Biological barriers to therapy with antisense and siRNA oligonucleotides

Abstract

Attaining the full therapeutic utility of antisense and siRNA oligonucleotides will require understanding of the biological barriers that stand between initial administration of these drugs and their final actions within cells. This review examines some of the key barriers that affect the biodistribution of oligonucleotides both in molecular form and when they are associated with nanocarriers. An understanding of the biological processes underlying these barriers will aid in the design of more effective delivery systems.

Figure 1

Chemical Modifications. The structures of various forms of chemically modified oligonucleotide residues discussed in the text are illustrated.

Figure 2

Oligonucleotide Pharmacokinetics. The normalized clearance rates of a chemically modified antisense oligonucleotide are illustrated in several species including man. Adapted from reference 28 with permission.

Fig 3

The Endothelial Lining. An idealized version of the endothelial lining is illustrated with indications of the large pore and small pore systems. Adapted with permission from reference 83.

Figure 4

Intracellular Trafficking of Oligonucleotides. RGD-623-Tamra is a 2′-OMe-PS antisense oligonucelotide that has a 5′-RGD targeting ligand and a 3′-Tamra fluorophore. Its distribution in cells is compared to that of caveolin (A) or the avb3 integrin (B) (its receptor) as visualized by immunostaining. Fletchings indicate areas of overlap. Adapted from reference 5 with permission.