Computational Modeling of Nanoparticle-cell Interactions
Quantitative models of nanoparticle uptake are being developed to describe the initial and key interactions of nanoparticles with cells which govern their cellular uptake. An understanding of these initial interactions will facilitate safe design of nanomaterials in the future.
Understanding the pathways to particle internalization is critical for understanding biocompability. Pathways will operate with different affinities, kinetics, and saturation levels, and are thereby expected to dictate cell dose (and potentially toxicity) accordingly. PNNL is developing experimental tools and computational approaches to understand the role that specific cell surface receptors play in mediating the initial interactions between nanomaterials and cells, and to determine the relationships between the surface physiochemical properties of nanomaterials and their cellular uptake and subsequent biological response.
The initial focus is on a class of cell surface receptors expressed primarily on macrophages known as scavenger receptors. Scavenger receptors are thought to bind and internalize a large group of anionic molecules such as oxidized lipoproteins, bacterial cell wall components, and anionic particulates, thus clearing them from systemic circulation and tissues. It has been previously shown that some large (>100 nm) particulates, such as SiO2 and TiO2, interact with macrophages through scavenger receptors. However, it is uncertain whether nanomaterials utilize similar mechanisms for cell entry.
Model cell systems were developed where either the expression of the endogenously expressed scavenger receptors is selectively silenced using siRNA viral transduction technologies, or where new scavenger receptors are being introduced and expressed. Flow cytometry along with live cell microscopy, including single molecule microscopy techniques are being used to investigate the effect of receptor manipulation on the binding and internalization of fluorescently-labeled nanomaterials bearing different surface chemistries.
Publications:
Waters KM, LM Masiello, RC Zangar, BJ Tarasevich, NJ Karin, RD Quesenberry, S Bandyopadhyay, JG Teeguarden, JG Pounds, and BD Thrall. 2008. "Macrophage Responses to Silica Nanoparticles are Highly Conserved across Particle Sizes." Toxicological Sciences 104(1):155-162.
Contact: Katrina Waters