PEG-b-PPA/DNA micelles improve transgene expression in rat liver through intrabiliary infusion

Department of Materials Science and Engineering, and Whitaker Biomedical Engineering Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
Journal of Controlled Release (Impact Factor: 7.71). 11/2007; 122(3):297-304. DOI: 10.1016/j.jconrel.2007.06.014
Source: PubMed


We have developed a new block copolymer gene carrier that comprises of a polyethylene glycol segment and a degradable cationic polyphosphoramidate (PPA) segment. This PEG-b-PPA copolymer carrier formed micelles upon condensation with plasmid DNA in aqueous solution. PEG-b-PPA/DNA micelles exhibited uniform and reduced particle size ranging from 80 to 100 nm and lowered surface charge, compared with complexes of DNA with the corresponding cationic PPA carrier. PEG-b-PPA/DNA micelles maintained similar transfection efficiency as PPA/DNA complexes, which was comparable to that of PEI/DNA complexes in HepG2 cells, but yielded about 16-fold lower transgene expression in primary rat hepatocytes than PPA/DNA complexes. Following bile duct infusion in Wistar rats, PEG-b-PPA/DNA micelles mediated 4-fold higher and more uniform gene expression in the liver than PPA/DNA complexes. Liver function tests and histopathological examination indicated that PEG-b-PPA/DNA micelles showed low toxicity and good biocompatibility in the liver. This study demonstrated the potential of PEG-b-PPA/DNA micelles as an efficient carrier for liver-targeted gene delivery.

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    • "Fibrotic rats were prepared by administering DMN (Kanemura et al., 2008) for 3 consecutive weeks and then not administering DMN for the next 7 days. The protocol for retrograde intrabiliary infusion was adapted from our previous work ( Jiang et al., 2007). Rats were anaesthetized with ketamine/xylazine, the common bile duct was canulated with a 32G needle (Hamilton), and a tie with 5-O silk sutures was placed to secure the needle. "
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