ABSTRACT
We have previously shown that synthetic archaeal lipid analogues are useful vectors for drug/gene delivery. We report herein the synthesis and gene transfer properties of a series of novel di- and tetraether-type archaeal derivatives with a poly(ethylene glycol) (PEG) chain and further equipped with a folic acid (FA) group. The synthetic strategy and the purification by dialysis ensured complete removal of free FA. The lipids were mixed with a conventional glycine betaine-based cationic lipid and the resulting formulations were tested in transfection assays after complexation with plasmid DNA. All four novel co-lipids afforded efficient in vitro gene transfection. Moreover, the FA-equipped derivatives permitted ligand/receptor-based targeted transfection; their activity was inhibited when free FA was added to the transfection medium. These novel archaeal derivatives equipped with FA-PEG moieties may thus be of great interest for targeted in vivo transfection.
Subject(s)
Folic Acid/chemistry , Genetic Vectors/chemical synthesis , Genetic Vectors/genetics , Lipids/chemical synthesis , Lipids/genetics , Transfection/methods , Archaea/chemistry , DNA/chemistry , Folic Acid/genetics , Genes, Reporter , Genetic Vectors/chemistry , HeLa Cells , Humans , Lipids/chemistry , Liposomes/chemistry , Molecular Conformation , Polyethylene Glycols/chemistry , StereoisomerismABSTRACT
New helper lipids, possessing an imidazole polar head, have been synthesized and included in formulations for transfection assays; these new helper lipids can improve the transfection by a factor of up to 100 compared to the use of DOPE as co-lipid.
Subject(s)
Amides/chemical synthesis , Amides/metabolism , Drug Design , Imidazoles/chemistry , Phosphoric Acids/chemical synthesis , Phosphoric Acids/metabolism , Transfection/methods , Amides/chemistry , Cell Line , Humans , Lipid Bilayers/chemistry , Phosphatidylethanolamines/metabolism , Phosphoramides , Phosphoric Acids/chemistryABSTRACT
A synthetic route for the preparation of symmetrical and unsymmetrical archaeal tetraether-like analogues has been described. The syntheses are based upon the elaboration of hemimacrocyclic tetraether lipid cores from versatile building blocks followed by simultaneous or sequential introduction of polar head groups. Functionalizations of the tetraether lipids with neutral lactose or phosphatidylcholine polar heads and cationic glycine betaine moieties were envisaged both to increase membrane stability and to exhibit interactions with charged nucleic acids. Additionally, mannose and lactose triantennary clusters designed as multivalent ligands for selective interaction with lectin-type receptors were also efficiently synthesized for active cell/tissue targeting.
