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

Abstract

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.

Keywords: cellular signaling; nanoparticles (NPs); reactive oxygen species (ROS); regenerative medicine; stem cells; toxicity.

Figure 1

Sources of Reactive oxygen species (ROS) generation. (A) Descriptive diagram outlining the extracellular and intracellular sources of ROS generation. The extracellular sources of ROS are represented by environmental pollutants, radiation exposure, microbial infection, and exposure to engineered Nanoparticles (NPs). Intracellular ROS can be generated from the mitochodria, endoplasmic reticulum (ER) stress, cellular-metabolizing enzymes, and the NOX family; and (B) a schematic diagram summarizing the formation of ROS from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochodria and the mechanisms involved in ROS scavenging of ROS. NOX: NADPH oxidase; SOD: superoxide dismutase; CAT: catalase; GPX: glutathione peroxidase; e⁻: electron; GR: glutathione reductase; Cyto-c: cytochrome c; and GSSG: Glutathione disulfide.

Figure 1

Sources of Reactive oxygen species (ROS) generation. (A) Descriptive diagram outlining the extracellular and intracellular sources of ROS generation. The extracellular sources of ROS are represented by environmental pollutants, radiation exposure, microbial infection, and exposure to engineered Nanoparticles (NPs). Intracellular ROS can be generated from the mitochodria, endoplasmic reticulum (ER) stress, cellular-metabolizing enzymes, and the NOX family; and (B) a schematic diagram summarizing the formation of ROS from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochodria and the mechanisms involved in ROS scavenging of ROS. NOX: NADPH oxidase; SOD: superoxide dismutase; CAT: catalase; GPX: glutathione peroxidase; e⁻: electron; GR: glutathione reductase; Cyto-c: cytochrome c; and GSSG: Glutathione disulfide.

Figure 2

The biomedical applications of metallic NPs and the mechanisms of NP-mediated ROS generation. (A) Summary of the nanomaterial applications in the medical field; (B) schematic diagram describing the mechanisms implicated in NP-induced ROS production. NPs can be internalized into the cell by (1) endocytosis; (2) formation of the endocytotic vesicles; and (3) release of particle ions from vesicles into the cell. The main factors responsible for ROS generation by NPs include: (a) interaction with the mitochodria; (b) interaction with NADPH oxidase; and (c) factors related to the physicochemical properties (size, shape, photoreactive properties, and surface chemistry). These factors lead to ROS generation and its consequences, including DNA damage, cell cycle arrest, alterations in apoptosis, and damage to the cell membrane.

Figure 2

The biomedical applications of metallic NPs and the mechanisms of NP-mediated ROS generation. (A) Summary of the nanomaterial applications in the medical field; (B) schematic diagram describing the mechanisms implicated in NP-induced ROS production. NPs can be internalized into the cell by (1) endocytosis; (2) formation of the endocytotic vesicles; and (3) release of particle ions from vesicles into the cell. The main factors responsible for ROS generation by NPs include: (a) interaction with the mitochodria; (b) interaction with NADPH oxidase; and (c) factors related to the physicochemical properties (size, shape, photoreactive properties, and surface chemistry). These factors lead to ROS generation and its consequences, including DNA damage, cell cycle arrest, alterations in apoptosis, and damage to the cell membrane.

Figure 3

TiO₂ NPs-induced ROS generation in human epidermal cells. Left panel showing 2′,7′-dichlorodihydrofluorescein diacetate (H₂DCFDA) staining for dose-dependent ROS generation in TiO₂ NPs-treated human epidermal cells (Magnification ×200). Right panel summarizing the role of ROS in TiO₂-induced cell death in human epidermal cells. (A) Control-untreated cells; (B–D) dose-dependent exposure to TiO₂ NPs. Right panel describing the proposed mechanism of ROS-mediated cytotoxicity in TiO₂ NPs-treated human epidermal cells. (Reproduced from [123] with permission of Elsevier and Copyright Clearance Center).

Figure 4

Diagram presenting the role of ROS production in the antimicrobial mechanism of IONPs against Escherichia coli and Bacillus subtilis. (Reproduced from [139], Copyright (2016) Creative Commons Attribution 4.0 International).

Figure 5

AgNP-exposed SH-SY5Y cells showed significant ROS production. Upper panel showing the readings of ROS level by spectrophotometer of dose-dependent treatment of AgNP. Lower panel presenting the fluorescent intensities of H₂DCFDA staining (Scale bars, 200 μm). * p < 0.05; ** p < 0.01; and NAC: N-acetyl cysteine. (Reproduced from [140] with permission of Copyright Wiley-VCH Verlag GmbH and Co. KGaA).

Figure 6

ROS scavenging potential of nanoceria in hydrogen peroxide H₂O₂-exposed L-132. (i) Control-untreated cell line; (ii) H₂O₂- exposed cells; (iii–vii) Time dependent BCNPs pretreatment in H₂O₂- exposed cells (Scale bars, 50 μm). (Reproduced from [158] with permission of The Royal Society of Chemistry).