An understanding of the interactions between nanoparticles and biological systems is of significant interest. Studies aimed at correlating the properties of nanomaterials such as size, shape, chemical functionality, surface charge, and composition with biomolecular signaling, biological kinetics, transportation, and toxicity in both cell culture and animal experiments are under way. These fundamental studies will provide a foundation for engineering the next generation of nanoscale devices. Here, we provide rationales for these studies, review the current progress in studies of the interactions of nanomaterials with biological systems, and provide a perspective on the long-term implications of these findings.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-bioeng-071811-150124

The effect of nanoparticle size, shape, and surface chemistry on biological systems.

Human exposure to nanoparticles is inevitable as nanoparticles become more widely used and, as a result, nanotoxicology research is now gaining attention. However, while the number of nanoparticle types and applications continues to increase, studies to characterize their effects after exposure and to address their potential toxicity are few in comparison. In the medical field in particular, nanoparticles are being utilized in diagnostic and therapeutic tools to better understand, detect, and treat human diseases. Exposure to nanoparticles for medical purposes involves intentional contact or administration; therefore, understanding the properties of nanoparticles and their effect on the body is crucial before clinical use can occur. This Review presents a summary of the in vitro cytotoxicity data currently available on three classes of nanoparticles. With each of these nanoparticles, different data has been published about their cytotoxicity due to varying experimental conditions as well as differing nanoparticle physiochemical properties. For nanoparticles to move into the clinical arena, it is important that nanotoxicology research uncovers and understands how these multiple factors influence the toxicity of nanoparticles so that their undesirable properties can be avoided.

Cytotoxicity of Nanoparticles

Many types of nanoparticles (NPs) are tested for use in medical products, particularly in imaging and gene and drug delivery. For these applications, cellular uptake is usually a prerequisite and is governed in addition to size by surface characteristics such as hydrophobicity and charge. Although positive charge appears to improve the efficacy of imaging, gene transfer, and drug delivery, a higher cytotoxicity of such constructs has been reported. This review summarizes findings on the role of surface charge on cytotoxicity in general, action on specific cellular targets, modes of toxic action, cellular uptake, and intracellular localization of NPs. Effects of serum and intercell type differences are addressed. Cationic NPs cause more pronounced disruption of plasma-membrane integrity, stronger mitochondrial and lysosomal damage, and a higher number of autophagosomes than anionic NPs. In general, nonphagocytic cells ingest cationic NPs to a higher extent, but charge density and hydrophobicity are equally important; phagocytic cells preferentially take up anionic NPs. Cells do not use different uptake routes for cationic and anionic NPs, but high uptake rates are usually linked to greater biological effects. The different uptake preferences of phagocytic and nonphagocytic cells for cationic and anionic NPs may influence the efficacy and selectivity of NPs for drug delivery and imaging.

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The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles.

There is extensive experimental evidence that oxidative damage permanently occurs to lipids of cellular membranes, proteins, and DNA. In nuclear and mitochondrial DNA, 8-hydroxy-2' -deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2' -deoxyguanosine (8-oxodG) is one of the predominant forms of free radical-induced oxidative lesions, and has therefore been widely used as a biomarker for oxidative stress and carcinogenesis. Studies showed that urinary 8-OHdG is a good biomarker for risk assessment of various cancers and degenerative diseases. The most widely used method of quantitative analysis is high-performance liquid chromatography (HPLC) with electrochemical detection (EC), gas chromatography-mass spectrometry (GC-MS), and HPLC tandem mass spectrometry. In order to resolve the methodological problems encountered in measuring quantitatively 8-OHdG, the European Standards Committee for Oxidative DNA Damage was set up in 1997 to resolve the artifactual oxidation problems during the procedures of isolation and purification of oxidative DNA products. The biomarker 8-OHdG or 8-oxodG has been a pivotal marker for measuring the effect of endogenous oxidative damage to DNA and as a factor of initiation and promotion of carcinogenesis. The biomarker has been used to estimate the DNA damage in humans after exposure to cancer-causing agents, such as tobacco smoke, asbestos fibers, heavy metals, and polycyclic aromatic hydrocarbons. In recent years, 8-OHdG has been used widely in many studies not only as a biomarker for the measurement of endogenous oxidative DNA damage but also as a risk factor for many diseases including cancer.

/pdf/8-hydroxy-2-deoxyguanosine-8-ohdg-a-critical-biomarker-of-45fgr7zv9y.pdf

8-hydroxy-2' -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis.

Gold nanoparticles have attracted enormous scientific and technological interest due to their ease of synthesis, chemical stability, and unique optical properties. Proof-of-concept studies demonstrate their biomedical applications in chemical sensing, biological imaging, drug delivery, and cancer treatment. Knowledge about their potential toxicity and health impact is essential before these nanomaterials can be used in real clinical settings. Furthermore, the underlying interactions of these nanomaterials with physiological fluids is a key feature of understanding their biological impact, and these interactions can perhaps be exploited to mitigate unwanted toxic effects. In this Perspective we discuss recent results that address the toxicity of gold nanoparticles both in vitro and in vivo, and we provide some experimental recommendations for future research at the interface of nanotechnology and biological systems.

