Towards Understanding Nanoparticle Uptake by the Liver: The Role of Flow Dynamics, Organ Microarchitecture and Cellular Phenotype

Use of nanoparticles for the diagnosis and treatment of disease is impeded by poor targeting efficiency. The majority of the injected dose accumulates in the liver, where it persists over time. Nanoparticle clearance by this organ is problematic as an insufficient dose is available to reach the disease site and there is potential for hepatotoxicity. Despite its relevance, the nanoparticle-liver interaction is poorly understood. In this thesis, hepatic accumulation of a model nanoparticle is examined. In Aim 1, we isolated and analyzed liver cells from a quantum dot-treated animal. We report that not only Kupffer cells, but also sinusoidal endothelial cells and hepatic B cells are important for quantum dot clearance. In Aim 2, we identify three factors that determine nanoparticle biodistribution patterns. Using mathematical modeling and experimental methods, we show that blood flow dynamics, organ microarchitecture and cellular phenotype govern the off-target accumulation of nanoparticles. These results suggest new strategies to improve nanoparticle delivery and in Aim 3 we demonstrate that manipulation of these factors can reduce quantum dot uptake by phagocytic cells. Finally, in Aim 4, the importance of macrophage phenotype in mediating nanoparticle clearance is demonstrated and we show that nanoparticle internalization selectively alters cellular function. In order to successfully translate nanoparticles from bench-to-bedside, the liver barrier must be solved. This thesis represents the first glimpse into the ‘blackbox’ and provides a foundation for future studies to improve the targeting efficiency and safety of nanoparticle-based technologies.Ph.D.2017-03-16 00:00:0