Acuitas Therapeutics, Vancouver, British Columbia, Canada.
Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
Mol Ther Nucleic Acids. 2013 Dec 17;2(12):e139. doi: 10.1038/mtna.2013.66.
Lipid nanoparticles (LNPs) encapsulating short interfering RNAs that target hepatic genes are advancing through clinical trials, and early results indicate the excellent gene silencing observed in rodents and nonhuman primates also translates to humans. This success has motivated research to identify ways to further advance this delivery platform. Here, we characterize the polyethylene glycol lipid (PEG-lipid) components, which are required to control the self-assembly process during formation of lipid particles, but can negatively affect delivery to hepatocytes and hepatic gene silencing in vivo. The rate of transfer from LNPs to plasma lipoproteins in vivo is measured for three PEG-lipids with dialkyl chains 14, 16, and 18 carbons long. We show that 1.5 mol % PEG-lipid represents a threshold concentration at which the chain length exerts a minimal effect on hepatic gene silencing but can still modify LNPs pharmacokinetics and biodistribution. Increasing the concentration to 2.5 and 3.5 mol % substantially compromises hepatocyte gene knockdown for PEG-lipids with distearyl (C18) chains but has little impact for shorter dimyristyl (C14) chains. These data are discussed with respect to RNA delivery and the different rates at which the steric barrier disassociates from LNPs in vivo.Molecular Therapy-Nucleic Acids (2013) 2, e139; doi:10.1038/mtna.2013.66; published online 17 December 2013.
脂质纳米颗粒（LNPs）将靶向肝脏基因的短干扰 RNA 包裹在内，正在临床试验中取得进展，早期结果表明，在啮齿动物和非人类灵长类动物中观察到的出色基因沉默也适用于人类。这一成功促使研究人员寻找进一步推进这一递送平台的方法。在这里，我们对聚乙二醇脂质（PEG-脂质）成分进行了表征，这些成分是控制脂质颗粒形成过程中自组装的必需条件，但会对向肝细胞的递送和体内肝脏基因沉默产生负面影响。我们测量了三种具有 14、16 和 18 个碳原子长的二烷基链的 PEG-脂质在体内从 LNPs 向血浆脂蛋白转移的速率。我们表明，1.5mol%的 PEG-脂质代表一个阈值浓度，在此浓度下，链长对肝脏基因沉默的影响最小，但仍可以改变 LNPs 的药代动力学和生物分布。将浓度增加到 2.5%和 3.5%会大大降低具有二硬脂酰基（C18）链的 PEG-脂质对肝细胞基因敲低的效果，但对较短的二肉豆蔻酰基（C14）链的影响很小。这些数据与 RNA 递送以及体内立体障碍与 LNPs 分离的不同速率有关。分子治疗-核酸（2013 年）2，e139；doi:10.1038/mtna.2013.66；在线发布于 2013 年 12 月 17 日。
