Novel Polyamine−Dialkyl Phosphate Conjugates for Gene Carriers. Facile Synthetic Route via an Unprecedented Dialkyl Phosphate

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Abstract
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 β-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.