A hepatocyte-targeted conjugate capable of delivering biologically active colchicine in vitro.
A derivative of colchicine was synthesized, in a manner that preserved its important structural features, and conjugated to an asialoglycoprotein. The conjugate was characterized by ultraviolet-visible spectrophotometry and protein analysis. An average coupling ratio of 2 mol of colchicine per mole of asialoglycoprotein was achieved. The conjugate was stable to incubation in serum but was split into its separate components under chemically reducing conditions. Incubation with cells in culture revealed that the conjugate had antiproliferative activity similar to that of colchicine, but only in asialoglycoprotein receptor-containing cells. There was no effect at all on asialoglycoprotein receptor (-) cells. Furthermore, the antiproliferative effect of the conjugate on receptor (+) cells was blocked by addition of a large molar excess of free asialoglycoprotein. Immunofluorescence microscopy revealed disruption of microtubules in cell cultures that were pretreated with the conjugate. These results indicate that a colchicine conjugate that is taken up specifically into cells by asialoglycoprotein receptors and released intracellularly in a biologically active form can be prepared.
Plourde
R
R
Immune Response Corporation, Carlsbad, California, USA.
Phillips
A T
AT
Wu
C H
CH
Hays
R M
RM
Chowdhury
J
J
Chowdhury
N
N
Wu
G Y
GY
D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins / Q000008:administration & dosage* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003078:Colchicine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004337:Drug Carriers; D006801:Humans; D007202:Indicators and Reagents; D008113:Liver Neoplasms; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D011956:Receptors, Cell Surface / Q000378:metabolism; D013053:Spectrophotometry; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D004337:Drug Carriers; D007202:Indicators and Reagents; D011956:Receptors, Cell Surface; D014404:Tubulin; D003078:Colchicine