Effects of spacers within a series of novel folate-containing lipoconjugates on the targeted delivery of nucleic acids

Abstract

Limitations regarding the targeted delivery of therapeutic nucleic acids into cancer cells can be overcome by developing a non-viral delivery system equipped with folate-containing conjugates. Here, we report the synthesis of novel folate-containing lipoconjugates (FLs), which differ by spacers between the hydrophobic domain and ligand (folic acid). FLs were incorporated into a liposome composed of the polycationic amphiphile 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride (2X3) and helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). At low (2/1) nitrogen to phosphate (N/P) ratio, liposomes containing 0.5 mol% FL with a short hydrophobic spacer and 2 mol% FL with medium hydrophilic spacer were compared with control liposomes containing 2 mol% FL with a polyethylene glycol spacer and showed higher transfection efficiency than non-targeted liposomal formulations and the commercial agent Lipofectamine 2000. At an N/P ratio of 4/1, the transfection efficiency of FL-containing liposomes were correlated neither with FL content within the liposomes nor FL structure.