Cellular factors that impact drug delivery

Despite efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain unclear. This talk will focus on: First, the cellular factors that influence the ability of polymeric micelles with cross-linked ionic cores carrying chemotherapeutic small molecules to exploit differential trafficking pathways in normal and cancer cells. Second, we examined cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy. We employed defined perturbations of cellular pathways paired with systems biology approaches to uncover protein-protein and protein–small molecule interactions. Niemann-Pick type C1 (NPC1) was uncovered to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes and lysosomes, and increased gene silencing of the target gene. Our data suggest that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways. Finally, I will discuss unpublished results on the endocytic mechanisms that influence DNA delivery mediated by degradable cationic gene delivery polymers, poly(β-amino ester)s (PBAEs). Overall, the mechanistic insights into intracellular delivery may guide the development of better drug/gene delivery systems.