Cellular Uptake, Dissolution, and Distribution of Cu and Zn Nanoparticles: Implications for Toxicity

Description

Metallic nanoparticles (NPs) are used in many sectors including cosmetics, materials, textiles, energy, and medicine. Of the many types of metallic-based NPs, Cu and Zn nanoparticles (nCuO and nZnO) are widely used as nanocatalysts and antibacterial agents, but their toxicity mechanisms are not well understood. Cu-NPs are also now extensively used in the production of Cu-mask which display superior protection against viruses. As a result of their small sizes, these NPs may be internalized into the cells and then interact with various macromolecules and organelles. The dissolution of potentially toxic metal ions can also cause cell death. Although there have been many studies on NP toxicity, the extent to which the biological effects are caused by the NPs, the dissolved metal ions in the external environment, or the metal ions released intracellularly, is largely unknown. Cellular toxicity may be directly dependent on the uptake pathway, cellular distribution, transformation, and excretion of NPs. Therefore, it is important to investigate the cellular uptake and intracellular behavior of NPs in order to better predict their biological effects and optimize their applications in biomedical fields. In this project, we propose to employ different novel bio-imaging techniques to study the cellular uptake, intracellular dissolution and targeted cellular organelles, as well as the controlling mechanisms of cytotoxicity of both nCuO and nZnO.  Our specific objectives will be to study their 1) cellular endocytosis and bioaccumulation processes; 2) subcellular dissolution, transport and localization; 3) cytotoxicity controlled by their subcellular dissolution and localization. With the application of novel Zn2+/Cu2+/Cu+ bioprobes, we will be able to quantify the differential dissolution of nCuO and nZnO externally and intracellularly. We will further conduct bio-imaging of subcellular localization and sensitive cellular/metabolic responses and identify the main chemical species responsible for NP nanotoxicity. Furthermore, we will for the first time track the high-resolution endocytosis kinetics of nCuO and nZnO using high time- and space-resolution electron microscopy technology. The applications of these novel bio-imaging techniques will allow us to address an important question regarding the intracellular dissolution of NP-derived metal ions as well as their targeting of sensitive organelles with predicted cellular toxicity. We thus envision that this project will provide critical information on cellular uptake and subcellular transformation processes of nCuO and nZnO, which are much needed for our understanding of their cellular toxicity and applications in biomedical fields.