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Bioconjug Chem. 2008 Nov 19;19(11):2182-8. doi: 10.1021/bc800270w.

Cellular delivery and biological activity of antisense oligonucleotides conjugated to a targeted protein carrier.

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Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.


Targeted delivery can potentially improve the pharmacological effects of antisense and siRNA oligonucleotides. Here, we describe a novel bioconjugation approach to the delivery of splice-shifting antisense oligonucleotides (SSOs). The SSOs are linked to albumin via reversible S-S bonds. The albumin is also conjugated with poly(ethylene glycol) (PEG) chains that terminate in an RGD ligand that selectively binds the alphavbeta3 integrin. As a test system, we utilized human melanoma cells that express the alphavbeta3 integrin and that also contain a luciferase reporter gene that can be induced by delivery of SSOs to the cell nucleus. The RGD-PEG-SSO-albumin conjugates were endocytosed by the cells in an RGD-dependent manner; using confocal fluorescence microscopy, evidence was obtained that the SSOs accumulate in the nucleus. The conjugates were able to robustly induce luciferase expression at concentrations in the 25-200 nM range. At these levels, little short-term or long-term toxicity was observed. Thus, the RGD-PEG-albumin conjugates may provide an effective tool for targeted delivery of oligonucleotides to certain cells and tissues.

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