CELL-TYPE-SPECIFIC AND LIGAND SPECIFIC ENHANCEMENT OF CELLULAR UPTAKEOF OLIGODEOXYNUCLEOSIDE METHYLPHOSPHONATES COVALENTLY-LINKED WITH A NEOGLYCOPEPTIDE, YEE(AH-GALNAC)(3)

A novel, structurally defined, and homogeneous oligodeoxynucleoside me thylphosphonate (oligo-MP) neoglycopeptide conjugate, [YEE(ah-GalNAc)( 3)]-SMCC-AET-pU(m)pT(7), has been synthesized. The linkage between the carbohydrate ligand and the oligo-MP is a metabolically stable thioet her. Experiments establish that uptake of this conjugate by human hepa tocellular carcinoma (Hep G2) is cell-type specific when compared with its uptake by human fibrosarcoma (HT 1080) and human promyleocytic le ukemia (HL-60). Uptake of the conjugate with Hep G2 cells can be total ly inhibited by the addition of a 100-fold excess of free YEE(ah-GalNA c)(3) in the culture medium indicating the observed cell uptake is lig and specific. The conjugate is rapidly taken in by Hep G2 cells in a l inear fashion reaching a saturation plateau of 26 pmol per 10(6) cells after 24 h. Conjugation of oligo-MPs to ligands for hepatic carbohydr ate receptors, such as YEE(ah-GalNAc)(3), represents an efficient and ligand-specific method for the intracellular delivery of oligo-MPs.