Arcturus Therapeutics Inc., 10628 Science Center Drive #250, San Diego, California 92121, United States.
SPTanis PharmaChem Consulting LLC, 1750 Oriole Ct, Carlsbad, California 92011, United States.
J Med Chem. 2020 Nov 12;63(21):12992-13012. doi: 10.1021/acs.jmedchem.0c01407. Epub 2020 Oct 29.
Ionizable cationic lipids are critical components involved in nanoparticle formulations, which are utilized in delivery platforms for RNA therapeutics. While general criteria regarding lipophilicity and measured p in formulation are understood to have impacts on utility , greater granularity with respect to the impacts of the structure on calculated and measured physicochemical parameters and the subsequent performance of those ionizable cationic lipids in studies would be beneficial. Herein, we describe structural alterations made within a lipid class exemplified by , which allow us to tune calculated and measured physicochemical parameters for improved performance, resulting in substantial improvements versus the state of the art at the outset of these studies, resulting in good activity within a range of measured basicity (p = 6.0-6.6) and lipophilicity (cLog = 10-14).
可离子化阳离子脂质是纳米颗粒制剂中关键的组成部分，这些制剂被用于 RNA 治疗药物的传递平台。虽然人们已经了解到关于亲脂性和制剂中测量的 p 的一般标准会对其用途产生影响，但对于结构对计算和测量物理化学参数的影响以及这些可离子化阳离子脂质在研究中的后续性能的更详细的了解将是有益的。在这里，我们描述了一类脂质中的结构改变，这些改变使我们能够调整计算和测量的物理化学参数以提高性能，从而与这些研究开始时的现有技术相比有了显著的提高，在一系列测量的碱性（p = 6.0-6.6）和亲脂性（cLog = 10-14）范围内具有良好的活性。
