specific material and matrix characteristics in order to obtain optimal classification results. As HSI is increasingly utilised for NP characterisation for clinical, environmental and health and safety applications, this investigation is important for further refining HSI protocols while ensuring appropriate data collection and analysis.

The Role of Reactive Oxygen Species (ROS) in the Biological Activities of Metallic Nanoparticles.

Nanoparticles (NPs) possess unique physical and chemical properties that make them appropriate for various applications. The structural alteration of metallic NPs leads to different biological functions, specifically resulting in different potentials for the generation of reactive oxygen species (ROS). The amount of ROS produced by metallic NPs correlates with particle size, shape, surface area, and chemistry. ROS possess multiple functions in cellular biology, with ROS generation a key factor in metallic NP-induced toxicity, as well as modulation of cellular signaling involved in cell death, proliferation, and differentiation. In this review, we briefly explained NP classes and their biomedical applications and describe the sources and roles of ROS in NP-related biological functions in vitro and in vivo. Furthermore, we also described the roles of metal NP-induced ROS generation in stem cell biology. Although the roles of ROS in metallic NP-related biological functions requires further investigation, modulation and characterization of metallic NP-induced ROS production are promising in the application of metallic NPs in the areas of regenerative medicine and medical devices.

Grouping nanomaterials to predict their potential to induce pulmonary inflammation.

The rapidly expanding manufacturing, production and use of nanomaterials have raised concerns for both worker and consumer safety. Various studies have been published in which induction of pulmonary inflammation after inhalation exposure to nanomaterials has been described. Nanomaterials can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Currently, efforts are made to increase the knowledge on the characteristics of nanomaterials that can be used to categorise them into hazard groups according to these characteristics. Grouping helps to gather information on nanomaterials in an efficient way with the aim to aid risk assessment. Here, we discuss different ways of grouping nanomaterials for their risk assessment after inhalation. Since the relation between single intrinsic particle characteristics and the severity of pulmonary inflammation is unknown, grouping of nanomaterials by their intrinsic characteristics alone is not sufficient to predict their risk after inhalation. The biokinetics of nanomaterials should be taken into account as that affects the dose present at a target site over time. The parameters determining the kinetic behaviour are not the same as the hazard-determining parameters. Furthermore, characteristics of nanomaterials change in the life-cycle, resulting in human exposure to different forms and doses of these nanomaterials. As information on the biokinetics and in situ characteristics of nanomaterials is essential but often lacking, efforts should be made to include these in testing strategies. Grouping nanomaterials will probably be of the most value to risk assessors when information on intrinsic characteristics, life-cycle, biokinetics and effects are all combined.

Case studies putting the decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) into practice.

Case studies covering carbonaceous nanomaterials, metal oxide and metal sulphate nanomaterials, amorphous silica and organic pigments were performed to assess the Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping). The usefulness of the DF4nanoGrouping for nanomaterial hazard assessment was confirmed. In two tiers that rely exclusively on non-animal test methods followed by a third tier, if necessary, in which data from rat short-term inhalation studies are evaluated, nanomaterials are assigned to one of four main groups (MGs). The DF4nanoGrouping proved efficient in sorting out nanomaterials that could undergo hazard assessment without further testing. These are soluble nanomaterials (MG1) whose further hazard assessment should rely on read-across to the dissolved materials, high aspect-ratio nanomaterials (MG2) which could be assessed according to their potential fibre toxicity and passive nanomaterials (MG3) that only elicit effects under pulmonary overload conditions. Thereby, the DF4nanoGrouping allows identifying active nanomaterials (MG4) that merit in-depth investigations, and it provides a solid rationale for their sub-grouping to specify the further information needs. Finally, the evaluated case study materials may be used as source nanomaterials in future read-across applications. Overall, the DF4nanoGrouping is a hazard assessment strategy that strictly uses animals as a last resort.

Comprehensive understanding of nano-sized particle separation processes using nanoparticle tracking analysis.

The understanding of nano-sized particle separation processes has been limited by difficulties of nanoparticle characterization. In this study, nanoparticle tracking analysis (NTA) was deployed to evaluate the absolute particle size distributions in laboratory scale flocculation and filtration experiments with silver nanoparticles. The results from NTA were consistent with standard theories of particle destabilization and transport. Direct observations of changes in absolute particle size distributions from NTA enhance both qualitative and quantitative understanding of particle separation processes of nano-sized particles.

