Controlling HBV Replication in Vivo by Intravenous Administration of Triggered PEGylated siRNA-Nanoparticles
| Autor: | Yukikazu Natori, Patricia L. Marion, Carol Crowther, Michael R Jorgensen, Patrick Arbuthnot, Masato Fujino, Felix H. Salazar, Soumia Kolli, Sergio Carmona, Andrew D. Miller, Maya Thanou |
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| Rok vydání: | 2009 |
| Předmět: |
Hepatitis B virus
Small interfering RNA Pharmaceutical Science Virus Replication medicine.disease_cause Polyethylene Glycols Mice RNA interference Cell Line Tumor Drug Discovery medicine Animals Humans Gene silencing Cationic liposome RNA Small Interfering Gene knockdown Molecular Structure Chemistry RNA Molecular biology Injections Intravenous Liposomes Systemic administration Nanoparticles Molecular Medicine |
| Zdroj: | Molecular Pharmaceutics. 6:706-717 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/mp800157x |
| Popis: | Harnessing RNA interference (RNAi) to inhibit hepatitis B virus (HBV) gene expression has promising application to therapy. Here we describe a new hepatotropic nontoxic lipid-based vector system that is used to deliver chemically unmodified small interfering RNA (siRNA) sequences to the liver. Anti HBV formulations were generated by condensation of siRNA (A component) with cationic liposomes (B component) to form AB core particles. These core particles incorporate an aminoxy cholesteryl lipid for convenient surface postcoupling of polyethylene glycol (PEG; C component, stealth/biocompatibility polymer) to give triggered PEGylated siRNA-nanoparticles (also known as siRNA-ABC nanoparticles) with uniform small sizes of 80-100 nm in diameter. The oxime linkage that results from PEG coupling is pH sensitive and was included to facilitate acidic pH-triggered release of nucleic acids from endosomes. Nanoparticle-mediated siRNA delivery results in HBV replication knockdown in cell culture and in murine hydrodynamic injection models in vivo. Furthermore repeated systemic administration of triggered PEGylated siRNA-nanoparticles to HBV transgenic mice results in the suppression of markers of HBV replication by up to 3-fold relative to controls over a 28 day period. This compares favorably to silencing effects seen during lamivudine treatment. Collectively these observations indicate that our PEGylated siRNA-nanoparticles may have valuable applications in RNAi-based HBV therapy. |
| Databáze: | OpenAIRE |
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