Novel polyamine-dialkyl phosphate conjugates for gene carriers. Facile synthetic route via an unprecedented dialkyl phosphate

To develop a novel nonviral gene carrier, three types of polyamine-dialky phosphates conjugates were synthesized via an unprecedented synthetic intermediate, dimerized dicetyl phosphate (DCP) anhydride, and the transfection efficiency and the complexation properties of the conjugate-DNA were evaluated. Condensation of DCP by 1,3,5-triisopropylbenzenesulfonyl chloride, TPSCI, gives the dimerized anhydride, which is stable enough to isolate by column chromatography in similar to90% yield. The anhydride is reactive with various amines, i.e., spermidine, spermine, and polyethylenimine (PEI-(1800)), providing corresponding polyamine-DCP conjugates via phosphoramidate linkage. The polyamine-DCP conjugates exhibited moderate transfection efficacy evaluated by P-galactosidase assay. The conjugate-DNA complex was observed by using an atomic force microscope (AFM), revealing that the PEI(1800)-DCP conjugate, which showed the most efficient transfection, enables the formation of the more compact complex with DNA.