Research strategies for safety evaluation of nanomaterials, Part I: evaluating the human health implications of exposure to nanoscale materials.

Nanotechnology has the potential to dramatically improve the effectiveness of a number of existing consumer and industrial products and could have a substantial impact on the development of new products ranging from disease diagnosis and treatment to environmental remediation. The broad range of possible nanotechnology applications could lead to substantive changes in industrial productivity, economic growth, and international trade. A continuing evaluation of the human health implications of exposure to nanoscale materials will be essential before the commercial benefits of these materials can be fully realized. The purpose of this article is to review the human health implications of exposure to nanoscale materials in the context of a toxicological risk evaluation, the current scope of U.S. Federal research on nanoscale materials, and selected toxicological studies associated with nanoscale materials to note emerging research in this area.     

Zero-Valent Iron Nanoparticles Remediate Nickel-Contaminated Aqueous Solutions and Biosolids-Amended Agricultural Soil

Nickel (Ni⁺²) accumulation in wastewater treatment sludge poses a potential environmental risk with biosolids-land application. An incubation experiment was conducted to evaluate the effect of nanoparticles of zero-valent iron (nZVI) on Ni⁺² sorption in biosolids-treated agricultural soils. Two application rates of biosolids (0, 5%, w/w) and four treatment levels (0, 1, 5, and 10 g/kg) of nZVI were examined, either separately or interactively. The results of this study showed significant differences in Ni⁺² sorption capacity between different nZVI treatments. The initial Ni⁺² concentration in biosolids-amended soil significantly affected Ni sorption in the soil treated with nZVI. The “H-shape” of sorption isotherm in nZVI-treated soil reflects strong interaction between the Ni concentration and the nZVI treatment, while the C-shape of sorption isotherm in biosolids-amended soil without the nZVI treatment indicates intermediate affinity for Ni⁺² sorption. Nickel retention in soil was increased with the increase of nZVI levels. The removal efficiency of Ni⁺² by nZVI from solution was increased with the increase of pH from 5 to 11 and reached a maximum of 99.56% at pH 11 and nZVI treatment of 10 g/kg. The Ni⁺² desorption rate decreased from 92 to 7, 4, and 1% with increasing nZVI treatment levels from 0 to 1, 5, and 10 g/kg, respectively, with a soil Ni⁺² concentration of 50 mg/L. The maximum adsorption capacity (𝑞_max) of 10 g/kg nZVI-treated soil was 333.3 mg/g, which was much higher than those from the other treatments of 0 (5 mg/g), 1 (25 mg/g), and 5 g/kg (125 mg/g). The underlying mechanism for Ni⁺² immobilization using nZVI in an aquatic environment is controlled by a sorption process, reduction of metal ion to zero-valent metal, as well as (co)precipitation. Moreover, increasing the nZVI treatment level in biosolids-amended soil significantly decreased bioavailable Ni⁺² concentrations in the soil.     

Single-Molecule Super-Resolution Imaging of T-Cell Plasma Membrane CD4 Redistribution upon HIV-1 Binding

The first step of cellular entry for the human immunodeficiency virus type-1 (HIV-1) occurs through the binding of its envelope protein (Env) with the plasma membrane receptor CD4 and co-receptor CCR5 or CXCR4 on susceptible cells, primarily CD4⁺ T cells and macrophages. Although there is considerable knowledge of the molecular interactions between Env and host cell receptors that lead to successful fusion, the precise way in which HIV-1 receptors redistribute to sites of virus binding at the nanoscale remains unknown. Here, we quantitatively examine changes in the nanoscale organisation of CD4 on the surface of CD4⁺ T cells following HIV-1 binding. Using single-molecule super-resolution imaging, we show that CD4 molecules are distributed mostly as either individual molecules or small clusters of up to 4 molecules. Following virus binding, we observe a local 3-to-10-fold increase in cluster diameter and molecule number for virus-associated CD4 clusters. Moreover, a similar but smaller magnitude reorganisation of CD4 was also observed with recombinant gp120. For one of the first times, our results quantify the nanoscale CD4 reorganisation triggered by HIV-1 on host CD4⁺ T cells. Our quantitative approach provides a robust methodology for characterising the nanoscale organisation of plasma membrane receptors in general with the potential to link spatial organisation to function.     

Emerging concepts in dendrimer‐based nanomedicine: from design principles to clinical applications

