Kurosaki Tomoaki, Kishikawa Reiko, Matsumoto Megumi, Kodama Yukinobu, Hamamoto Tomoyuki, To Hideto, Niidome Takuro, Takayama Kozo, Kitahara Takashi, Sasaki Hitoshi
Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
J Control Release. 2009 Jun 19;136(3):213-9. doi: 10.1016/j.jconrel.2009.02.005. Epub 2009 Feb 20.
We newly prepared lipopolyplexes containing N-lauroylsarcosine (LS) as a hybrid vector for pulmonary gene delivery via the systemic route. Lipopolyplexes were composed of polyethylenimine (PEI), N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethlylammonium chloride (DOTMA), LS, and plasmid DNA (pDNA). The particle size of lipopolyplex of PEI, DOTMA, and pDNA (lipopolyplex 2P-2D) was not largely changed by the addition of LS, although the addition of LS decreased the high zeta potential. Lipopolyplexes containing LS with low zeta potential showed little aggregation with erythrocytes and low cytotoxicity. In HepG2 cells, lipopolyplexes containing LS showed high transgene efficiency comparable to lipopolyplex 2P-2D. After intravenous injection of the complexes into mice, lipopolyplexes containing LS showed high transgene efficiency, comparable to lipopolyplex 2P-2D. In particular, lipopolyplexes containing LS showed extremely high transgene efficiency in the lung. As a result of the analysis to identify optimum formulations, we discovered that LS contributed to the high transgene efficiency in the lung as 76.7% of the contribution index. These results suggest that lipopolyplexes containing LS are safe and useful gene delivery vectors with lung directivity.
我们新制备了含有N-月桂酰肌氨酸（LS）的脂质多聚体，作为一种混合载体，用于通过全身途径进行肺部基因递送。脂质多聚体由聚乙烯亚胺（PEI）、N-[1-(2,3-二油酰氧基)丙基]-N,N,N-三甲基氯化铵（DOTMA）、LS和质粒DNA（pDNA）组成。尽管添加LS会降低高ζ电位，但PEI、DOTMA和pDNA的脂质多聚体（脂质多聚体2P-2D）的粒径并未因添加LS而发生很大变化。含有低ζ电位LS的脂质多聚体与红细胞的聚集很少，细胞毒性也很低。在HepG2细胞中，含有LS的脂质多聚体表现出与脂质多聚体2P-2D相当的高转基因效率。将复合物静脉注射到小鼠体内后，含有LS的脂质多聚体表现出与脂质多聚体2P-2D相当的高转基因效率。特别是，含有LS的脂质多聚体在肺部表现出极高的转基因效率。作为确定最佳配方分析的结果，我们发现LS对肺部高转基因效率的贡献为贡献指数的76.7%。这些结果表明，含有LS的脂质多聚体是安全且有用的具有肺部靶向性的基因递送载体。
