Abstract
There is an increasing trend in the number of approved oligonucleotide therapeutics in the world. Recently approved therapeutics include: gapmer-type antisense oligonucleotides, splice-switching antisense oligonucleotides, siRNA encapsulated in nanoparticles or conjugated with triantennary N-acetylgalactosamine (GalNAc), and CpG oligonucleotide. Except for the nanoparticle-formulated siRNA, all these therapeutics share the structural characteristics common to hydrophilic macromolecules, but differ in many aspects, including the location of the target molecule/target cells, administration route, and tissue distribution. Because only the fraction of the administered dose reaching the target exhibits therapeutic effects, the tissue distribution of oligonucleotide therapeutics is one of the most critical parameters that determines the success in the development. Protein binding is a most important characteristic for those administered subcutaneously or intravenously, but the binding characteristic has hardly been actively optimized. Protein binding is important not only for the tissue distribution but for the induction of adverse reactions. Ligand conjugation can increase the distribution of oligonucleotide therapeutics to target cells. GalNAc has been used as a ligand to deliver siRNA to hepatocytes that express GalNAc-recognizing asialoglycoprotein receptors. The cells that can be targeted with oligonucleotide therapeutics so far, however, are limited to hepatocytes and dystrophic muscle cells. In this article, the current status and perspectives of the delivery of oligonucleotide therapeutics are discussed, focusing on the possible role of drug delivery systems in widening their therapeutic application.
