Ionizable lipid 4 is an ionizable cationic lipid (pKa = 6.1) and a hydrogen peroxide-induced rearrangement product of the cationic lipid CA-lipid 5.[1] Charge-altering lipid nanoparticles (CALNPs) containing CA-lipid 5 and encapsulating siRNA against EGFP undergo hydrogen peroxide-induced removal of the phenylboronic acid groups from CA-lipid 5 in MCF-7 cells in vitro, generating ionizable lipid 4-containing LNPs with reduced positive charges at physiological pH, facilitating intracellular siRNA release and gene silencing. LNPs containing ionizable lipid 4 and encapsulating siRNA against PLK1 reduce tumor volume in an MCF-7 mouse xenograft model less effectively than CALNPs containing CA-lipid 5.
References:
[1].Yang, F., Lei, L., Wang, X., et al.Engineering cell-selective charge-altering lipid nanoparticles for efficient siRNA delivery in vivoCCS ChemistryOnline ahead of print(2024).