Jiang Xuan, Dai Hui, Ke Chyan-Ying, Mo Xiao, Torbenson Michael S, Li Zhiping, Mao Hai-Quan
Department of Materials Science and Engineering, and Whitaker Biomedical Engineering Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
J Control Release. 2007 Oct 8;122(3):297-304. doi: 10.1016/j.jconrel.2007.06.014. Epub 2007 Jun 22.
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.
我们开发了一种新型嵌段共聚物基因载体，它由聚乙二醇链段和可降解的阳离子聚磷酰胺（PPA）链段组成。这种PEG-b-PPA共聚物载体在水溶液中与质粒DNA缩合时形成胶束。与DNA与相应阳离子PPA载体形成的复合物相比，PEG-b-PPA/DNA胶束呈现出均匀且减小的粒径，范围为80至100nm，表面电荷降低。PEG-b-PPA/DNA胶束维持了与PPA/DNA复合物相似的转染效率，在HepG2细胞中与PEI/DNA复合物相当，但在原代大鼠肝细胞中转基因表达比PPA/DNA复合物低约16倍。在Wistar大鼠胆管灌注后，PEG-b-PPA/DNA胶束在肝脏中介导的基因表达比PPA/DNA复合物高4倍且更均匀。肝功能测试和组织病理学检查表明，PEG-b-PPA/DNA胶束在肝脏中显示出低毒性和良好的生物相容性。本研究证明了PEG-b-PPA/DNA胶束作为肝脏靶向基因递送有效载体的潜力。
