General Nanotoxicity Mechanism

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General Nanotoxicity Mechanism

The  use and investigation of nanomaterials for novel biomedical applications has  been increasing rapidly in last few years. One may concern limited the usage of  nanomaterials is their toxicology to the human body and environment. Some susceptible groups, such as diseased, neonate, pregnant,  and aged populations, are more easily suffering from the exposure to  nanomaterials due to their compromised immunity, reduced protection mechanism,  and impaired self-repair ability. A variety of instinct properties of nanoparticles  may affect their nanotoxicity, such as size, surface, shape, charges, functional  groups, chemical composites, UV light activation, aggregation and dissolution, and  their interaction with cells. The detailed mechanisms and effects cytotoxicity,  genotoxicity, and immunotoxicity of nanoparticles have not yet been fully clear.  But some general mechanisms are discussed below, such as the overproduction of  ROS, inflammation, non-degradation or self-degradation, and change in cell  morphology and cytoskeleton network. In order to use nanomaterials in a safe  and well-controlled manner to benefit of mankind, long-term nanotoxicity  studies are required, as well as optimizing properties of nanoparticles to  reduce and even diminish the toxicity.

1. Overproduction of ROS

The  generation of the reactive oxygen species (ROS) is considered to be the  foremost mechanism of nanotoxicity. In general, most cell types can tolerate  the small and transient increases of ROS. However, high levels or long time  enhanced level of ROS will cause cell damage. When exposed to nanoparticles,  cells will significantly overproduce ROS, resulting in the generation of oxidative  stress. ROS can interact with cellular macromolecules including functional  proteins and DNA, resulting in the signal transductions disruption and  dysfunction. Therefore, these overproduce ROS-affected cells may fail to  maintain their normal physiological functions, which lead to the unregulated  cell signaling, change in cell motility, DNA damage, autophagy, apoptosis, necrosis,  fibrosis, and carcinogenesis. The induction of ROS has also been frequently reported  for a variety of nanoparticles, especially metal- and carbon- based nanoparticles.  For example, quantum dots and carbon nanotubes have been frequently reported to  show their nanotoxicity due to the induced ROS overproduction.

2. Inflammation-Mediated  Nanotoxicity

Immune  system is the first safeguard and self-defense mechanism of the human body to  resist the potential toxicity of the infection, malignancy, and exogenous  agents. The exposure to nanoparticles often causes some immune perturbation, for  example, elevate or suppress the immune response. The immune toxicity of  nanoparticles is also related to the ROS generation. Studies have shown that upon  the exposure of nanoparticles, mitochondria can produce ROS and trigger the  activation of inflammasomes in phagocytic cells. The phagocyte-derived ROS are  also known to injure human tissues and to contribute to inflammatory response. Inflammation  has been shown to be an important cause of toxicity and promote cell death. For  example, the production of a variety of pro-inflammatory cytokines, such as  TNF-a, IL-1, and IL-8, will end up with induced-apoptosis and autophagy. Some  studies showed that the lipid-based nanoparticles can activate the complement  cascade and lead to hypersensitivity reactions and anaphylaxis.

3. Nanoparticle Degradability

For  nanoparticles, some of them can be degraded easily in the human body microenvironment  while some other are non-degradable or slow degradable and will accumulate in  the organs or cells leading to some unknown long-term toxic effect. One major  concern is the potential interaction or interference of nanoparticles with various  biological processes. The small size, high surface area, and high local charge  densities can make nanoparticles easily interact with surrounding biological  molecules. For example, the surface charges on nanoparticles can favor their binding  of serum enzymes, leading to a so-called protein corona and affect enzymatic regulatory  mechanisms.

For degradable nanoparticles, their intracellular toxic  effect is also one of the important mechanisms. The destabilization of  nanoparticle can lead to the release of toxic components and the change the microenvironment  in the body. In general, nanoparticles can be internalized by cells via endocytic  mechanisms. The pH values in endosomes (pH~6) and lysosomes (pH~4.5) are much  lower than the extracellular environment (pH~7). The local pH change and the  presence of degradative enzymes in the cells, such as cathepsin L, make some  nanoparticles degradable and lose their coating on their surface. For example,  studies have shown that some iron oxide nanoparticles are acid etching in the acidic  environment of the endosomes and generate free ions, resulting in the decrease  of the size, the loss of their magnetic function, and even effects on cell  homeostasis. Quantum dots have also been found to be acid etching by the  physiologically relevant concentrations of hydrogen peroxide and hypochlorous  acid, which are the products of phagocytes.

4. Cell Morphology and Cytoskeleton Defects

Although the detailed mechanism is still unclear, nanoparticles  with certain physical dimensions can alter the cellular morphology or affect the  cellular functional components such  as the cytoskeleton network, mitochondria, and synaptic machinery. It is a  common sense that cell functions are based on the normal morphology  and well-functional of all components. The cytoskeleton plays a significant role  in cell shape, motility, division cells-extracellular  matrix adhesive interaction, and neuronal architecture formation. The  cytoskeletal deformations will decrease the capacity of cell functions. For  example, silver particles have been shown to induce  neurotoxicity by disrupting destruct tubulin and actin cytoskeletal proteins,  dissolving synaptic proteins, and compromising mitochondria function.

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