Suppression of nanoparticle cytotoxicity approaching in vivo serum concentrations: limitations of in vitro testing for nanosafety

Kim, Jong Ah; Salvati, Anna; Åberg, Christoffer; Dawson, Kenneth A.

doi:10.1039/c4nr04970e

Cited by 82 publications

(94 citation statements)

References 34 publications

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“…Also, Wang et al have shown that the protein corona protects the cells from damage until the corona proteins are degraded within lysosomes [63]. We observed that the membrane damage induced by 25 nm SNPs in serum-free medium was reduced not only by addition of serum, like also observed by Kim et al [64], but also after addition of single-serum proteins like BSA (bovine serum albumin) (Additional file 5). These results agree well with the research performed by Gualtieri et al which revealed a reduced cytotoxicity of SNPs in the presence of BSA and demonstrated that the surface coating of the particles is primarily responsible for the protective effect [62].…”

Section: Discussionsupporting

confidence: 81%

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Quantification of Internalized Silica Nanoparticles via STED Microscopy

Peuschel

Ruckelshausen

Cavelius

et al. 2015

BioMed Research International

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The development of safe engineered nanoparticles (NPs) requires a detailed understanding of their interaction mechanisms on a cellular level. Therefore, quantification of NP internalization is crucial to predict the potential impact of intracellular NP doses, providing essential information for risk assessment as well as for drug delivery applications. In this study, the internalization of 25 nm and 85 nm silica nanoparticles (SNPs) in alveolar type II cells (A549) was quantified by application of super-resolution STED (stimulated emission depletion) microscopy. Cells were exposed to equal particle number concentrations (9.2 × 1010 particles mL−1) of each particle size and the sedimentation of particles during exposure was taken into account. Microscopy images revealed that particles of both sizes entered the cells after 5 h incubation in serum supplemented and serum-free medium. According to the in vitro sedimentation, diffusion, and dosimetry (ISDD) model 20–27% of the particles sedimented. In comparison, 102-103 NPs per cell were detected intracellularly serum-containing medium. Furthermore, in the presence of serum, no cytotoxicity was induced by the SNPs. In serum-free medium, large agglomerates of both particle sizes covered the cells whereas only high concentrations (≥ 3.8 × 1012 particles mL−1) of the smaller particles induced cytotoxicity.

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Section: Discussionsupporting

confidence: 81%

“…This should be taken into account when comparing results of different studies. In comparison to other studies using commercial nanoparticles or even larger particles [11, 64], the nanoparticles used in this study were custom-made, corroborating the generality of the protective effect of the protein corona.…”

Section: Discussionsupporting

confidence: 78%

Quantification of Internalized Silica Nanoparticles via STED Microscopy

Peuschel

Ruckelshausen

Cavelius

et al. 2015

BioMed Research International

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“…Furthermore, nanoparticle size and crystalline structure have been studied as underlying characteristics for nanoparticle toxicity. 27–30 TEM images demonstrated that anatase TiO 2 nanoparticles had the characteristic spherical crystal structure while rutile nanoparticles had typical rod-like crystal structure (Fig 1). The anatase and rutile TiO 2 nanoparticles utilized for this study were both reported as 50 nm in diameter by the manufacturer, thus allowing for observations of crystal structure influence on nanoparticle toxicity independent of particle size.…”

Section: Resultsmentioning

confidence: 98%

Mitochondrial dysfunction and loss of glutamate uptake in primary astrocytes exposed to titanium dioxide nanoparticles

et al. 2015

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Titanium Dioxide (TiO2) nanoparticles is currently the second most produced engineered nanomaterial in the world with vast usage in consumer products leading to recurrent human exposure. Animal studies indicate significant nanoparticle accumulation in the brain while cellular toxicity studies demonstrate negative effects on neuronal cell viability and function. However, the toxicological effects of nanoparticles on astrocytes, the most abundant cells in the brain, have not been extensively investigated. Therefore, we determined the sub-toxic effect of three different TiO2 nanoparticles (rutile, anatase and commercially available P25 TiO2 nanoparticles) on primary rat cortical astrocytes. We evaluated some events related to astrocyte functions and mitochondrial dysregulation: (1) glutamate uptake; (2) redox signaling mechanisms by measuring ROS production; (3) the expression patterns of dynamin-related proteins (DRPs) and mitofusins 1 and 2, whose expression is central to mitochondrial dynamics; and (4) mitochondrial morphology by MitoTrackerR Red CMXRos staining. Anatase, rutile and P25 were found to have LC50 values of 88.22 ± 10.56 ppm, 136.0 ± 31.73 ppm and 62.37 ± 9.06 ppm respectively indicating nanoparticle specific toxicity. All three TiO2 nanoparticles induced a significant loss in glutamate uptake indicative of loss in vital astrocyte function. TiO2 nanoparticles also induced increase in reactive oxygen species generation, and decrease in mitochondrial membrane potential, suggesting mitochondria damage. TiO2 nanoparticle exposure altered expression patterns of DRPs at low concentrations (25 ppm) and apoptotic fission at high concentrations (100 ppm). TiO2 nanoparticles exposure also resulted in changes to mitochondrial morphology confirmed by mitochondrial staining. Collectively, our data provide compelling evidence that TiO2 nanoparticles exposure has potential implications in astrocytes-mediated neurological dysfunction.

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“…In last few years a wide range of nanoformulations have emerged although their translational impact overall has been disappointing with poor in vitro -in vivo correlation [128][129][130]. There are challenges in characterization of NPs under physiologically relevant conditions.…”

Section: Discussionmentioning

confidence: 99%