Competition between auger recombination and hot-carrier trapping in PL intensity fluctuations of type II nanocrystals.

Performing time-tagged, time-correlated, single-photon-counting studies on individual colloidal nanocrystal quantum dots (NQDs), the evolution of photoluminescence (PL) intensity-fluctuation behaviors in near-infrared (NIR) emitting type II, InP/CdS core-shell NQDs is investigated as a function of shell thickness. It is observed that Auger recombination and hot-carrier trapping compete in defining the PL intensity-fluctuation behavior for NQDs with thin shells, whereas the role of hot-carrier trapping dominates for NQDs with thick shells. These studies further reveal the distinct ramifications of altering either the excitation fluence or repetition rate. Specifically, an increase in laser pump fluence results in the creation of additional hot-carrier traps. Alternately, higher repetition rates cause a saturation in hot-carrier traps, thus activating Auger-related PL fluctuations. Furthermore, it is shown that Auger recombination of negatively charged excitons is suppressed more strongly than that of positively charged excitons because of the asymmetry in the electron-hole confinement in type II NQDs. Thus, this study provides new understanding of how both NQD structure (shell thickness and carrier-separation characteristics) and excitation conditions can be used to tune the PL stability, with important implications for room-temperature single-photon generation. Specifically, the first non-blinking NQD capable of single-photon emission in the near-infrared spectral regime is described.

Toxicity and genotoxicity of organic and inorganic nanoparticles to the bacteria Vibrio fischeri and Salmonella typhimurium.

The present work aimed at evaluating the toxicity and genotoxicity of two organic (vesicles composed of sodium dodecyl sulphate/didodecyl dimethylammonium bromide-SDS/DDAB and of monoolein and sodium oelate-Mo/NaO) and four inorganic (titanium oxide-TiO2, silicon titanium-TiSiO4, Lumidot-CdSe/ZnS, and gold nanorods) nanoparticles (NP), suspended in two aqueous media (Milli Q water and American Society for Testing and Materials (ASTM) hardwater), to the bacteria Vibrio fischeri (Microtox test) and Salmonella typhimurium-his⁻ (Ames test with strains TA98 and TA100). Aiming a better understanding of these biological responses physical and chemical characterization of the studied NP suspensions was carried out. Results denoted a high aggregation state of the NP in the aqueous suspensions, with the exception of SDS/DDAB and Mo/NaO vesicles, and of nanogold suspended in Milli Q water. This higher aggregation was consistent with the low values of zeta potential, revealing the instability of the suspensions. Regarding toxicity data, except for nano TiO2, the tested NP significantly inhibited bioluminescence of V. fischeri. Genotoxic effects were only induced by SDS/DDAB and TiO2 for the strain TA98. A wide range of toxicity responses was observed for the six tested NP, differing by more than 5 orders of magnitude, and suggesting different modes of action of the tested NP.

A link between nanoparticles and Parkinson's disease. Which nanoparticles are most harmful?

Nowadays, different kinds of nanoparticles (NPs) are produced around the world and used in many fields and products. NPs can enter the body and aggregate in the various organs including brain. They can damage neurons, in particular dopaminergic neurons in the substantia nigra (SN) and striatal neurons which their lesion is associated with Parkinson's disease (PD). So, NPs can have a role in PD induction along with other agents and factors. PD is the second most common neurodegenerative disease in the world, and in patients, its symptoms progressively worsen day by day through different pathways including oxidative stress, neuroinflammation, mitochondrial dysfunction, α-synuclein increasing and aggregation, apoptosis and reduction of tyrosine hydroxylase positive cells. Unfortunately, there is no effective treatment for PD. So, prevention of this disease is very important. On the other hand, without having sufficient information about PD inducers, prevention of this disease would not be possible. Therefore, we need to have sufficient information about things we contact with them in daily life. Since, NPs are widely used in different products especially in consumer products, and they can enter to the brain easily, in this review the toxicity effects of metal and metal oxide NPs have been evaluated in molecular and cellular levels to determine potential of different kinds of NPs in development of PD.

A Systematic comparison of in vitro cell uptake and in vivo biodistribution for three classes of gold nanoparticles with saturated PEG coatings.

