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Impact of silica nanoparticle design on cellular toxicity and hemolytic activity.

ABSTRACT: Understanding the toxicity of silica nanoparticles (SiO(2)) on the cellular level is crucial for rational design of these nanomaterials for biomedical applications. Herein, we explore the impacts of geometry, porosity, and surface charge of SiO(2) on cellular toxicity and hemolytic activity. Nonporous Sto?ber silica nanospheres (115 nm diameter), mesoporous silica nanospheres (120 nm diameter, aspect ratio 1), mesoporous silica nanorods with aspect ratio of 2, 4, and 8 (width by length 80 × 200 nm, 150 × 600 nm, 130 × 1000 nm), and their cationic counterparts were evaluated on macrophages, lung carcinoma cells, and human erythrocytes. It was shown that the toxicity of SiO(2) is cell-type dependent and that surface charge and pore size govern cellular toxicity. Using inductively coupled plasma mass spectrometry, the cellular association of SiO(2) was quantitated with the association amount increasing in the following order: mesoporous SiO(2) (aspect ratio 1, 2, 4, 8) < amine-modified mesoporous SiO(2) (aspect ratio 1, 2, 4, 8) < amine-modified nonporous Sto?ber SiO(2) < nonporous Sto?ber SiO(2). Geometry did not seem to influence the extent of SiO(2) association at early or extended time points. The level of cellular association of the nanoparticles was directly linked to the extent of plasma membrane damage, suggesting a biological cause-and-effect relationship. Hemolysis assay showed that the hemolytic activity was porosity- and geometry-dependent for bare SiO(2) and surface-charge-dependent for amine-modified SiO(2). A good correlation between hemolytic activity and cellular association was found on a similar dosage basis. These results can provide useful guidelines for the rational design of SiO(2) in nanomedicine.

SUBMITTER: Yu T

PROVIDER: S-EPMC3238493 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Impact of silica nanoparticle design on cellular toxicity and hemolytic activity.

Yu Tian T Malugin Alexander A Ghandehari Hamidreza H

ACS nano 20110608 7

Understanding the toxicity of silica nanoparticles (SiO(2)) on the cellular level is crucial for rational design of these nanomaterials for biomedical applications. Herein, we explore the impacts of geometry, porosity, and surface charge of SiO(2) on cellular toxicity and hemolytic activity. Nonporous Stöber silica nanospheres (115 nm diameter), mesoporous silica nanospheres (120 nm diameter, aspect ratio 1), mesoporous silica nanorods with aspect ratio of 2, 4, and 8 (width by length 80 × 200 n ...[more]

PMID: 21630682

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Project description:We have developed structure/toxicity relationships for amorphous silica nanoparticles (NPs) synthesized through low-temperature colloidal (e.g., Stöber silica) or high-temperature pyrolysis (e.g., fumed silica) routes. Through combined spectroscopic and physical analyses, we have determined the state of aggregation, hydroxyl concentration, relative proportion of strained and unstrained siloxane rings, and potential to generate hydroxyl radicals for Stöber and fumed silica NPs with comparable primary particle sizes (16 nm in diameter). On the basis of erythrocyte hemolytic assays and assessment of the viability and ATP levels in epithelial and macrophage cells, we discovered for fumed silica an important toxicity relationship to postsynthesis thermal annealing or environmental exposure, whereas colloidal silicas were essentially nontoxic under identical treatment conditions. Specifically, we find for fumed silica a positive correlation of toxicity with hydroxyl concentration and its potential to generate reactive oxygen species (ROS) and cause red blood cell hemolysis. We propose fumed silica toxicity stems from its intrinsic population of strained three-membered rings (3MRs) along with its chainlike aggregation and hydroxyl content. Hydrogen-bonding and electrostatic interactions of the silanol surfaces of fumed silica aggregates with the extracellular plasma membrane cause membrane perturbations sensed by the Nalp3 inflammasome, whose subsequent activation leads to secretion of the cytokine IL-1?. Hydroxyl radicals generated by the strained 3MRs in fumed silica, but largely absent in colloidal silicas, may contribute to the inflammasome activation. Formation of colloidal silica into aggregates mimicking those of fumed silica had no effect on cell viability or hemolysis. This study emphasizes that not all amorphous silicas are created equal and that the unusual toxicity of fumed silica compared to that of colloidal silica derives from its framework and surface chemistry along with its fused chainlike morphology established by high-temperature synthesis (>1300 °C) and rapid thermal quenching.

Project description:BACKGROUND:Silica nanoparticles (SiNPs) are widely used for biosensing and diagnostics, and for the targeted delivery of therapeutic agents. Safety concerns about the biomedical and clinical applications of SiNPs have been raised, necessitating analysis of the effects of their intrinsic properties, such as sizes, shapes, and surface physicochemical characteristics, on human health to minimize risk in biomedical applications. In particular, SiNP size-associated toxicological effects, and the underlying molecular mechanisms in the vascular endothelium remain unclear. This study aimed to elucidate the detailed mechanisms underlying the cellular response to exposure to trace amounts of SiNPs and to determine applicable size criteria for biomedical application. METHODS:To clarify whether these SiNP-mediated cytotoxicity due to induction of apoptosis or necrosis, human ECs were treated with SiNPs of four different non-overlapping sizes under low serum-containing condition, stained with annexin V and propidium iodide (PI), and subjected to flow cytometric analysis (FACS). Two types of cell death mechanisms were assessed in terms of production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress induction, and autophagy activity. RESULTS:Spherical SiNPs had a diameter of 21.8 nm; this was further increased to 31.4, 42.9, and 56.7 nm. Hence, we investigated these effects in human endothelial cells (ECs) treated with these nanoparticles under overlap- or agglomerate-free conditions. The 20-nm SiNPs, but not SiNPs of other sizes, significantly induced apoptosis and necrosis. Surprisingly, the two types of cell death occurred independently and through different mechanisms. Apoptotic cell death resulted from ROS-mediated ER stress. Furthermore, autophagy-mediated necrotic cell death was induced through the PI3K/AKT/eNOS signaling axis. Together, the present results indicate that SiNPs within a diameter of?<?20-nm pose greater risks to cells in terms of cytotoxic effects. CONCLUSION:These data provide novel insights into the size-dependence of the cytotoxic effects of silica nanoparticles and the underlying molecular mechanisms. The findings are expected to inform the applicable size range of SiNPs to ensure their safety in biomedical and clinical applications.

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Impact of silica nanoparticle design on cellular toxicity and hemolytic activity.

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Impact of silica nanoparticle design on cellular toxicity and hemolytic activity.

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