Amine-modified poly(vinyl alcohol)s as non-viral vectors for siRNA delivery: effects of the degree of amine substitution on physicochemical properties and knockdown efficiency.

Juliane Nguyen, Regina Reul, Susanne Roesler, Eyas Dayyoub, Thomas Schmehl, Tobias Gessler, Werner Seeger, Thomas H Kissel

Index: Pharm. Res. 27(12) , 2670-82, (2010)

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Abstract

The objective of this study was to investigate how the degree of amine substitution of amine-modified poly(vinyl alcohol) (PVA) affects complexation of siRNA, protection of siRNA against degrading enzymes, intracellular uptake and gene silencing.A series of DEAPA-PVA polymers with increasing amine density was synthesized by modifying the hydroxyl groups in the PVA backbone with diethylamino propylamine groups using CDI chemistry. These polymers were characterized with regard to their ability to complex and protect siRNA against RNase. Finally, their potential to mediate intracellular uptake and gene silencing in SKOV-luc cells was investigated.A good correlation between amine density and siRNA complexation as well as protection of siRNA against RNase was found. Consisting solely of tertiary amines, this class of polymer was able to mediate efficient gene silencing when approximately 30% of the hydroxyl groups in the PVA backbone were modified with diethylamino propylamine groups. Polymers with a lower amine density (up to 23%) were inefficient in gene silencing, while increasing the amine density to 48% led to non-specific knockdown effects.DEAPA-PVA polymers were shown to mediate efficient gene silencing and offer a promising platform for further structural modifications.