There are a number of modifications you can make to increase the stability of your oligo in the target cell. Which modification you utilise will depend on your application.
For instance an antisense oligo often replaces phosphate linkages with phosphorothioate linkages to improve nuclease stability. Similarly 2'-modified nucleosides, e.g. 2'-OMe incorporations, are often used for this purpose. This is particularly true for gapmers where the 3' and 5' ends are protected against RNase H but the central section is recognised by the enzyme.
It is also possible to use PNA rather than DNA where the peptide like backbone is completely resistant to nucleases.
You may also want to add a modifier that will improve cellular uptake such as cholesterol, tocopherol, palmitoyl or one of our vitamin reagents.
Our Guidebook for the Synthesis of Oligonucleotides has some information on these modifiers in the following sections; backbone modification, modifications for nuclease resistance, therapeutics. You can download this here.
You may also find the book 'Therapeutic Oligonucleotides" edited by Jen Kurreck useful; see: http://pubs.rsc.org/en/content/ebook/978-0-85404-116-9#!divbookcontent.
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