The radical nature of oxidative stress triggered by metal nanoparticles

Nanomaterials have unique chemical and physical properties and therefore have many exciting applications. However, the impact of nanomaterials on human health and environment is poorly understood. In order to enable future development of nanotechnology, basic understanding of how nanomaterials interact with cells is urgently needed.Some studies found that toxic effects of nanoparticles in cells are usually dominated by oxidative stress, e.g., generation of reactive oxygen species. Two possible explanations can be used to account for this phenomenon. Firstly, oxidative stress could be caused by the natural reaction of the cell to the nanoparticle exposure, triggered by the stimulation of receptors by the nanoparticles or disruption of normal biochemical mechanisms. Secondly, reactive oxygen species could be generated directly by reaction of cell constituents with the nanoparticles. The relative role of these two factors is not currently understood.In a recent project, we found that some metal nanoparticles are capable of generating free radicals upon reaction with oxygen and organic compounds. This is not surprising as the high surface energy of nanoparticles is expected to result in high chemical reactivity. Inspired by these results, we propose that the oxidative stress triggered by metal nanoparticles in cells may be related to their reactivity, e.g., their ability to generate free radicals upon reaction with oxygen and organic compounds. This project is aimed at establishing such structure-reactivity-toxicity relationship. We will investigate the properties of a broad range of nanoparticles in biological and non-biological environments. The nanoparticle-initiated free radical flux in organic and aqueous systems will be compared to oxidative stress in cells. Formation of radicals will be detected using EPR spectroscopy. A significant advantage of this method is that it can be applied to biological as well as non-biological systems. Additionally, it provides structural and quantitative information on the free radicals formed. We will also determine which cell constituents are most reactive with nanoparticles, in order to unravel the main routes of nanoparticle toxicity and link this toxicity to the particle structure, morphology and chemical composition. We believe that this study will not only provide comparative information of nanoparticle toxicity, but will also lead to a deeper understanding of what properties of nanoparticles are responsible for causing oxidative stress. Such molecular understanding-based knowledge is essential for predicting toxicity of new materials and finding ways for reducing undesired effects on health and environment. We believe that in the long term, such mechanistic studies will help to ensure safety of the future applications of nanomaterials.

The main beneficiaries of this project can be categorised into several groups: 1) Academic beneficiaries. These will include nanotoxicologists, as this project proposes a new approach to understanding nanoparticle toxicity. Our approach is based on the search for mechanistic understanding of toxicity by exploring non-biological model systems. Materials scientists will benefit from the new information on the free radical generation at the nanoparticle surface. In the long term, this reactivity can be exploited in catalytic or sensor applications. Scientists interested in oxidative stress and other free radical processes in biological environment, will also benefit from this project. 2) Policy makers will benefit in the long term, as our project will contribute to the knowledge about the safety of nanoparticles. We believe this knowledge is essential for making well-informed decisions about the future development of nanotechnology. 3) General public and nanotechnology industries will benefit in the long term, as the information on nanotoxicology will help define the rules for the safe use of nanomaterials. This in turn will lead to the incorporation of safe nanomaterials into new practical applications. 4) The PDRA researcher involved in the project will benefit from extensive training in a broad range of techniques and expertise in topical areas. The PI and Co-I will benefit from this project which is a new collaboration. In order to ensure that the potential impact of the project is fully realised, we will disseminate the results of this project through presentations at relevant conferences including the user community, e.g., nanotoxicology and nanomedicine. The results will also be published in high-impact journals. Dissemination will be greatly facilitated by our interactions with the existing nanotoxicology networks, and establishment of new collaborations. We will also include this project in our outreach activities, to promote the importance of scientific research in this important area.