Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
ACS Appl Mater Interfaces. 2018 Jan 24;10(3):2302-2311. doi: 10.1021/acsami.7b15982. Epub 2018 Jan 11.
Lipid nanoparticles (LNPs) currently comprise the most effective carrier class for the delivery of small RNAs. Among lipid carriers, charge-unbalanced lipids are relatively unexplored synthetically. Herein, we developed and evaluated a novel collection of compounds for small interfering RNA (siRNA) delivery, termed cationic quaternary ammonium sulfonamide amino lipids (CSALs). The formulated CSAL LNPs containing cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine, and lipid poly(ethylene glycol) exhibited biophysical property trends directly related to the CSAL chemical structure. Lead CSAL LNPs were identified using an siRNA delivery screen. Further chemical synthesis using a rational structure-guided design showed that the head group structure could alter the pK and other physical properties that modulated delivery efficacy. Shorter-chained dimethylamino head groups, acetate side chains, and higher tail carbon numbers were favorable for delivery. This led to a further study of A3-OAc-C2Me LNPs, which enabled in vivo delivery to normal mouse lungs and subcutaneous and orthotopic lung tumors. Incorporation of CSALs into liver-targeting formulations shifted the in vivo delivery of these carriers to the lungs. This study highlights the importance of the cationic lipid structure in LNPs and provides further design guidelines for nucleic acid carriers.
脂质纳米颗粒（LNPs）目前是递送小 RNA 最有效的载体。在脂质载体中，带电荷的不平衡脂质在合成方面的研究相对较少。在此，我们开发并评估了一系列新型化合物，用于小干扰 RNA（siRNA）的递送，称为阳离子季铵磺酰胺氨基脂质（CSALs）。含有胆固醇、1,2-二硬脂酰-sn-甘油-3-磷酸胆碱和脂质聚乙二醇的配方 CSAL LNPs 表现出与 CSAL 化学结构直接相关的物理性质趋势。通过 siRNA 递送筛选确定了先导 CSAL LNPs。进一步使用合理的结构导向设计进行化学合成表明，头基结构可以改变 pK 和其他调节递送功效的物理性质。短链二甲基氨基头基、乙酸盐侧链和更高的尾部碳原子数有利于递送。这导致了对 A3-OAc-C2Me LNPs 的进一步研究，其能够将体内递送至正常小鼠肺部和皮下及原位肺肿瘤。将 CSAL 纳入肝靶向制剂将这些载体的体内递送转移到肺部。这项研究强调了 LNPs 中阳离子脂质结构的重要性，并为核酸载体提供了进一步的设计指南。
