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The interactions of amphiphilic antisense oligonucleotides with serum proteins and their effects on in vitro silencing activity

Paper ID Volume ID Publish Year Pages File Format Full-Text
6621 506 2012 11 PDF Available
Title
The interactions of amphiphilic antisense oligonucleotides with serum proteins and their effects on in vitro silencing activity
Abstract

Antisense oligonucleotides (AONs) are a class of compounds with high therapeutic potential. One of the challenges facing this platform is the development of effective techniques to achieve cellular delivery. AON conjugates, in which traditional AONs are attached to certain biomolecules, can exhibit improved intracellular bioavailability in the absence of delivery systems. In this study, the lipophilic moieties docosahexaenoic acid, cholesterol, and docosanoic acid (DSA) were conjugated to various phosphorothioated DNA and chemically-modified 2′-fluoro-arabinonucleic acid AONs via an amino-hexanol-linker added to the 5′-end of the molecule. The gene silencing potential of these compounds was evaluated in vitro in the absence or presence of a transfecting agent (polyion complex micelle). Incubation with sub-micromolar concentration of DSA-conjugates could, in the absence of serum proteins, downregulate more than 60% of the targeted mRNA under carrier-free and carrier-loaded delivery methods. Gene silencing activity of carrier-free DSA-conjugates was, however, decreased in a dose-dependent fashion by adding albumin in the transfection medium. Supplementing the medium with free fatty acid prevented the interaction of the DSA-conjugate with albumin, and restored its silencing activity. These findings suggest that strategies aiming at preventing the association of hydrophobized AONs to serum proteins at the site of action may improve their activity.

Keywords
Nucleic acid; Antisense oligonucleotide; Docosanoic acid; Albumin; Polymeric micelle; Fatty acid
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The interactions of amphiphilic antisense oligonucleotides with serum proteins and their effects on in vitro silencing activity
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 33, Issue 25, September 2012, Pages 5955–5965
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us