title: Cell-type specific and ligand specific enhancement of cellular uptake of oligodeoxynucleoside methylphosphonates covalently linked with a neoglycopeptide, YEE(ah-GalNAc)3.
abstract: A novel, structurally defined, and homogeneous oligodeoxynucleoside methylphosphonate (oligo-MP) neoglycopeptide conjugate, [YEE(ah-GalNAc)3]-SMCC-AET-pUmpT7, has been synthesized. The linkage between the carbohydrate ligand and the oligo-MP is a metabolically stable thioether. Experiments establish that uptake of this conjugate by human hepatocellular carcinoma (Hep G2) is cell-type specific when compared with its uptake by human fibrosarcoma (HT 1080) and human promyleocytic leukemia (HL-60). Uptake of the conjugate with Hep G2 cells can be totally inhibited by the addition of a 100-fold excess of free YEE(ah-GalNAc)3 in the culture medium indicating the observed cell uptake is ligand specific. The conjugate is rapidly taken in by Hep G2 cells in a linear fashion reaching a saturation plateau of 26 pmol per 10(6) cells after 24 h. Conjugation of oligo-MPs to ligands for hepatic carbohydrate receptors, such as YEE(ah-GalNAc)3, represents an efficient and ligand-specific method for the intracellular delivery of oligo-MPs.
authors.affiliation: Department of Biochemistry, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hangeland
authors.forename: J T
authors.initials: JT
authors.lastname: Levis
authors.forename: Y C
authors.initials: YC
authors.lastname: Lee
authors.forename: P O
authors.initials: PO
authors.lastname: Ts'o
mesh_terms: D001483:Base Sequence; D002236:Carbohydrate Conformation; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D009928:Organ Specificity; D014407:Tumor Cells, Cultured
chemical_list: C099032:(YEE(ah-GalNAc)3)-SMCC-AET-pU(m)pT(7); D006020:Glycopeptides; D009838:Oligodeoxyribonucleotides