Synthesis and characterization of a trigalactosylated bisacridine compound to target DNA to hepatocytes.

We have synthesized three bisacridine intercalators containing a galactose residue(s) to target DNA to cell surface receptors for use in gene-delivery systems. Each of the bisacridines could intercalate into DNA with micromolar dissociation constants. Bisacridines containing a single galactose on either a three- or six-carbon spacer from the secondary amine of spermidine-bisacridine could mediate binding of DNA to the soluble galactose receptor Ricinus communis lectin (RCA I), but not to the asialoglycoprotein receptor on primary hepatocytes. A trigalactosyl dilysyl bisacridine [(Gal-6)3Lys2-bA] compound could mediate the binding of DNA to both the ricin lectin and to primary hepatocytes. Binding of the (Gal-6)3Lys2-bA-DNA to the hepatocytes could be blocked by asialoorosomucoid. On the basis of luciferase expression, (Gal-6)3Lys2-bA did not induce transfection of the hepatocytes when attached to the pCLUC4 plasmid encoding the firefly luciferase gene.