Metal-Based Nanoparticle Interactions with the Nervous System: The Challenge of Brain Entry and the Risk of Retention in the Organism

This review of metal-based nanoparticles focuses on factors influencing their distribution into the nervous system, evidence they enter brain parenchyma, and nervous system responses. Gold is emphasized as a model metal-based nanoparticle and for risk assessment in the companion review. The anatomy and physiology of the nervous system, basics of colloid chemistry, and environmental factors that influence what cells see are reviewed to provide background on the biological, physical–chemical, and internal milieu factors that influence nervous system nanoparticle uptake. The results of literature searches reveal little nanoparticle research included the nervous system, which about equally involved in vitro and in vivo methods, and very few human studies. The routes of uptake into the nervous system and mechanisms of nanoparticle uptake by cells are presented with examples. Brain nanoparticle uptake inversely correlates with size. The influence of shape has not been reported. Surface charge has not been clearly shown to affect flux across the blood-brain barrier. There is very little evidence for metal-based nanoparticle distribution into brain parenchyma. Metal-based nanoparticle disruption of the blood-brain barrier and adverse brain changes have been shown, and are more pronounced for spheres than rods. Study concentrations need to be put in exposure contexts. Work with dorsal root ganglion cells and brain cells in vitro show the potential for metal-based nanoparticles to produce toxicity. Interpretation of these results must consider the ability of nanoparticles to distribute across the barriers protecting the nervous system. Effects of the persistence of poorly soluble metal-based nanoparticles are of particular concern

Carboxylic acids and light interact to affect nanoceria stability and dissolution in acidic aqueous environments

Cerium atoms on the surfaces of nanoceria (i.e., cerium oxide in the form of nanoparticles) can store or release oxygen, cycling between Ce3+ and Ce4+; therefore, they can cause or relieve oxidative stress within living systems. Nanoceria dissolution occurs in acidic environments. Nanoceria stabilization is a known problem even during its synthesis; in fact, a carboxylic acid, namely citric acid, is used in many synthesis protocols. Citric acid adsorbs onto nanoceria surfaces, limiting particle formation and creating stable dispersions with extended shelf life. To better understand factors influencing the fate of nanoceria, its dissolution and stabilization have been previously studied in vitro using acidic aqueous environments. Nanoceria agglomerated in the presence of some carboxylic acids over 30 weeks, and degraded in others, at pH 4.5 (i.e., the pH value in phagolysosomes). Plants release carboxylic acids, and cerium carboxylates are found in underground and aerial plant parts. To further test nanoceria stability, suspensions were exposed to light and dark conditions, simulating plant environments and biological systems. Light induced nanoceria agglomeration in the presence of some carboxylic acids. Nanoceria agglomeration did not occur in the dark in the presence of most carboxylic acids. Light initiates free radicals generated by ceria nanoparticles. Nanoceria completely dissolved in the presence of citric, malic, and isocitric acid when exposed to light, attributed to nanoceria dissolution, release of Ce3+ ions, and formation of cerium coordination complexes on the ceria nanoparticle surface that inhibit agglomeration. Key functional groups of carboxylic acids that prevented nanoceria agglomeration were identified. A long carbon chain backbone containing a carboxylic acid group geminal to a hydroxy group in addition to a second carboxylic acid group may optimally complex with nanoceria. The results provide mechanistic insight into the role of carboxylic acids in nanoceria dissolution and its fate in soils, plants, and biological systems

Method for Improving Consolidation of Powder Resin

A method for improving consolidation of powder resin is provided. The method broadly includes the steps of: (1) sorting particles of the powder resin according to their diameter; (2) combining the sorted particles having a first diameter D1 with the sorted particles having a second diameter D2 so as to form a particle mixture; (3) applying a vibration to the particle mixture; (4) heating the particle mixture; and (5) delivering the particle mixture through a nozzle or into a mold. The particle diameters D1 and D2 are chosen so that once combined there is optimal close packing of the three-dimensional spaces between the powder resin particles

