Synergistic Silencing: Combinations of Lipid-Like Materials for Improved siRNA Delivery

Tuesday, October 18, 2011: 5:05 PM
L100 I (Minneapolis Convention Center)
Kathryn A. Whitehead1, Gaurav Sahay2, Kevin Love3, Christopher Alabi2, Robert Langer3 and Daniel Anderson3, (1)Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, (2)Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, (3)Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA

Despite the promise of RNA interference therapeutics, progress towards the clinic has been slowed by the difficulty of delivering short interfering RNA (siRNA) into cellular targets within the body. Nearly all siRNA delivery vehicles developed to date employ a single cationic or ionizable material. In order to increase the material space available for development of siRNA delivery therapeutics, this study examined the possibility of using binary combinations of ionizable lipid-like materials to synergistically achieve gene silencing. Interestingly, it was found that ineffective single lipid-like materials could be formulated together in a single delivery vehicle to induce near-complete knockdown both in vitro and in vivo. Synergistic liver delivery in mice was initially observed at doses of 5 mg/kg total siRNA, with the most efficacious binary combination demonstrating an IC50 value of 1.5 mg/kg. Microscopy experiments suggested that synergistic action resulted when combining materials that respectively mediated cellular uptake and endosomal escape, two important steps in the delivery process. Together, the data indicate that formulating lipid-like materials in combination can significantly improve siRNA delivery outcomes while increasing the material space available for therapeutic development.

Extended Abstract: File Not Uploaded
See more of this Session: Biomaterials for Nucleic Acid Delivery
See more of this Group/Topical: Materials Engineering and Sciences Division