Towards Assessing and Mitigating the Toxicity of Metal Nanoparticles

University Of Pittsburgh, Pittsburgh PA

Investigators

Abstract

CBET 1236258 The present project aims to advance the current understanding of nanomaterials toxicity with a specific focus on size-dependent toxicity of metal nanoparticles (NPs) in the "non-scalable regime" (1 nm - 10 nm). The approach is based on the combination of the synthesis of finely controlled and well-characterized metal nanoparticles, with the use of zebrafish models for fast toxicological screening and mechanistic studies It builds onto the expertise of an engineer who is an expert on nanomaterials synthesis, characterization, and application, combined with that of a medical researcher who is an expert on zebrafish models of human disease. The proposed work exploits a number of unique reagents and facilities, including the University of Pittsburgh's zebrafish facility, one of the largest in the world. The proposed approach will be applied to three metals with broad relevance in nanomaterials application in consumer products and industrial processes (Ag, Fe, and Ni), and comprises specifically the following steps: - Size-controlled synthesis of metal nanoparticles with dimensions in the 1 - 10 nm range (plus controls in the size range of 30 - 100 nm), and careful and extensive characterization of these materials prior to toxicological studies. -Identification of size- and dose- dependent toxicity of these engineered NPs via zebrafish studies. - Mechanistic studies of organ-specific toxicity to identify target organs in comparison to the respective free metal salt and as function of particle size. - Finally, investigation of the impact of porous silica coatings on the toxicity of metal nanoparticles as a potential means to mitigate NP toxicity without impacting accessibility and hence functionality of the engineered NPs. Overall, the proposed approach aims to develop methodology for fast and reliable screening of nanoparticle toxicity, improve understanding of nanotoxicity in the "non-scalable" size regime (<10 nm), and demonstrate an approach towards mitigating nanoparticle toxicity via porous coatings. Intellectual Merit The project directly addresses the fundamental challenge posed by the multidisciplinary nature of nanotoxicological studies. By focusing on two aspects of scientific significance as well as great practical importance: the systematic study of size-dependent nanotoxicity in the "non-scalable" regime, which has been largely neglected to-date, and the study of porous coatings as a means towards mitigating the toxicity of metal nanoparticles, it aims to enable significant advances towards a better fundamental understanding of the toxicity of metals at the nanoscale. The project will furthermore establish zebrafish studies as a fast and robust screening tool for nanotoxicological studies. By using transgenic zebrafish lines expressing reporter genes under tissue specific promoters, rapid evaluation of potential target organs for (size-specific) NP toxicity will be possible for the first time. This will enable establishing whether nanomaterials are subject to size-dependent fundamental changes in toxicity and target pathways, similar to the well-established fundamental changes in chemical reactivity for metal NPs in the sub-10 nm range. Broader Impact Demonstration of fast and reliable screening tools for nanotoxicity and development of an improved fundamental understanding of the toxicity of materials in the nanoscale regime could have profound impact on the development and implementation of safe "nano-enabled" consumer products. Fast and cost-efficient screening would pave the way towards robust and responsible implementation of NPs in nanomaterials-based consumer and industrial products, further accelerating the market penetration of these materials with potentially huge impact on quality of life. An improved understanding of the basic principles of nanotoxicity would furthermore help to (pre-emptively) guide the design of novel nanomaterials with safety built into their design. Finally, such an understanding could yield reliable guidelines for legislative action on nanomaterials.