Evaluation of the Toxicity Associated With Complex Engineered Nanomaterials Utilizing In Vivo and in Vitro Models

Nanomaterials are about to fundamentally alter how we exploit the chemical and physical properties of materials. Due to their unique properties, they are being rapidly incorporated into products and industrial applications. However, there is growing concern that these materials will display unexpected nano-specific toxicity that will occur through mechanisms that cannot be extrapolated from the analogous bulk material. Consequently, there is a critical need to develop toxicity screening methods that are able to detect toxicity at the nano-scale. Furthermore, it is imperative to derive structure-toxicity correlations that can be used to design safer nanomaterials a priori. Industry rarely uses individually structured nanoparticles (NPs) due to their instability. To overcome NP deactivation and promote stability, nano-enabled materials are often designed as multi-component materials which embed active NPs within a protective matrix, referred to as complex engineered nanomaterials (CENs). However, most nanotoxicity studies to-date focus on individually structured NPs, rather than CEN structures. Moreover, these structures offer a unique opportunity to systematically study how nano-structuring influences the NPs physicochemical properties, which in turn, affects toxicity. By correlating the physicochemical properties of these complex structures with the toxicity of the CENs, it is possible to derive structure-toxicity correlations. These correlations can help identify structures that minimize properties that cause toxicity, while still providing NP functionality. In this work, we systematically study the toxicity associated with CENs. We investigate three structures that allow us to systematically study the effect nano-embedding has on toxicity: i.) metal NPs deposited on a silica support ii.) metal NPs embedded throughout a porous silica NP and iii.) metal NPs encapsulated in a hollow core surrounded by a silica shell. These CENs underwent rigorous characterization including analyzing the CENs’ size, surface area, ion dissolution, aggregation and settling. Both in vitro (3T3 fibroblasts) and in vivo (zebrafish; Danio rerio) toxicity tests were conducted. The physicochemical characterization was correlated with toxicity studies to determine structure-toxicity correlations. Overall, we showed that embedding the NP, and reducing ion dissolution, led to a reduction in toxicity. Our results suggest that CENs offer a relatively straightforward stepping stone towards the rational design of safer nanomaterials