Cellular Factors that Impact Drug Delivery
Gaurav Sahay, Ph.D.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
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 Finally,I will discuss unpublished results on the endocytic mechanisms that influence DNA delivery mediated by degradable cationic gene delivery polymers, poly (β-amino ester)s (PBAEs).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.
Dr. Gaurav Sahay is currently a postdoctoral associate with Prof. Robert S Langer and Prof. Daniel G Anderson at the Koch Institute for Integrative Cancer Research at MIT. He received his PhD from the Lab of Dr. Alexander Kabanov at the University of Nebraska Medical Center (UNMC) (now at UNC-Chapel Hill). He holds a Masters in Pharmacology from UNMC and Bachelors in Pharmacy from University of Pune. His work is on the interface of nanotechnology, cell biology and drug delivery. At MIT he has performed studies that uncover cellular factor(s) that impact nanoparticle mediated drug delivery. Dr. Sahay utilized novel cellular trafficking probes in combination with automated high-throughput confocal microscopy as well as defined perturbations of cellular pathways paired with systems biology to reveal endocytic regulators that influence internalization and efficiency of siRNA delivery by lipid nanoparticles and identified productive sites for endosomal escape (Sahay et al., Nature Biotech July 2013). In addition, he has studied cellular uptake of nanoparticle libraries carrying siRNA and is currently investigating cellular processes that impact nanoparticle-mediated drug delivery in-vivo.