The use of synthetic polymers for delivery of therapeutic antisense oligodeoxynucleotides

Abstract

Developed over the past two decades, the antisense strategy has become a technology of recognised therapeutic potential, and many of the problems raised earlier in its application have been solved to varying extents. However, the adequate delivery of antisense oligodeoxynucleotides to individual cells remains an important and inordinately difficult challenge. Synthetic polymers appeared on this scene in the middle 1980s, and there is a surprisingly large variety used or proposed so far as agents for delivery of oligodeoxynucleotides. After discussing the principles of antisense strategy, certain aspects of the ingestion of macromolecules by cells, and the present situation of delivery procedures, this article analyses in detail the attempts to use synthetic polymers as carrier matrices and or cell membrane permeabilisation agents for delivery of antisense oligodeoxynucleotides. Structural aspects of various polymers, as well as the results, promises and limitations of their use are critically evaluated.

MicroRNAs: A Puzzling Tool in Cancer Diagnostics and Therapy

“…The poor relative stability in the biological fluid, as well as the negative charge of mRNA molecules, make difficult the cellular uptake of miRNAs and their specific distribution into tissue (47,48). To overcome these obstacles many strategies, including viral vector transportation, nanoparticle and cationic lipids inclusion, as well as chemical modification, have been investigated (49)(50)(51)(52)(53). However, approaches, such as anti-miRs and cationic lipids-linked miRNAs delivery, have elicited toxicity in vivo (39).…”

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

“…PEG coupling to both the 3' and 5' terminal positions of an antisense ODN produced more than 10-fold increase in exonuclease stability, while having no effect on the ability of hybridization (488). Furthermore, the cellular uptake of ODNs can also benefit from PEGylation (496). This is possibly due to the introduction of hydrophobicity and shielding of negative charges of ODNs by PEG.…”

Oligonucleotide Structure Influences the Interactions between Cationic Polymers and Oligonucleotides

“…This model has been used previously, among other applications, for the interpretation of oligocation/oligonucleotide binding 24 . The McGhee-von Hippel isotherm relates via statistical thermodynamics a quantity, ν, equal to the moles bound of ligand per mole of lattice sites, to the free ligand concentration [L], the number of sites occupied per ligand n, and the equilibrium constant K for binding of a ligand to a site: (2) Putting this into terms of the fraction of oligonucleotide bound, f, and the pLL:ODN charge ratio, r, results in the implicit expression: (3) where D T is the total concentration of ODN in the system (bound plus free). While this cannot be solved explicitly for either f or r, it can be solved for f in terms of the ratio ϕ = f/r.…”