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J Gene Med. 2003 Dec;5(12):1039-45.

In vivo knockdown of gene expression in brain cancer with intravenous RNAi in adult rats.

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Department of Medicine, UCLA, Los Angeles, CA 90024, USA.



Gene silencing in mammalian cells is possible with RNA interference (RNAi) with expression plasmids that encode for short hairpin RNAs (shRNA) that hybridize to a specific sequence within a target mRNA. The limiting factor in developing RNAi therapeutics in mammals is the gene delivery system.


The present studies describe the production of anti-luciferase shRNA expression plasmids, which are encapsulated in the interior of 85 nm pegylated immunoliposomes (PILs). C6 rat glioma cells, permanently transfected with the luciferase gene, are implanted in the caudate-putamen nucleus of adult rats, which produces luciferase-expressing intracranial brain cancer. The PILs are targeted across the blood-brain barrier and across the tumor cell membrane in vivo with a monoclonal antibody (MAb) to the rat transferrin receptor (TfR). The TfRMAb is tethered to the tips of 1-2% of the poly(ethylene glycol) strands conjugated to the surface of the liposome.


The TfRMAb-targeted PILs inhibit luciferase gene expression in the brain cancer by 90%, and this effect persists for at least 5 days after a single intravenous injection of 10 micro g/rat of plasmid DNA. RNAi therapy directed against the luciferase gene caused no change in expression of tumor gamma-glutamyl transpeptidase. Targeting the empty expression plasmid with the TfRMAb-PIL resulted in no change in luciferase activity in the brain cancer in vivo.


In vivo RNAi is enabled with a new form of gene delivery system that encapsulates expression plasmids in PILs, which are targeted to distant sites based on the specificity of a receptor-specific monoclonal antibody. The combined application of the PIL gene delivery system and RNAi expression plasmids enables gene silencing in remote sites such as brain cancer in mammals after intravenous administration.

[Indexed for MEDLINE]

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