(298e) Cellular Trafficking of Dextran Functionalized Silica Nanoparticles for Effective siRNA Delivery

Clinical applications of genetic therapies, including delivery of short, interfering RNAs (siRNAs) for RNA interference (RNAi), have been hampered by difficulties in delivering nucleic acids to cells in sufficient quantities to achieve silencing. On the cellular level, delivery efficiency is hindered by our lack of knowledge on how siRNA-vehicle complexes traffic across the plasma membrane and into the cytoplasm. Although some information is emerging, additional studies on the relationship between chemical and physical characteristics of the vehicles and their mode of uptake or trafficking within the cells are required. To address this challenge, we have developed novel dextran functionalized silica solid-core nanoparticles (NPs) with the ability to effectively deliver siRNA to human lung cancer (H1299) cells expressing an enhanced green fluorescent protein (EGFP). Through modifications to the particle size and amine content, we are able to relate the chemical and physical characteristics to changes in cellular uptake, endocytotic trafficking, and ultimately silencing efficiency. We will discuss the effect of endocytotic inhibitors on these cellular processes with respect to time and NP characteristics. Finally, we will explore the differences in silencing kinetics between lipid, polymer, and solid-core delivery vehicles.