A great deal of attention has been focused on nanoparticles for cancer therapy, with the promise of tumor-selective delivery. However, despite intense work in the field over many years, the biggest obstacle to this vision remains extremely low delivery efficiency of nanoparticles into tumors. Due to the cost, time, and impact on the animals for in vivo studies, the nanoparticle field predominantly uses cellular uptake assays as a proxy to predict in vivo outcomes. Extensive research has focused on decreasing macrophage uptake in vitro as a proxy to delay nanoparticle accumulation in the mononuclear phagocytic system (MPS), mainly the liver and spleen, and thereby increase tumor accumulation. We have recently reported novel synthetic methods employing small molecule crosslinkers for the controlled assembly of small nanoparticles into larger aggregates and found that these nanoaggregates had remarkably high surface coverage and low cell uptake, even in macrophages. We further found that this extremely low cellular uptake could be recapitulated on solid gold nanoparticles by densely coating their surface with small molecules. Here we report our studies on the biodistribution and clearance of these materials in comparison to more conventional PEGylated gold nanoparticles. It was expected that the remarkably low macrophage uptake in vitro would translate to extended blood circulation time in vivo, but instead we found no correlation between either surface coverage or in vitro macrophage cell uptake and in vivo blood circulation. Gold nanoaggregates accumulate more rapidly and to a higher level in the liver compared to control gold nanoparticles. The lack of correlation between in vitro macrophage uptake and in vivo blood circulation suggests that the field must find other in vitro assays to use as a primary proxy for in vivo outcomes or use direct in vivo experimentation as a primary assay.

Gold nanoparticle/multi-walled carbon nanotube modified glassy carbon electrode as a sensitive voltammetric sensor for the determination of diclofenac sodium.

A simple and highly sensitive sensor for the determination of diclofenac sodium based on gold nanoparticle/multi-walled carbon nanotube modified glassy carbon electrode is reported. Scanning electron microscopy along with energy dispersive X-ray spectroscopy, electrochemical impedance spectroscopy, cyclic voltammetry and square wave voltammetry was used to characterize the nanostructure and performance of the sensor and the results were compared with those obtained at the multi-walled carbon nanotube modified glassy carbon electrode and bare glassy carbon electrode. Under the optimized experimental conditions diclofenac sodium gave linear response over the range of 0.03-200µmolL(-1). The lower detection limits were found to be 0.02µmolL(-1). The effect of common interferences on the current response of DS was investigated. The practical application of the modified electrode was demonstrated by measuring the concentration of diclofenac sodium in urine and pharmaceutical samples. This revealed that the gold nanoparticle/multiwalled carbon nanotube modified glassy carbon electrode shows excellent analytical performance for the determination of diclofenac sodium in terms of a very low detection limit, high sensitivity, very good accuracy, repeatability and reproducibility.

Development of an analytical method for assessment of silver nanoparticle content in biological matrices by inductively coupled plasma mass spectrometry.

Silver nanoparticles (AgNPs) are a broad class of synthetic nanoparticles that are utilized in a wide variety of consumer products as antimicrobial agents. Despite their widespread use, a detailed understanding of their toxicological characteristics and biological and environmental hazards is not available. To support research into the biodistribution and toxicology of AgNPs, it is necessary to develop a suitable method for the assessment of AgNP content in biological samples. Two methods were developed and validated to analyze citrate-coated AgNP content that utilize acid digestion of rodent feces and liver tissue samples, and a third method was developed for the dilution and direct analysis of rodent urine samples. Following sample preparation, the silver content of each sample was determined by inductively coupled plasma mass spectrometry (ICP-MS) to quantify the silver and AgNP levels present. Analysis of rat feces matrix yielded analytical recoveries ranging from 82 to 93 %. Liver tissue spiked with a formulation of AgNPs over a range of concentrations yielded analytical recoveries between 88 and 90 %, providing acceptable accuracy results. The analysis of silver in urine samples exhibited recovery values ranging from 80 to 85 % for AgNP formulations and 62-84 % for standard silver ion solutions. All determinations exhibited a high degree of analytical precision. The results obtained here suggest that matrix interference plays a minimal role in AgNP recovery in feces and liver tissue, while the urine matrix can exhibit a significant effect on the determination of silver content.

From basic physics to mechanisms of toxicity: the "liquid drop" approach applied to develop predictive classification models for toxicity of metal oxide nanoparticles.

