Efficient delivery of intact phosphodiester oligonucleotides by poly-beta-amino esters

Journal of Controlled Release : Official Journal of the Controlled Release Society
K RemautS C De Smedt

Abstract

Due to their great instability, phosphodiester antisense oligonucleotides (PO-ODNs) are rapidly degraded in the intracellular environment, which limits their biological activity. The release of PO-ODNs during a prolonged period of time could however greatly enhance their antisense effect by creating a pool of intact PO-ODNs at any time point. Poly-beta-aminoesters are biodegradable cationic polymers which show potential for the controlled release of short DNA fragments like ODNs and small interfering RNA (siRNA). In this research we evaluated biodegradable poly-beta-aminoesters as carriers for PO-ODNs and compared the antisense activity with nuclease stable phosphothioate (PS) ODNs. PBAE1 polymers were not able to generate an antisense effect with PO- or PS-ODNs, most likely due to their poor cellular uptake. When complexed to PBAE2 polymers at N/P ratio 10, both PO- and PS-ODNs downregulated the targeted protein expression with 70%. By confocal imaging we observed a high concentration of released PO-ODNs that formed nuclear bodies in the nucleoplasm. The ODNs in these nuclear bodies were still intact as could be demonstrated by Fluorescence Resonance Energy Transfer (FRET) and acceptor photobleaching. This was in clear contras...Continue Reading

Citations

Jul 5, 2012·Journal of Drug Targeting·Zong-Wei WuShu-Yi Lin
Sep 14, 2010·Journal of Controlled Release : Official Journal of the Controlled Release Society·Kevin BraeckmansStefaan C De Smedt
Oct 27, 2017·Advanced Healthcare Materials·Caroline M CurtinFergal J O'Brien

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