Low Dose Of Nanoparticles Research Articles

Antioxidant hepatic lipid metabolism can be promoted by orally administered inorganic nanoparticles

Accumulation of inorganic nanoparticles in living organisms can cause an increase in cellular reactive oxygen species (ROS) in a dose-dependent manner. Low doses of nanoparticles have shown possibilities to induce moderate ROS increases and lead to adaptive responses of biological systems, but beneficial effects of such responses on metabolic health remain elusive. Here, we report that repeated oral administrations of various inorganic nanoparticles, including TiO2, Au, and NaYF4 nanoparticles at low doses, can promote lipid degradation and alleviate steatosis in the liver of male mice. We show that low-level uptake of nanoparticles evokes an unusual antioxidant response in hepatocytes by promoting Ces2h expression and consequently enhancing ester hydrolysis. This process can be implemented to treat specific hepatic metabolic disorders, such as fatty liver in both genetic and high-fat-diet obese mice without causing observed adverse effects. Our results demonstrate that low-dose nanoparticle administration may serve as a promising treatment for metabolic regulation.

Air-Liquid Interface Exposure of Lung Epithelial Cells to Low Doses of Nanoparticles to Assess Pulmonary Adverse Effects.

Reliable and predictive in vitro assays for hazard assessments of manufactured nanomaterials (MNMs) are still limited. Specifically, exposure systems which more realistically recapitulate the physiological conditions in the lung are needed to predict pulmonary toxicity. To this end, air-liquid interface (ALI) systems have been developed in recent years which might be better suited than conventional submerged exposure assays. However, there is still a need for rigorous side-by-side comparisons of the results obtained with the two different exposure methods considering numerous parameters, such as different MNMs, cell culture models and read outs. In this study, human A549 lung epithelial cells and differentiated THP-1 macrophages were exposed under submerged conditions to two abundant types of MNMs i.e., ceria and titania nanoparticles (NPs). Membrane integrity, metabolic activity as well as pro-inflammatory responses were recorded. For comparison, A549 monocultures were also exposed at the ALI to the same MNMs. In the case of titania NPs, genotoxicity was also investigated. In general, cells were more sensitive at the ALI compared to under classical submerged conditions. Whereas ceria NPs triggered only moderate effects, titania NPs clearly initiated cytotoxicity, pro-inflammatory gene expression and genotoxicity. Interestingly, low doses of NPs deposited at the ALI were sufficient to drive adverse outcomes, as also documented in rodent experiments. Therefore, further development of ALI systems seems promising to refine, reduce or even replace acute pulmonary toxicity studies in animals.

A high-throughput microscopy method for single-cell analysis of event-time correlations in nanoparticle-induced cell death

The temporal context of cell death decisions remains generally hidden in ensemble measurements with endpoint readouts. Here, we describe a method to extract event times from fluorescence time traces of cell death-related markers in automated live-cell imaging on single-cell arrays (LISCA) using epithelial A549 lung and Huh7 liver cancer cells as a model system. In pairwise marker combinations, we assess the chronological sequence and delay times of the events lysosomal membrane permeabilization, mitochondrial outer membrane permeabilization and oxidative burst after exposure to 58 nm amino-functionalized polystyrene nanoparticles (PS-NH2 nanoparticles). From two-dimensional event-time scatter plots we infer a lysosomal signal pathway at a low dose of nanoparticles (25 µg mL−1) for both cell lines, while at a higher dose (100 µg mL−1) a mitochondrial pathway coexists in A549 cells, but not in Huh7. In general, event-time correlations provide detailed insights into heterogeneity and interdependencies in signal transmission pathways.

Control of viscous fingering by nanoparticles.

A substantial viscosity increase by the addition of a low dose of nanoparticles to the base fluids can well influence the dynamics of viscous fingering. There is a lack of detailed theoretical studies that address the effect of the presence of nanoparticles on unstable miscible displacements. In this study, the impact of nonreactive nanoparticle presence on the stability and subsequent mixing of an originally unstable binary system is examined using linear stability analysis (LSA) and pseudospectral-based direct numerical simulations (DNS). We have parametrized the role of both nondepositing and depositing nanoparticles on the stability of miscible displacements using the developed static and dynamic parametric analyses. Our results show that nanoparticles have the potential to weaken the instabilities of an originally unstable system. Our LSA and DNS results also reveal that nondepositing nanoparticles can be used to fully stabilize an originally unstable front while depositing particles may act as temporary stabilizers whose influence diminishes in the course of time. In addition, we explain the existing inconsistencies concerning the effect of the nanoparticle diffusion coefficient on the dynamics of the system. This study provides a basis for further research on the application of nanoparticles for control of viscosity-driven instabilities.

