Oligonucleotide therapeutics have the potential to treat a myriad of different diseases, however, their efficient delivery to targeted cells and organs remains challenging. Their high molecular size and anionic backbone hinder their cellular uptake. In addition, unmodified oligonucleotides are prone to endonuclease degradation, rapid elimination from the systemic circulation, and can trigger an immune response. Various delivery technologies have been developed to improve oligonucleotide cell delivery, including viral and non-viral carriers, and direct conjugation of oligonucleotides to ligand moieties, such as lipids.  

While the conjugation of N-acetylgalactosamine (GalNAc) residues has proven to be a clinically validated way of delivering therapeutic oligonucleotides to the liver, extrahepatic tissue delivery remains challenging. The conjugation of long-chain fatty acids and their derivatives, such as lauric acid (C12), palmitic acid (C16), stearic acid (C18) and docosanoic acid (C22) have been shown to support the delivery of therapeutic oligonucleotides to non-liver tissues.¹ 

Conjugating a stearyl lipophilic chain (C18) to siRNA has been shown to support the development of nonviral delivery systems targeting cancer cells.² 

Compared to cholesterol conjugates, the C18 stearyl moiety is less lipophilic but exhibits enhanced binding to serum albumin, a property that can facilitate improved cellular internalisation.³ 

Our Stearamido-C7 CE-Phosphoramidite (LK2603) and CPG (BG8-1009) allow you to easily conjugate a stearyl modification to your oligonucleotides. 

If you require an alternative lipophilic modifier, explore our NAT toolbox, which offers a wide range of options to suit your needs. 

References

¹ Annabelle Biscans, Andrew Coles, Reka Haraszti, Dimas Echeverria, Matthew Hassler, Maire Osborn, Anastasia Khvorova, Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo, Nucleic Acids Research, Volume 47, Issue 3, 20 February 2019, Pages 1082–1096, https://doi.org/10.1093/nar/gky1239 

² Sarett SM, Werfel TA, Lee L, Jackson MA, Kilchrist KV, Brantley-Sieders D, et al. Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing. Proc Natl Acad Sci U S A. 2017 Aug 8;114(32):E6490–E6497. doi:10.1073/pnas.1621240114. 

³ Nagaoka M, Liao W, Kusamori K, Nishikawa M. Targeted delivery of immunostimulatory CpG oligodeoxynucleotides to antigen-presenting cells in draining lymph nodes by stearic acid modification and nanostructurization. Int J Mol Sci. 2022;23(3):1350. doi:10.3390/ijms23031350.