HEPATOCYTE-TARGETED DRUG CONJUGATES

摘要

The invention provides conjugates for targeting a therapeutic agent to a cell with asialoglycoprotein receptors. The conjugates comprise a therapeutic agent and ligand for the asialoglycoprotein receptor, wherein the therapeutic agent and the ligand are linked by a bridging agent. The bridging agent can be a crosslinker, a polyfunctional carrier molecule or a crosslinker and a polyfunctional carrier molecule. In a preferred embodiment, the therapeutic agent is a nucleoside analog or colchicine and the ligand is asialoorosomucoid, arabinogalactan or a Tris-(N-acetyl galactosamine aminohexyl glycoside) amide of tyrosyl(glutamyl)-glutamate. Preferred crosslinkers include aminoacyl derivatives, carboxyacyl derivatives, phosphate, peptides and reductively-labile crosslinkers. Preferred polyfunctional carrier molecules include polyamino acids and polysaccharides. The conjugates of the invention can be used to target a therapeutic agent to a cell, for example to inhibit viral DNA replication in a virally-infected hepatocyte.