PEG-b-PPA/DNA micelles improve transgene expression in rat liver through intrabiliary infusion.
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.
Jiang
Xuan
X
Department of Materials Science and Engineering, and Whitaker Biomedical Engineering Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
Dai
Hui
H
Ke
Chyan-Ying
CY
Mo
Xiao
X
Torbenson
Michael S
MS
Li
Zhiping
Z
Mao
Hai-Quan
HQ
D000818:Animals; D001652:Bile Ducts; D001672:Biocompatible Materials / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D004337:Drug Carriers / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry; D018390:Gene Targeting / Q000379:methods*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007260:Infusion Pumps; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D010755:Organophosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D014162:Transfection; D019076:Transgenes / Q000235:genetics
D001672:Biocompatible Materials; D004337:Drug Carriers; D008823:Micelles; D010755:Organophosphates; D011092:Polyethylene Glycols; D004247:DNA