/pdf/toxicity-and-cellular-uptake-of-gold-nanoparticles-what-we-3wmuqcjs9l.pdf

Toxicity and cellular uptake of gold nanoparticles: what we have learned so far?

Nanotechnology makes use of the special surface properties of extremely small particles. In this rapidly growing field, many different materials are produced for a multitude of diverse applications. Possible adverse health effects of these materials however are so far scarcely investigated and are therefore a special task of toxicology. Although strategies for risk assessment have been suggested, the authors of the current review emphasize the fact that on the cellular, subcellular and molecular levels, interactions between nanoparticles (NP) and target cells relevant for the induction of possible adverse health effects are poorly understood. On the basis of existing literature, the potentially most relevant cellular target sites of NP as well as the so far known major molecular events specifically induced by these xenobiotics are reviewed. Starting with NP uptake across the cell membrane, mechanisms of generation of reactive oxygen species and the activation of redox-sensitive signalling cascades are des...

Cellular responses to nanoparticles: Target structures and mechanisms

Rationale: Inflammatory reactions of the airways induced by nanoparticles of occupational and environmental origin contribute to organ-specific and systemic human diseases. Because this kind of exposure in modern societies is often unavoidable, a strategy of molecular prevention on an individual level could help to prevent inflammation-derived secondary diseases.Objectives: To test whether the compatible solute ectoine [(S)-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid], which is known to reduce cell stress effects on a molecular level, prevents nanoparticle-induced lung inflammation.Methods: Inflammatory parameters were studied in Fischer 344 rats treated with model carbon nanoparticles. The molecular effects of ectoin on proinflammatory signal transduction were demonstrated in the rat and in the human system using cultured lung epithelial cells.Measurements and Main Results: Ectoine, given with or before the nanoparticles, dose-dependently reduced neutrophil inflammation in the lung. This prev...

The Compatible Solute Ectoine Protects against Nanoparticle-induced Neutrophilic Lung Inflammation

DNA damage due to reactive oxygen or nitrogen species is proposed to be involved in the molecular mechanism of asbestos-induced carcinogenicity. However, indications for this hypothesis came mainly from in vitro assays using cultured cells or cell-free systems. In the present study, the mutagenicity of crocidolite fibers and the underlying molecular mechanisms were investigated in vivo. Mutation frequencies were determined in DNA of omenta, a relevant target tissue for mesothelioma carcinogenesis, using lacI transgenic rats. The mutagenic effect of 2 and 5 mg of crocidolite asbestos was demonstrated, with a maximal relative increase in mutation frequency of 3.4 compared with the control group. The molecular analysis of the mutations revealed striking differences according to mutation types between asbestos-induced mutations and spontaneous mutations. Therefore, a specific molecular mechanism induced by crocidolite that differs from that induced by the generation of spontaneous mutations can be proposed. G to T transversions, which are known to be induced by the premutagenic DNA adduct 8-hydroxydeoxyguanosine (8-OHdG), were the most prominent mutation type (29%) within crocidolite-induced mutations. In additional experiments, 8-OHdG in DNA of omenta from rats treated with 1 or 2 mg of crocidolite asbestos was determined. Levels of 8-OHdG in animals treated with crocidolite were significantly increased compared with negative controls. These data give strong evidence for the involvement of reactive oxygen or nitrogen species in crocidolite-induced mutagenesis in vivo.

https://cancerres.aacrjournals.org/content/canres/62/1/99.full.pdf

Distinct Spectrum of Mutations Induced by Crocidolite Asbestos: Clue for 8-Hydroxydeoxyguanosine-dependent Mutagenesis in Vivo

Apoptosis and proliferation are important causes of adverse health effects induced by inhaled ultrafine particles. The molecular mechanisms of particle cell interactions mediating these end points ...

Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R

Human malignant mesotheliomas are induced almost exclusively by fibrous dusts. The nature of interactions between fibers and target cells, and the molecular mechanisms leading to tumorigenesis, are not yet understood. Here, the mRNA expression patterns at different stages of asbestos-induced carcinogenesis in rats were monitored by suppression subtractive hybridization (SSH) and array assay. Several genes were upregulated in pretumorous tissues from asbestos-treated rats, in asbestos-induced tumors and in cells treated with asbestos in vitro. The upregulation of the proto-oncogene c-myc, fra-1 and egfr in fiber-induced carcinogenesis was demonstrated at different stages of carcinogenesis. A possible role of Fra-1 as one of the dimeric proteins generating the AP-1 transcription factor was substantiated by its dose-dependent expression in mesothelial cells treated with asbestos in vitro. The upregulation of osteopontin (an extracellular matrix protein) and of zyxin and integrin-linked kinase (intracellular proteins associated with the focal adhesion contact), indicate that fibers may affect integrin-linked signal transduction and extracellular matrix proteins.

Klaus Unfried

Papers

Cellular responses to nanoparticles: Target structures and mechanisms

The Compatible Solute Ectoine Protects against Nanoparticle-induced Neutrophilic Lung Inflammation

Distinct Spectrum of Mutations Induced by Crocidolite Asbestos: Clue for 8-Hydroxydeoxyguanosine-dependent Mutagenesis in Vivo

Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R

mRNA expression patterns in different stages of asbestos-induced carcinogenesis in rats.