Dendrimers are discrete nanostructures/nanoparticles with ‘onion skin‐like’ branched layers. Beginning with a core, these nanostructures grow in concentric layers to produce stepwise increases in size that are similar to the dimensions of many in vivo globular proteins. These branched tree‐like concentric layers are referred to as ‘generations’. The outer generation of each dendrimer presents a precise number of functional groups that may act as a monodispersed platform for engineering favourable nanoparticle–drug and nanoparticle–tissue interactions. These features have attracted significant attention in medicine as nanocarriers for traditional small drugs, proteins, DNA/RNA and in some instances as intrinsically active nanoscale drugs. Dendrimer‐based drugs, as well as diagnostic and imaging agents, are emerging as promising candidates for many nanomedicine applications. First, we will provide a brief survey of recent nanomedicines that are either approved or in the clinical approval process. This will be followed by an introduction to a new ‘nanoperiodic’ concept which proposes nanoparticle structure control and the engineering of ‘critical nanoscale design parameters’ (CNDPs) as a strategy for optimizing pharmocokinetics, pharmocodynamics and site‐specific targeting of disease. This paradigm has led to the emergence of CNDP‐directed nanoperiodic property patterns relating nanoparticle behaviour to critical in vivo clinical translation issues such as cellular uptake, transport, elimination, biodistribution, accumulation and nanotoxicology. With a focus on dendrimers, these CNDP‐directed nanoperiodic patterns are used as a strategy for designing and optimizing nanoparticles for a variety of drug delivery and imaging applications, including a recent dendrimer‐based theranostic nanodevice for imaging and treating cancer. Several emerging preclinical dendrimer‐based nanotherapy concepts related to inflammation, neuro‐inflammatory disorders, oncology and infectious and ocular diseases are reviewed. Finally we will consider challenges and opportunities anticipated for future clinical translation, nanotoxicology and the commercialization of nanomedicine.     

Research strategies for safety evaluation of nanomaterials, part VII: evaluating consumer exposure to nanoscale materials.

Considerable media attention has recently been given to novel applications for products that contain nanoscale materials. These products could have utility in several industries that market consumer products, including textiles, sporting equipment, cosmetics, consumer electronics, and household cleaners. Some of the purported benefits of these products include improved performance, convenience, lower cost, as well as other desirable features, when compared to the conventional products that do not contain nanoscale materials. Although there are numerous likely consumer advantages from products containing nanoscale materials, there is very little information available regarding consumer exposure to the nanoscale materials in these products or any associated risks from these exposures. This paper seeks to review a limited subset of products that contain nanoscale materials, assess the available data for evaluating the consumer exposures and potential hazards associated with these products, and discuss the capacity of U.S. regulatory agencies to address the potential risks associated with these products.     

Near-infrared-emissive polymersomes: self-assembled soft matter for in vivo optical imaging

We demonstrate that synthetic soft materials can extend the utility of natural vesicles, from predominantly hydrophilic reservoirs to functional colloidal carriers that facilitate the biomedical application of large aqueous-insoluble compounds. Near-infrared (NIR)-emissive polymersomes (50-nm- to 50-microm-diameter polymer vesicles) were generated through cooperative self assembly of amphiphilic diblock copolymers and conjugated multi(porphyrin)-based NIR fluorophores (NIRFs). When compared with natural vesicles comprised of phospholipids, polymersomes were uniquely capable of incorporating and uniformly distributing numerous large hydrophobic NIRFs exclusively in their lamellar membranes. Within these sequestered compartments, long polymer chains regulate the mean fluorophore-fluorophore interspatial separation as well as the fluorophore-localized electronic environment. Porphyrin-based NIRFs manifest photophysical properties within the polymersomal matrix akin to those established for these high-emission dipole strength fluorophores in organic solvents, thereby yielding uniquely emissive vesicles. Furthermore, the total fluorescence emanating from the assemblies gives rise to a localized optical signal of sufficient intensity to penetrate through the dense tumor tissue of a live animal. Robust NIR-emissive polymersomes thus define a soft matter platform with exceptional potential to facilitate deep-tissue fluorescence-based imaging for in vivo diagnostic and drug-delivery applications.     

Simulated atmospheric processing of iron oxyhydroxide minerals at low pH: Roles of particle size and acid anion in iron dissolution

A number of recent studies have shown that iron dissolution in Fe-containing dust aerosol can be linked to source material (mineral or anthropogenic), mineralogy, and iron speciation. All of these factors need to be incorporated into atmospheric chemistry models if these models are to accurately predict the impact of Fe-containing dusts into open ocean waters. In this report, we combine dissolution measurements along with spectroscopy and microscopy to focus on nanoscale size effects in the dissolution of Fe-containing minerals in low-pH environments and the importance of acid type, including HNO₃, H₂SO₄, and HCl, on dissolution. All of these acids are present in the atmosphere, and dust particles have been shown to be associated with nitrate, sulfate, and/or chloride. These measurements are done under light and dark conditions so as to simulate and distinguish between daytime and nighttime atmospheric chemical processing. Both size (nano- versus micron-sized particles) and anion (nitrate, sulfate, and chloride) are found to play significant roles in the dissolution of α-FeOOH under both light and dark conditions. The current study highlights these important, yet unconsidered, factors in the atmospheric processing of iron-containing mineral dust aerosol.     

Research strategies for safety evaluation of nanomaterials, Part III: nanoscale technologies for assessing risk and improving public health.

Risk assessment in the environmental health sciences focuses on understanding the nature of environmental exposures and the potential harm posed by those exposures which in turn is determined by the perturbation of biological pathways and the individual's susceptibility to damage. While there are extensive research efforts ongoing in these areas, progress in each is currently slowed by technological limitations including comprehensive assessment of multiple exposures in real time and dynamic assessment of biological response with high temporal and quantitative resolution. This Forum article discusses recent technological innovations capitalizing on the emergent properties of nanoscale materials and their potential adaptation to improving individual exposure assessment, determination of biological response, and environmental remediation. The ultimate goal is to raise the environmental health science community's awareness of these possibilities and encourage the development of improved strategies for assessing risk and improving public health.