Many metal oxide nanoparticles are able to cause persistent stress to live organisms, including humans, when discharged to the environment. To understand the mechanism of metal oxide nanoparticles' toxicity and reduce the number of experiments, the development of predictive toxicity models is important. In this study, performed on a series of nanoparticles, the comparative quantitative-structure activity relationship (nano-QSAR) analyses of their toxicity towards E. coli and HaCaT cells were established. A new approach for representation of nanoparticles' structure is presented. For description of the supramolecular structure of nanoparticles the "liquid drop" model was applied. It is expected that a novel, proposed approach could be of general use for predictions related to nanomaterials. In addition, in our study fragmental simplex descriptors and several ligand-metal binding characteristics were calculated. The developed nano-QSAR models were validated and reliably predict the toxicity of all studied metal oxide nanoparticles. Based on the comparative analysis of contributed properties in both models the LDM-based descriptors were revealed to have an almost similar level of contribution to toxicity in both cases, while other parameters (van der Waals interactions, electronegativity and metal-ligand binding characteristics) have unequal contribution levels. In addition, the models developed here suggest different mechanisms of nanotoxicity for these two types of cells.

Green nanotechnology - a new hope for medical biology.

The development of eco-friendly technologies in material synthesis is of considerable importance to expand their biological applications. Nowadays, a variety of green nanoparticles with well-defined chemical composition, size, and morphology have been synthesized by different methods and their applications in many cutting-edge technological areas have been explored. This review highlights the classification of nanoparticles giving special emphasis on biosynthesis of metal nanoparticle by viable organisms. It also focuses on the applications of these biosynthesized nanoparticles in a wide spectrum of potential areas of medical biology including catalysis, targeted drug delivery, cancer treatment, antibacterial agents and as biosensors.

Impact of organic and inorganic nanomaterials in the soil microbial community structure.

In this study the effect of organic and inorganic nanomaterials (NMs) on the structural diversity of the soil microbial community was investigated by Denaturing Gradient Gel Electrophoresis, after amplification with universal primers for the bacterial region V6-V8 of 16S rDNA. The polymers of carboxylmethyl-cellulose (CMC), of hydrophobically modified CMC (HM-CMC), and hydrophobically modified polyethylglycol (HM-PEG); the vesicles of sodium dodecyl sulphate/didodecyl dimethylammonium bromide (SDS/DDAB) and of monoolein/sodium oleate (Mo/NaO); titanium oxide (TiO(2)), titanium silicon oxide (TiSiO(4)), CdSe/ZnS quantum dots, gold nanorods, and Fe/Co magnetic fluid were the NMs tested. Soil samples were incubated, for a period of 30 days, after being spiked with NM suspensions previously characterized by Dynamic Light Scattering (DLS) or by an ultrahigh-resolution scanning electron microscope (SEM). The analysis of similarities (ANOSIM) of DGGE profiles showed that gold nanorods, TiO(2), CMC, HM-CMC, HM-PEG, and SDS/DDAB have significantly affected the structural diversity of the soil bacterial community.

Silver nanoparticles effects on epididymal sperm in rats.

The motivation of our study was to examine the acute effects of intravenously administered a single bolus dose of silver nanoparticles (AgNPs) on rat spermatogenesis and seminiferous tubules morphology. In the treated rats compared to the vehicle treated control animals, the experiments revealed a size-dependent (20nm and 200nm), dose-dependent (5 and 10mg/kg body mass) and time-dependent (24h, 7 and 28days) decrease the epididymal sperm count measured by histological methods. In parallel AgNPs injection increased the level of DNA damage in germ cells, as measured by alkaline comet assay. Histological examination of the testes showed change in the testes seminiferous tubule morphometry in 200nm Ag NPs treated rats. No change of body weight, adipose tissue distribution and the frequency of abnormal spermatozoa was observed. Twenty nanometers AgNP appeared to be more toxic than 200nm ones.

Evaluation of genotoxicity of amine-terminated water-dispersible FePt nanoparticles in the Ames test and in vitro chromosomal aberration test.

Genotoxicity of superparamagnetic iron-platinum (FePt) nanoparticles (NPs) capped with 2-aminoethanethiol (AET) was evaluated using the bacterial reverse mutation assay (Ames test) and in vitro chromosomal aberration test. Mutagenicity of AET-capped FePt NPs was found to be negative in the Ames test, while clastogenicity of FePt NPs seemed to be false-positive in the in vitro chromosomal aberration test using Chinese hamster lung fibroblast cells. However, further detailed in vitro genotoxicity tests, such as DNA adduct studies, are necessary to conclude that a positive aberration result is irrelevant.