The delivery of therapeutic oligonucleotides

Abstract

The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the first antisense drug and with promising developments in late stage clinical trials using siRNA or splice switching oligonucleotides. However, effective delivery of oligonucleotides to their intracellular sites of action remains a major issue. This review will describe the biological basis of oligonucleotide delivery including the nature of various tissue barriers and the mechanisms of cellular uptake and intracellular trafficking of oligonucleotides. It will then examine a variety of current approaches for enhancing the delivery of oligonucleotides. This includes molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugates and small molecules that improve oligonucleotide delivery. The merits and liabilities of these approaches will be discussed in the context of the underlying basic biology.

lncRNA in the liver: Prospects for fundamental research and therapy by RNA interference

“…Cationic lipids alone do not provide 34 efficient delivery; therefore helper lipids should be used. Three types of helper lipids are excessive off-targeting due to low "chemical stickiness" and are able to cross 4 physiological barriers in a more or less controlled manner[94, 95]. However, most of the 5 lipid-like materials tested in the past were used only for in vitro transfection and this data 6 cannot guarantee in vivo efficacy.…”

Drug delivery system of therapeutic oligonucleotides

“…One is improvement of stability to nucleases in the body, another is improvement of binding affinity to serum proteins like albumin or others so that excretion from the kidney is delayed (5,6).…”

“…The center of the gapmer ASO consists of a 5-10 base gap of DNA. The gapmer binds to the target mRNA and forms a DNA/RNA heteroduplex, that is recognized by RNase H and enables it to cleave the target mRNA (5,28). There are three examples of ligand-conjugated ASO (Figure 4).…”

Development of Protecting Groups for Prodrug-Type Oligonucleotide Medicines

“…To date, the typical DDSs of oligonucleotide drugs are: (i) using nanoparticles as carriers, (ii) conjugating small molecules and/or polymers to improve the cellular membrane permeability of oligonucleotides; and (iii) developing prodrug-type oligonucleotide medicines. In this review, we have focused on (iii), the development of prodrug-type oligonucleotide medicines; (i) and (ii), which have been discussed in depth elsewhere, [3][4][5][6][7] are not in the focus.…”