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.
Haensler
J
J
School of Pharmacy, University of California, San Francisco 94143-0446.
Szoka
F C
FC
D000166:Acridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001212:Asialoglycoproteins / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D005690:Galactose / Q000032:analysis / Q000378:metabolism*; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D037102:Lectins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D009961:Orosomucoid / Q000031:analogs & derivatives / Q000378:metabolism; D037121:Plant Lectins; D010957:Plasmids; D051381:Rats; D014162:Transfection
D000166:Acridines; D001212:Asialoglycoproteins; D007364:Intercalating Agents; D037102:Lectins; D009961:Orosomucoid; D037121:Plant Lectins; C017707:Ricinus communis agglutinin-1; C017030:asialoorosomucoid; D004247:DNA; D008156:Luciferases; D005690:Galactose