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Publisher Summary The selective inhibition of gene expression through specific oligonucleotide binding to key mRNA target sequences is the goal of antisense strategies. However, from the beginning, antisense strategies have faced several obstacles, such as in vivo stability of the oligonucleotide, cellular uptake, efficiency of hybridization of the antisense agent to the mRNA target, selectivity of oligonucleotide binding, and inhibition of gene expression. Of these factors, the low and nonselective cellular uptake of antisense oligonucleotides has hindered its therapeutic usefulness most severely. A versatile method to specifically and efficiently deliver an antisense oligonucleotide to the intracellular medium of a particular cell within a single organ would have a pronounced effect on the realization of effective antisense therapies. This chapter describes an approach for the ligand-directed delivery of antisense oligonucleotides. Paramount to this approach is the design and synthesis of a molecular scaffold symbolized as “A-L-P” with “A” representing a unique ligand, specific for a receptor on the surface of the target cell. The “P” represents the “payload” portion, typically an oligonucleotide, which is linked uniquely to the ligand through the linker (the “L” portion). The methods describe A-L-P neoglycoconjugate formation, the cellular uptake of these ligand-linker-oligonucleotide conjugates via receptor-mediated endocytosis, their in vivo biodistribution, and their effectiveness toward the inhibition of expression of an integrated hepatitis B virus (HBV). |
