Delivery of Oligonucleotides: Efficiency with Lipid Conjugation and Clinical Outcome

Abstract

Oligonucleotides have shifted drug discovery into a new paradigm due to their ability to silence the genes and inhibit protein translation. Importantly, they can drug the un-druggable targets from the conventional small-molecule perspective. Unfortunately, poor cellular permeability and susceptibility to nuclease degradation remain as major hurdles for the development of oligonucleotide therapeutic agents. Studies of safe and effective delivery technique with lipid bioconjugates gains attention to resolve these issues. Our review article summarizes the physicochemical effect of well-studied hydrophobic moieties to enhance the cellular entry of oligonucleotides. The structural impacts of fatty acids, cholesterol, tocopherol, and squalene on cellular internalization and membrane penetration in vitro and in vivo were discussed first. The crucial assays for delivery evaluation within this section were analyzed sequentially. Next, we provided a few successful examples of lipid-conjugated oligonucleotides advanced into clinical studies for treating patients with different medical backgrounds. Finally, we pinpointed current limitations and outlooks in this research field along with opportunities to explore new modifications and efficacy studies.

Lipid and Peptide-Oligonucleotide Conjugates for Therapeutic Purposes: From Simple Hybrids to Complex Multifunctional Assemblies

“…Imetelstat (GRN163L, Geron) is a lipid-oligonucleotide conjugate with palmitic acid at the 5′-end that is designed to inhibit telomerase activity [ 223 ]. Currently, a phase III clinical trial has finalized with positive results for the treatment of myelofibrosis [ 224 ].…”

“…The cholesterol moiety is used to enhance delivery to hepatocytes. Phase II clinical trials demonstrate good pharmacokinetic properties in a single-dose study [ 224 ]. Recent studies show that ARC-520 is active in HBV patients; but absolute Hepatitis B antigen reduction is moderate [ 225 ].…”

Cationic lipid modification of DNA tetrahedral nanocages enhances their cellular uptake

“…24–26 Various reports found the covalent conjugation of lipids with general oligonucleotides improve their therapeutic applications. 27–30 Therefore, combining negatively charged DNA nanostructures with a binary system having a positively charged head group and a hydrophobic tail can be a useful strategy to neutralize the negative charge on DNA nanostructures and to enhance the internalization with the lipid bilayer of the cell membrane. 27,28,31,32…”

“…[24][25][26] Various reports found the covalent conjugation of lipids with general oligonucleotides improve their therapeutic applications. [27][28][29][30] Therefore, combining negatively charged DNA nanostructures with a binary system having a positively charged head group and a hydrophobic tail can be a useful strategy to neutralize the negative charge on DNA nanostructures and to enhance the internalization with the lipid bilayer of the cell membrane. 27,28,31,32 In this study, we represent the non-covalent functionalization of a model cage, DNA tetrahedron (TD), with a cationic lipid N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) at different ratios and study their cellular uptake.…”

Effective carrier-free gene-silencing activity of sphingosine-modified siRNAs

“…16 Alternatively, fatty acids are more desirable for siRNA delivery due to their safer toxicity profile in comparison to cholesterol, as well as their interesting accumulation patterns and gene silencing activity in various tissues such as muscles. 14–18…”