Toward Tuning the Surface Functionalization of Small Ceria Nanoparticles

Understanding and controlling the performance of ceria nanoparticle (CNP) catalysts requires knowledge of the detailed structure and property of CNP surfaces and any attached functional groups. Here we report thermogravimetric analysis results showing that hydrothermally synthesized ∼30 nm CNPs are decorated with 12.9 hydroxyl groups per nm2 of CNP surface.Quantum mechanical calculations of the density and distribution of bound surface groups imply a scaling relationship for surface group density that balances formal charges in the functionalized CNP system. Computational results for CNPs with only hydroxyl surface groups yield a predicted density of bound hydroxyl groups for ∼30 nm CNPs that is ∼33% higher than measured densities. Quantitative agreement between predicted and measured hydroxylsurface densities is achieved when calculations consider CNPs with both –OH and –Ox surface groups. For this more general treatment of CNP surface functionalizations, quantum mechanical calculations predict a range of stable surface group configurations that depend on the chemical potentials of O and H, and demonstrate the potential to tune CNP surfacefunctionalizations by varying temperature and/or partial pressures of O2 and H2O

Applying Accelerator Mass Spectrometry for Low-Level Detection of Complex Engineered Nanoparticles in Biological Media

Complex engineered nanoparticles (CENPs), which have different core and surface components, are being developed for medicinal, pharmaceutical and industrial applications. One of the key challenges for environmental health and safety assessments of CENPs is to identify and quantity their transformations in biological environments. This study reports the effects of in vivo exposure of citrate-coated nanoalumina with different rare isotope labels on each component. This CENP was dosed to the rat and accelerator mass spectrometry (AMS) was used to quantify 26Al, 14C, and their ratio in the dosing material and tissue samples. For CENPs detected in the liver, the rare isotope ratio, 14C/26Al, was 87% of the dosing material\u27s ratio. The citrate coating on the nanoalumina in the liver was stable or, if it degraded, its metabolites were incorporated with nearby tissues. However, in brain and bone where little alumina was detected, the rare isotope ratio greatly exceeded that of the dosing material. Therefore, in the animal, citrate dissociated from CENPs and redistributed to brain and bone. Tracking both the core and surface components by AMS presents a new approach for characterizing transformations of CENPs components in biological milieu or environments

Brain Microvascular Endothelial Cell Association and Distribution of a 5 nm Ceria Engineered Nanomaterial

PURPOSE: Ceria engineered nanomaterials (ENMs) have current commercial applications and both neuroprotective and toxic effects. Our hypothesis is that ceria ENMs can associate with brain capillary cells and/or cross the blood-brain barrier. METHODS: An aqueous dispersion of ∼5 nm ceria ENM was synthesized and characterized in house. Its uptake space in the Sprague Dawley rat brain was determined using the in situ brain perfusion technique at 15 and 20 mL/minute flow rates; 30, 100, and 500 μg/mL ceria perfused for 120 seconds at 20 mL/minute; and 30 μg/mL perfused for 20, 60, and 120 seconds at 20 mL/minute. The capillary depletion method and light and electron microscopy were used to determine its capillary cell and brain parenchymal association and localization. RESULTS: The vascular space was not significantly affected by brain perfusion flow rate or ENM, demonstrating that this ceria ENM did not influence blood-brain barrier integrity. Cerium concentrations, determined by inductively coupled plasma mass spectrometry, were significantly higher in the choroid plexus than in eight brain regions in the 100 and 500 μg/mL ceria perfusion groups. Ceria uptake into the eight brain regions was similar after 120-second perfusion of 30, 100, and 500 μg ceria/mL. Ceria uptake space significantly increased in the eight brain regions and choroid plexus after 60 versus 20 seconds, and it was similar after 60 and 120 seconds. The capillary depletion method showed 99.4% ± 1.1% of the ceria ENM associated with the capillary fraction. Electron microscopy showed the ceria ENM located on the endothelial cell luminal surface. CONCLUSION: Ceria ENM association with brain capillary endothelial cells saturated between 20 and 60 seconds and ceria ENM brain uptake was not diffusion-mediated. During the 120-second ceria ENM perfusion, ceria ENM predominately associated with the surface of the brain capillary cells, providing the opportunity for its cell uptake or redistribution back into circulating blood

Ceria-Engineered Nanomaterial Distribution in, and Clearance from, Blood: Size Matters