Reduced Cationic Nanoparticle Cytotoxicity Based on Serum Masking of Surface Potential.

Functionalization of nanoparticles with cationic moieties, such as polyethyleneimine (PEI), enhances binding to the cell membrane; however, it also disrupts the integrity of the cell's plasma and vesicular membranes, leading to cell death. Primary fibroblasts were found to display high surface affinity for cationic iron oxide nanoparticles and greater sensitivity than their immortalized counterparts. Treatment of cells with cationic nanoparticles in the presence of incremental increases in serum led to a corresponding linear decrease in cell death. The surface potential of the nanoparticles also decreased linearly as serum increased and this was strongly and inversely correlated with cell death. While low doses of nanoparticles were rendered non-toxic in 25% serum, large doses overcame the toxic threshold. Serum did not reduce nanoparticle association with primary fibroblasts, indicating that the decrease in nanoparticle cytotoxicity was based on serum masking of the PEI surface, rather than decreased exposure. Primary endothelial cells were likewise more sensitive to the cytotoxic effects of cationic nanoparticles than their immortalized counterparts, and this held true for cellular responses to cationic microparticles despite the much lower toxicity of microparticles compared to nanoparticles.

Short- and Long-Term Effects of Prenatal Exposure to Iron Oxide Nanoparticles: Influence of Surface Charge and Dose on Developmental and Reproductive Toxicity.

Iron oxide nanoparticles (NPs) are commonly utilized for biomedical, industrial, and commercial applications due to their unique properties and potential biocompatibility. However, little is known about how exposure to iron oxide NPs may affect susceptible populations such as pregnant women and developing fetuses. To examine the influence of NP surface-charge and dose on the developmental toxicity of iron oxide NPs, Crl:CD1(ICR) (CD-1) mice were exposed to a single, low (10 mg/kg) or high (100 mg/kg) dose of positively-charged polyethyleneimine-Fe2O3-NPs (PEI-NPs), or negatively-charged poly(acrylic acid)-Fe2O3-NPs (PAA-NPs) during critical windows of organogenesis (gestation day (GD) 8, 9, or 10). A low dose of NPs, regardless of charge, did not induce toxicity. However, a high exposure led to charge-dependent fetal loss as well as morphological alterations of the uteri (both charges) and testes (positive only) of surviving offspring. Positively-charged PEI-NPs given later in organogenesis resulted in a combination of short-term fetal loss (42%) and long-term alterations in reproduction, including increased fetal loss for second generation matings (mice exposed in utero). Alternatively, negatively-charged PAA-NPs induced fetal loss (22%) earlier in organogenesis to a lesser degree than PEI-NPs with only mild alterations in offspring uterine histology observed in the long-term.

High-throughput, quantitative assessment of the effects of low-dose silica nanoparticles on lung cells: Grasping complex toxicity with a great depth of field

The toxicity of manufactured fumed silica nanoparticles (NPs) remains poorly investigated compared to that of crystalline silica NPs, which have been associated with lung diseases after inhalation. Amorphous silica NPs are a raw material for manufactured nanocomposites, such as cosmetics, foods, and drugs, raising concerns about their potential toxicity. The size of the NPs was determined by dynamic light scattering and their shape was visualized by atomic force microscopy (10 ± 4 nm). The pertinent toxicological concentration and dynamic ranges were determined using viability tests and cellular impedance. We combined transcriptomics and proteomics to assess the cellular and molecular effects of fumed silica in A549 human alveolar epithelial cells. The “no observed transcriptomic adverse effect level” (NOTEL) was set to 1.0 μg/cm2, and the “lowest observed adverse transcriptional effect level” (LOTEL) was set at 1.5 μg/cm2. We carried out genome-wide expression profiles with microarrays and identified, by shotgun proteomics, the exoproteome changes in lung cells after exposure to NP doses (0.1, 1.0, 1.5, 3.0, and 6.0 μg/cm2) at two time points (24 h and 72 h). The data revealed a hierarchical, dose-dependent cellular response to silica NPs. At 1.5 μg/cm2, the Rho signaling cascade, actin cytoskeleton remodeling, and clathrin-mediated endocytosis were induced. At 3.0 μg/cm2, many inflammatory mediators were upregulated and the coagulation system pathway was triggered. Lastly, at 6.0 μg/cm2, oxidative stress was initiated. The proteins identified in the extracellular compartment were consistent with these findings. The alliance of two high-throughput technologies allowed the quantitative assessment of the cellular effects and molecular consequences of exposure of lung cells to low doses of NPs. These results were obtained using a pathway-driven analysis instead of isolated genes. As in photography, toxicogenomics allows, at the same time, the visualization of a wide spectrum of biological responses and a “zoom in” to the details with a great depth of field. This study illustrates how such an approach based on human cell culture models is a valuable predictive screening tool to evaluate the toxicity of many potentially harmful emerging substances, alone or in mixtures, in the framework of future regulatory reinforcements.

