Phosphodiester antisense oligonucleotide

This approach has recently been applied to the association of a phosphodiester antisense oligonucleotide directed against the 3 non-translated region of the PKCa gene with nanospheres prepared from PIBCA. These nanospheres were able to inhibit PKCot neoexpression in cultured Hep G6 cells. 

Wojcik, W. J., Swoveland, P., Zhang, X., and Vanguri, P. (1996). Chronic intrathecal infusion of phosphorothioate or phosphodiester antisense oligonucleotides against cytokine responsive gene-2/IP-lO in experimental allergic encephalomyelitis of lewis rat. J. Pharmacol Exp. Ther. 278, 404-410. 

Modification of the Phosphodiester Backbone. Oligonucleotides having modified phosphate backbones have been extensively studied (46). Because altering the backbone makes derivatives generally more resistant to degradation by cellular nucleases, these materials have the potential to be more resilient antisense dmgs. 

PO, PSs, PS, 20-mer antisense oligonucleotide complementary to the human c-myc mRNA with different intemucleotide linkages PO, phosphodiester PS3, three phosphorothioate linkages on both ends PS, phosphore thioate. RBC, red blood cells HSA, human serum albumin, a Yoshida el al., 1996 b Takakura et al., 1996 c Nishida et al., 1989. 

Dendrimers have been successfully used as a delivery system for antisense oligonucleotides (ODNs). ° "" Hughes et al. " reported the significant enhancement of the effectiveness of antisense ODNs in the presence of non-toxic concentrations of G5 PAMAM dendrimer. Bielinska et al. " reported the enhanced activity of antisense ODNs and antisense cDNA plasmids in the presence of PAMAM dendrimers in an in vitro cell culture system. Dendrimer was believed to enhance the transfer of ODN into cells. The electrostatic binding of the phosphodiester ODNs to dendrimers also extended their intracellular survival. Dendrimers at concentrations required to be effective ODN carriers were reported to be non-cytotoxic. 

Deverre, J.R., Boutet, V., Boquet, D., Ezan, E., Grassi, J., and Grognet, J. M. (1997) A competitive enzyme hybridization assay for plasma determination of phosphodiester and phosphorothioate antisense oligonucleotides. Nucleic Acids Research, 25, 3584 3589. 

Up to now, these mononuclear complexes do not fulfill the requirements for an efficient in vitro or in vivo DNA or RNA hydrolysis, especially because the rate constant acceleration is too slow to allow the cleavage of phosphodiester bonds of DNA within hours or minutes under physiological conditions. Efforts were made to enhance their cleavage efficiency by tethering them to antisense oligonucleotides (see Section III,C,6). 

Fig. 8.4. First-generation generalized structures of natural DNA (phosphodiester) and three antisense oligonucleotide derivatives tested as antisense drugs. (Adapted from Agrawal S, Iyer RP. Perspectives in antisense therapeutics. Pharmacol Ther 1997 76 151-160 with permission.)...

Krieg, A. M. (1993) Uptake and efficacy of phosphodiester and modified antisense oligonucleotides in primary cell cultures Clin Chem. 39,710-712... 

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