AIMS: Characterize different sized ceria-engineered nanomaterial (ENM) distribution in, and clearance from, blood (compared to the cerium ion) following intravenous infusion. MATERIALS & METHODS: Cerium (Ce) was quantified in whole blood, serum and clot (the formed elements) up to 720 h. RESULTS: Traditional pharmacokinetic modeling showed best fit for 5 nm ceria ENM and the cerium ion. Ceria ENMs larger than 5 nm were rapidly cleared from blood. After initially declining, whole blood 15 and 30 nm ceria increased (results that have not been well-described by traditional pharmacokinetic modeling). The cerium ion and 5 and 55 nm ceria did not preferentially distribute into serum or clot, a mixture of cubic and rod shaped ceria was predominantly in the clot, and 15 and 30 nm ceria migrated into the clot over 4 h. CONCLUSION: Reticuloendothelial organs may not readily recognize five nm ceria. Increased ceria distribution into the clot over time may be due to opsonization. Traditional pharmacokinetic analysis was not very informative. Ceria ENM pharmacokinetics are quite different from the cerium ion

Surface-Controlled Dissolution Rates: A Case Study of Nanoceria in Carboxylic Acid Solutions

Nanoparticle dissolution in local milieu can affect their ecotoxicity and therapeutic applications. For example, carboxylic acid release from plant roots can solubilize nanoceria in the rhizosphere, affecting cerium uptake in plants. Nanoparticle dispersions were dialyzed against ten carboxylic acid solutions for up to 30 weeks; the membrane passed cerium-ligand complexes but not nanoceria. Dispersion and solution samples were analyzed for cerium by inductively coupled plasma mass spectrometry (ICP-MS). Particle size and shape distributions were measured by transmission electron microscopy (TEM). Nanoceria dissolved in all carboxylic acid solutions, leading to cascades of progressively smaller nanoparticles and producing soluble products. The dissolution rate was proportional to nanoparticle surface area. Values of the apparent dissolution rate coefficients varied with the ligand. Both nanoceria size and shape distributions were altered by the dissolution process. Density functional theory (DFT) estimates for some possible Ce(IV) products showed that their dissolution was thermodynamically favored. However, dissolution rate coefficients did not generally correlate with energy of formation values. The surface-controlled dissolution model provides a quantitative measure for nanoparticle dissolution rates: further studies of dissolution cascades should lead to improved understanding of mechanisms and processes at nanoparticle surfaces

Carboxylic Acids Accelerate Acidic Environment-Mediated Nanoceria Dissolution

Ligands that accelerate nanoceria dissolution may greatly affect its fate and effects. This project assessed the carboxylic acid contribution to nanoceria dissolution in aqueous, acidic environments. Nanoceria has commercial and potential therapeutic and energy storage applications. It biotransforms in vivo. Citric acid stabilizes nanoceria during synthesis and in aqueous dispersions. In this study, citrate-stabilized nanoceria dispersions (∼4 nm average primary particle size) were loaded into dialysis cassettes whose membranes passed cerium salts but not nanoceria particles. The cassettes were immersed in iso-osmotic baths containing carboxylic acids at pH 4.5 and 37 °C, or other select agents. Cerium atom material balances were conducted for the cassette and bath by sampling of each chamber and cerium quantitation by ICP-MS. Samples were collected from the cassette for high-resolution transmission electron microscopy observation of nanoceria size. In carboxylic acid solutions, nanoceria dissolution increased bath cerium concentration to \u3e96% of the cerium introduced as nanoceria into the cassette and decreased nanoceria primary particle size in the cassette. In solutions of citric, malic, and lactic acids and the ammonium ion ∼15 nm, ceria agglomerates persisted. In solutions of other carboxylic acids, some select nanoceria agglomerates grew to ∼1 micron. In carboxylic acid solutions, dissolution half-lives were 800–4000 h; in water and horseradish peroxidase they were ≥55,000 h. Extending these findings to in vivo and environmental systems, one expects acidic environments containing carboxylic acids to degrade nanoceria by dissolution; two examples would be phagolysosomes and in the plant rhizosphere

Biodistribution and Biopersistence of Ceria Engineered Nanomaterials: Size Dependence

The aims were to determine the biodistribution, translocation, and persistence of nanoceria in the brain and selected peripheral organs. Nanoceria is being studied as an anti-oxidant therapeutic. Five, 15, 30, or 55 nm ceria was iv infused into rats which were terminated 1, 20, or 720 h later. Cerium was determined in blood, brain, liver, and spleen. Liver and spleen contained a large percentage of the dose, from which there was no significant clearance over 720 h, associated with adverse changes. Very little nanoceria entered brain parenchyma. The results suggest brain delivery of nanoceria will be a challenge. FROM THE CLINICAL EDITOR: This team of investigators revealed that nanoceria, which is being studied as an anti-oxidant, has very limited uptake by the brain regardless of the range of sizes studied, suggesting major challenges in the application of this novel approach in the central nervous system