(14b) Targeted, Systemic Delivery of Sirna for Cancer: From Concept to Clinic

One of the ultimate 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 are investigating the potential of targeted nanoparticles for the systemic delivery of siRNA in cancer, and have shown 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 [1]. Targeted nanoparticles can 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 corrected 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 carry a large amount of chemically unmodified siRNA (as compared to attachment of siRNA directly to targeting ligands such as aptamers and antibodies) as the polycation protects the RNA from degradation and traffics it into cells where the kinetics of gene inhibition are the same for chemically modified and unmodified siRNA [3,4]. Using a combination of PET and bioluminescent imaging, we will show that the biodistribution of the nanoparticles is not a strong function of the presence of the targeting ligand, while the uptake and function in tumor cells is critically dependent on the function of the targeting ligand [5]. Also, we will show that repetitive dosing in monkeys with the cyclodextrin-containing polycation nanoparticles can be safely accomplished without eliciting complement activation or interferon and other immunostimulatory processes [6]. This system will enter human clinical trials within the next few months.

[1] Hu-Lieskovan S et al. Cancer Res., 65(2005) 8984-8992.

[2] Pun SH et al., Cancer Biology & Therapy, 3(2004) 641-650.

[3] Bartlett DW and Davis ME, Nucleic Acids Res., 34(2006) 322-333.

[4] Layzer JM et al. RNA, 10(2004) 766-771.

[5] Bartlett DW et al., PNAS, 104(2007) 15549-15554.

[6] Heidel JD et al., PNAS, 104(2007) 5715-5721.