Antisense oligonucleotides delivery system

J. H. Jeong, S. W. Kim and T. G. Park, A new antisense oligonucleotide delivery system based on self-assembled ODN-PEG hybrid conjugate micelles. /. Control. Release, 93,183-191 (2003). 

The potential of the chemically modified nucleic acid molecules has been proven by in vitro studies however, the in vivo therapeutic applicability of these molecules seems to be unsatisfactory because of their possible toxic effects (largely unknown) and adverse bioavailability. In this view, both antisense and transfection technologies require reliable and efficient systems for their delivery into target cells. On the basis of this consideration, the development of an efficient nucleic acid delivery system represents one of the key steps for these therapeutic agents, which are necessary for a practical clinical utilization of natural or unnatural oligonucleotides. 

I. Aynie, C. Vauthier, E. Fattal, and M. Foulquier, Alginate nanoparticles as a noval carrier for antisense oligonucleotides, in Future Strategies for Drug Delivery with Particulate Systems, Stuttgart, 1997, pp. 11-16. 

Vinogradov, S., Batrakova, E. and Kabanov. A. (1999b) Poly(ethylene glycol)-polyethyleneimine NanoGel particles novel drug delivery systems for antisense oligonucleotides. Colloids and Surfaces B Biointerfaces, 16, 291-304. 

Similar to pDNA, the pharmacokinetics of oligonucleotides can be controlled by using delivery systems. Mahato et al. (1997) studied the pharmacokinetic characteristics of antisense oligonucleotides complexed with Gal-PLL or mannosylated PLL (Man-PLL), whose mannose residues can be recognized by mannose... 

Boado et al. [28] devised delivery systems based on conjugates of streptavidin and the 0X26 monoclonal antibody directed to the transferrin receptor as a carrier for the transport of ASO. These delivery systems were found to transport peptide nucleic acid antisense molecules, but not ASO, across the BBB. These authors attributed this difference to preferential binding of phosphorothioate oligonucleotide to plasma protein instead of the antibody complex, which reduced their transport. 

Systemic Delivery and Pre-clinical Evaluation of Nanoparticles Containing Antisense Oligonucleotides and siRNAs... 

Key Words Raf-1 Antisense oligonucleotide siRNA Cationic liposomes Dimyristoyl 1,2-diacy 1-3-tri methyl ammonium-propane (DMTAP) Systemic delivery Toxicology Pharmacokinetics and biodistribution Ionizing radiation Prostate cancer. 

We and others have demonstrated that Raf-1 protein serine/threonine kinase is a druggable signaling molecule in cancer therapy (1,13,17,21-25). Our laboratory has developed a novel cationic liposomal formulation for systemic delivery of intact raf ASO (LErafAON) to normal and tumor tissues in mice (13,17). The liposome-entrapped raf antisense oligonucleotide (LErafAON) is also the first liposomal ASO drug tested in humans (26,27). Systemically delivered cationic liposomal nanoparticles containing rafsiRNA (LErafsiRNA) also inhibit Raf-1 protein expression in tumor and most normal tissues in human prostate tumor (PC-3)-bearing athymic mice (Fig. 1 and Color Plate 1, see Color Plate Section). 

Aynie IC, Vauthier C, Fattal E, Foulquier M, Couvreur P (1998) Alginate nanoparticles as a novel carrier for antisense oligonucleotide. In Diederichs JE, Muler R (eds), Future Strategies of Drug Delivery with Particulate Systems. Stuttgart Medipharm Scientific Publisher, pp 5-10... 

Lochmann, D., et al. (2005), Albumin-protamine-oligonucleotide nanoparticles as a new antisense delivery system. Part 1 Physicochemical characterization, Eur. J. Pharm. Biopharm., 59(3), 419—429. 

An improved system for the delivery of antisense oligonucleotides uses a carbodiimide mediated covalent conjugate with a copolymer of vinyl pyrrolidone and 2-hydroxyethyl methacrylate. ... 

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. 

Aynie, I. Vauthier, C. Chacun, H. Fattal, E. Couvreur, P. Spongelike alginate nanopartides as a new potential system for the delivery of antisense oligonucleotides, antisense. Nucleic Acid Drug Dev. 1999, 9, 301-312. 

Garcia-Chaumont C, Seksek O, Grzybowska J, Borowski E, Bolard J (2000) Delivery systems for antisense oligonucleotides. Pharmacol Ther 87 255-277... 

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