Department of Chemistry, University of Louisville, 2320 S. Brook Street, Louisville, Kentucky 40292, USA.
ChemMedChem. 2011 Nov 4;6(11):2063-9. doi: 10.1002/cmdc.201100259. Epub 2011 Aug 31.
The manipulation of the cationic lipid structures to increase polynucleotide binding and delivery properties, while also minimizing associated cytotoxicity, has been a principal strategy for developing next-generation transfection agents. The polar (DNA binding) and hydrophobic domains of transfection lipids have been extensively studied; however, the linking domain comprising the substructure used to tether the polar and hydrophobic domains has attracted considerably less attention as an optimization variable. Here, we examine the use of an oxime ether as the linking domain. Hydrophobic oxime ethers were readily assembled via click chemistry by oximation of hydrophobic aldehydes using an aminooxy salt. A facile ligation reaction delivered the desired compounds with hydrophobic domain asymmetry. Using the MCF-7 breast cancer, H1792 lung cancer and PAR C10 salivary epithelial cell lines, our findings show that lipoplexes derived from oxime ether lipids transfect in the presence of serum at higher levels than commonly used liposome formulations, based on both luciferase and green fluorescent protein (GFP) assays. Given the biological compatibility of oxime ethers and their ease of formation, this functional group should find significant application as a linking domain in future designs of transfection vectors.
阳离子脂质结构的操纵，以增加多核苷酸结合和传递性质，同时最小化相关的细胞毒性，一直是开发下一代转染剂的主要策略。转染脂质的极性（DNA 结合）和疏水区已被广泛研究；然而，连接子域，包括用于连接极性和疏水区的亚结构，作为一个优化变量，受到的关注要少得多。在这里，我们研究了肟醚作为连接子域的用途。肟醚通过肟化疏水性醛使用氨基氧基盐，通过点击化学很容易组装。通过简单的连接反应，用疏水性不对称的肟醚脂传递所需的化合物。使用 MCF-7 乳腺癌、H1792 肺癌和 PAR C10 唾液上皮细胞系，我们的研究结果表明，基于荧光素酶和绿色荧光蛋白（GFP）测定，与常用的脂质体制剂相比，在血清存在的情况下，来自肟醚脂质体的脂质体转染水平更高。鉴于肟醚的生物相容性及其易于形成，该官能团在未来的转染载体设计中应作为连接子域得到广泛应用。
