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, TPSCl, gives the dimerized anhydride, which is stable enough to isolate by column chromatography in ~90% 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 (beta)-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.