PEG-PLA/PLGA Nanoparticles for In-Vivo RNAi Delivery
R.R. Shinde, M.H. Bachmann, Q. Wang, R. Kasper and C.H. Contag
Stanford University, US
nanoparticle, nanoprecipitation, siRNA, PLA, PLGA, HCV, IRES, bioluminescence
The potential of nucleic acid-based therapies for a range of diseases is anticipated to be quite significant. However, their utility has been limited by inefficient delivery methods and an inability to direct therapies to the target tissue. Currently, liposomes and cationic materials are being investigated as delivery vehicles for nucleic acids. RNAi is emerging as a robust method of contolling gene expression with a tremendous number of applications in cell culture. Translation of this nucleic acid-based therapy to animals models and clinical studies will require significant advances in delivery. Here we have encapsulated RNAi into polylactic acid (PLA) and polylactic/glycolic acid (PLGA) polymers with a PEG coating. . The PEG coating reduces RES uptake and presents a platform for attaching ligands and antibodies to enhance target specificity of the nanoparticles. In order to demonstrate the feasibility of our RNAi encapsulated nanoparticles, we have targeted the internal ribosome entry site (IRES) of Hepatitis-C Virus (HCV) as a means of controlling viral replication in liver. HCV infection can lead to hepatocellular carcinoma and/or cirrhosis of the liver and an effective antiviral is a critical unmet medical need. We have developed an animal model for control of expression from the HCV IRES that would allow for long term studies of a therapeutic RNAi molecule directed against the HCV-IRES, wherein the efficacy of the treatment can be monitored noninvasively using in vivo bioluminescence imaging (BLI). Fabrication of RNAi nanoparticles was via nanoprecipitation techniques, and the nanoparticles have been characterized for size, encapsulation efficiency and release kinetics. These initial results provide useful information for further optimizing the manufacture of PEG-PLA/PLGA based RNAi nanoparticles for in-vivo delivery. We also show that encapsulating the RNAi helps prevent their degradation by nucleases by targeting HCV-IRES in mice.
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Nanotech 2007 Conference Program Abstract