| Abstract
| - Antisense oligonucleotides have been covalently attached toasialoglycoprotein (ASGP) via disulfidebond conjugation chemistry. These conjugates were characterizedextensively by an array of chemical,chromatographic, and spectroscopic means. Multiple (approximatelysix) oligonucleotides can beconjugated to each ASGP molecule. The molecular conjugates wereused to deliver antisenseoligonucleotides complementary to the mRNA of the interleukin 6 signaltransduction protein (gp130)to modulate the acute phase response of hepatoma (HepG2) cells invitro. These conjugates werebiologically active, as measured by inhibition of thecytokine-stimulated up-regulation of the acutephase protein haptoglobin. The level of inhibition was comparableto that found with previoustechnology featuring noncovalent complexes ofASGP−poly(l-lysine) and oligonucleotide.Because ofthe ability to control the stoichiometry of the conjugate and itsunimolecular nature (as opposed tobimolecular for the noncovalent conjugates), this methodology holdsgreat promise for furtherdevelopment and application.
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