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Nanomaterials are engineered structures with at least one dimension of 100 nanometers or less. These materials are increasingly being used for commercial purposes such as fillers, opacifiers, catalysts, semiconductors, cosmetics, microelectronics, and drug carriers. Materials in this size range may approach the length scale at which some specific physical or chemical interactions with their environment can occur. As a result, their properties differ substantially from those bulk materials of the same composition, allowing them to perform exceptional feats of conductivity, reactivity, and optical sensitivity. Possible undesirable results of these capabilities are harmful interactions with biological systems and the environment, with the potential to generate toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials in the marketplace is urgently required and achievable.

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Toxic Potential of Materials at the Nanolevel

Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older bio-kinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.

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Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles

Rapid growth in nanotechnology is increasing the likelihood of engineered nanomaterials coming into contact with humans and the environment. Nanoparticles interacting with proteins, membranes, cells, DNA and organelles establish a series of nanoparticle/biological interfaces that depend on colloidal forces as well as dynamic biophysicochemical interactions. These interactions lead to the formation of protein coronas, particle wrapping, intracellular uptake and biocatalytic processes that could have biocompatible or bioadverse outcomes. For their part, the biomolecules may induce phase transformations, free energy releases, restructuring and dissolution at the nanomaterial surface. Probing these various interfaces allows the development of predictive relationships between structure and activity that are determined by nanomaterial properties such as size, shape, surface chemistry, roughness and surface coatings. This knowledge is important from the perspective of safe use of nanomaterials.

Understanding biophysicochemical interactions at the nano–bio interface

Liposomes — microscopic phospholipid bubbles with a bilayered membrane structure — have received a lot of attention during the past 30 years as pharmaceutical carriers of great potential. More recently, many new developments have been seen in the area of liposomal drugs — from clinically approved products to new experimental applications, with gene delivery and cancer therapy still being the principal areas of interest. For further successful development of this field, promising trends must be identified and exploited, albeit with a clear understanding of the limitations of these approaches.

Recent advances with liposomes as pharmaceutical carriers.

The kinetics and extent of low-pH induced fusion of influenza virus and Sendai virus with large unilamellar liposomes were investigated with fluorescence assays for lipid mixing. The model views the overall fusion reaction as a sequence of a second-order process of virus-liposome aggregation, which is partially reversible, followed by the first-order fusion reaction itself. The calculations gave good simulations and predictions for the kinetics and extent of fusion at different virus/liposome concentrations and ratios, and provided a pattern of the dependence of viral fusion activity on liposome composition, i.e., acidic and neutral phospholipids, cholesterol and gangliosides. The fusion products consist of a single virus particle and several liposomes, indicating negative cooperativity between viral glycoproteins and those present in the fusion products. At pH 5.0 and 37°C very high rate constants for aggregation and fusion were obtained and essentially all of the virus particles were capable of fusing with cardiolipin liposomes. At higher pH values the rate constants of fusion were considerably smaller for all liposome compositions and the percent of virus particles capable of fusing was lowered, whereas the aggregation rate constants were only moderately affected. The fusion activity of influenza virus was reduced by its exposure to low pH, The inactivation reflected intramembrane events and was independent of virus concentrations. A mode of virus inactivation due to formation of clusters of glycoproteins in its membrane at low pH is consistent with our results.

Kinetics and Extent of Fusion of Influenza Virus and Sendai Virus with Liposomes

Phospholipid molecules constitute the essential building blocks of biological membranes. They are arranged according to a bilayer structure while membrane proteins are embedded in or attached to this double layer of lipid molecules. Besides phospholipids, eukaryotic cell and organelle membranes may contain two other lipid classes:cholesterol and glycosphingolipids. As may be anticipated, proteins and the various lipid classes are not uniformly distributed among membranes, given the distinct functions of the intracellular organelles. Yet, de novo biosynthesis of both lipids and proteins occurs primarily at the endoplasmic reticulum. This implies that specific mechanisms must exist that determine the fate and distribution of these compounds among membranes. Obviously, this sets particular requirements to intracellular sorting and transport phenomena.

Transport of Lipids and Proteins During Membrane Flow in Eukaryotic Cells

Cell and model membrane interactions

An essential prerequisite for a virus to infect a cell is its ability to deposit the nucleocapsid into the cytoplasm of that ‘host’-cell. In the case of enveloped viruses, the nucleocapsid is surrounded by a membrane, consisting of a lipid bilayer that resembles the plasma membrane composition of the host-cell in which the virus was grown, and a unique set of virus-specific membrane proteins. To get access to the cytoplasm, the nucleocapsid must therefore traverse two membrane barriers. To accomplish this crossing, a virus uses a most efficient mechanism, namely membrane fusion. The cellular site where this fusion process occurs depends on the family to which the virus belongs. Some virions (for example, those belonging to the paramyxoviruses such as Sendai virus, Newcastle disease virus and measles virus) fuse directly with the plasma membrane at neutral pH. Most viruses, however, are first internalized by receptor-mediated endocytosis and subsequently fuse in the endosomal compartment ‘from within’ (Fig. 1). It has been shown that these viruses [such as orthomyxoviruses (influenza), toga viruses (Semliki Forest virus, SFV), and rhabdoviruses (vesicular stomatitus virus, VSV)] require a mild acidic pH in order to acquire fusogenic capacity (White et al., 1983).

Significance of hydrophobic interactions in membrane fusion of enveloped viruses

https://www.jbc.org/content/284/31/20773.full.pdf

Dick Hoekstra

Papers

Kinetics and Extent of Fusion of Influenza Virus and Sendai Virus with Liposomes

Transport of Lipids and Proteins During Membrane Flow in Eukaryotic Cells

Cell and model membrane interactions

Significance of hydrophobic interactions in membrane fusion of enveloped viruses

Regulatory subunit I-controlled protein kinase A activity is required for apical bile canalicular lumen development in hepatocytes.