(352g) Invited Speaker: Targeted Nanoparticle Delivery of siRNA: From Concept to Clinic Conference: AIChE Annual MeetingYear: 2011Proceeding: 2011 AIChE Annual MeetingGroup: Materials Engineering and Sciences DivisionSession: Biomaterials for Nucleic Acid Delivery Time: Tuesday, October 18, 2011 - 5:25pm-5:50pm Authors: Davis, M. E., California Institute of Technology One of the major challenges in the development of siRNA-based therapeutics for human use is their effective, systemic delivery. This issue is of particular relevance for cancer as there remains a lack of effective treatments for metastatic disease. We have been investigating the potential of targeted nanoparticles for the systemic delivery of siRNA in cancer, and have reported that transferrin targeted nanoparticles formulated with a cyclodextrin-containing polycation and anti-EWS-FLI1 siRNA can be effective anti-tumor agents in a mouse model of Ewing’s Sarcoma . Targeted nanoparticles show behaviors that provide advantages in the systemic delivery of siRNA. For example, they can protect and deliver non-chemically modified siRNA, they can deliver a large “packet” of siRNA, they can have tunable binding affinities to target cell surfaces and when correctly assembled can systemically deliver siRNA without immune stimulation. Nanoparticles in the size range of 50-100 nm can circulate and localize in tumors [1,2]. These particles can carry a large amount of siRNA as the polycation protects the RNA from degradation and transports it into cells where the kinetics of gene inhibition are a strong function of the cell doubling time . Using a combination of PET and bioluminescent imaging, the biodistribution of the nanoparticles is shown to not be a strong function of the presence of the targeting ligand, while the uptake and function in tumor cells are critically dependent on the function of the targeting ligand . We have confirmed this behavior with other targeted nanoparticles . Repetitive dosing in monkeys with the cyclodextrin-containing polycation nanoparticles can be safely accomplished without eliciting complement activation or interferon and other immunostimulatory processes . This delivery system entered a Phase I clinical trial in 2008 , and results from the clinical trial [8,9] and how they compare to results from animal studies will be discussed.  Hu-Lieskovan S et al., Cancer Res., 65 (2005) 8984-8992.  Pun SH et al., Cancer Biology & Therapy, 3 (2004) 641-650.  Bartlett DW and Davis ME, Nucleic Acids Res., 34 (2006) 322-333. Bartlett DW et al., PNAS, 104 (2007) 15549-15554.  Choi, CHJ et al., PNAS, 107 (2010) 1235-1240. Heidel JD et al., PNAS, 104 (2007) 5715-5721. Davis, ME, Mol. Pharm., 6 (2009) 659-668. Davis, ME et al., Nature, 464 (2010) 1067- 1070. Ribas, A et al, ASCO Abstract No. 3022 (2010).