Property-Driven Design and Development of Lipids for Efficient Delivery of siRNA

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 pKa in formulation are understood to have impacts
on utility in vivo, 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 in vivo studies would be beneficial. Herein,
we describe structural alterations made within a lipid class exemplified
by 4, 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 in vivo activity
within a range of measured basicity (pKa = 6.0–6.6) and lipophilicity (cLogD = 10–14).