CD44 Targeting Magnetic Glyconanoparticles for Atherosclerotic Plaque Imaging

The cell surface adhesion molecule CD44 plays important roles in the initiation and development of atherosclerotic plaques. We aim to develop nanoparticles that can selectively target CD44 for the non-invasive detection of atherosclerotic plaques by magnetic resonance imaging. Magnetic glyconanoparticles with hyaluronan immobilized on the surface have been prepared. The binding of these nanoparticles with CD44 was evaluated in vitro by enzyme linked immunosorbent assay, flow cytometry and confocal microscopy. In vivo magnetic resonance imaging of plaques was performed on an atherosclerotic rabbit model. The magnetic glyconanoparticles can selectively bind CD44. In T2* weighted magnetic resonance images acquired in vivo, significant contrast changes in aorta walls were observed with a very low dose of the magnetic nanoparticles, allowing the detection of atherosclerotic plaques. Furthermore, imaging could be performed without significant delay after probe administration. The selectivity of hyaluronan nanoparticles in plaque imaging was established by several control experiments. Magnetic nanoparticles bearing surface hyaluronan enabled the imaging of atherosclerotic plaques in vivo by magnetic resonance imaging. The low dose of nanoparticles required, the possibility to image without much delay and the high biocompatibility are the advantages of these nanoparticles as contrast agents for plaque imaging.

Effect of magnet implant on iron biodistribution of Fe@C nanoparticles in the mouse

The in vivo biodistribution of Fe@C nanoparticles (NP) was tested in mice bearing an inflammatory focus induced by injecting carrageenan into an air pouch previously formed on their back. The animals were intravenously injected NP with a high (60 mg/kg) or a low iron dose (6 mg/kg) and sacrificed 2 h later. Blood and organ samples (liver, spleen, lung, and kidney) were obtained; washed exudates were also collected. Iron concentration in plasma, blood cells, organs, and exudates was determined by flameless atomic-absorption-spectroscopy after digestion of organic material. Pouch exudate volume increased in all groups of mice with experimental inflammation. After i.v. administration of the high and low dose of NP, iron in exudate increased by 83.3% and 92.2%, respectively. A similar increase in hepatic iron appeared after the high dose (78%), but no increase appeared after the low dose. When the magnet was present, a 157% and 119% increase of iron in exudate appeared after both doses of NPs, but only the high dose of NP increased iron liver (60%). The presence of a magnetic field in the pouch favored selective biodistribution of NP in the inflammatory focus. These results indicate that mice with an inflammatory compartment are suitable for primary screening of different NP types. They also show that selective biodistribution is greater when a low dose of NP was used and that distribution in the target organ was increased by the magnetic field.

Fluorometric method for the simultaneous quantitation of differently-sized nanoparticles in rodent tissue

The oral absorption and systemic translocation of particulate matter via the gastrointestinal tract has been shown by a number of laboratories using a wide variety of particles in different animal species. While there is debate on the magnitude of particle intestinal translocation, which is encumbered by the differing experimental protocols, particularly the method of quantitation of absorbed material, few have sought to examine the pharmacokinetic aspects of particle absorption. We describe in this communication the development of a simple and a rapid fluorometric assay of quantifying tissue-laden fluorescent nanoparticles that is able to isolate, detect and quantify the presence of two or more particle populations differing both in their size and fluorescent label. Six types of polystyrene nanoparticles incorporating different fluorescent markers were spiked in whole livers. The fluorophores were extracted using our previously developed method of freeze-drying the tissue and using chloroform as the extractive solvent. Only two types of particle populations, orange-labelled 40 nm and Fluoroscein-emitting 500 nm nanoparticles, were sufficiently recoverable and provided a high signal-to-noise ratio for further work. The amount of tissue and type of biological tissue type also impacted on the nanoparticle recovery and detection, reflecting, perhaps, the quenching effects of interacting tissue-derived molecules. In addition, the results also indicate that the use of nanoparticles incorporating fluorescent dyes that have emission over 500 nm overcome the tissue interfering autofluorescence for low doses of nanoparticles. The use of this fluorometric method has several advantages compared with other modes of quantitation in that it is rapid, non-radioactive and the marker is non-leaching. More importantly, it allows the simultaneous detection of multiple fluorophores such that two or more different fluorescent particle populations can be detected in the same sample. This may enable the uncharted area of pharmacokinetic parameters, such as the impedance, augmentation or site of gut uptake of differently sized particles to be studied.