Abstract
The polymer OEI-HD-1, a degradable 25 kDa carrier for siRNA transfer based on β-propionamide-crosslinked oligoethylenimine, was functionalized to further improve biocompatibility and/or endosomolytic characteristics of the polymer. For this purpose OEI-HD-1 was either modified with succinic acid to reduce cationic charge density; alternatively OEI-HD-1 was grafted with 1 molar equivalent of 5 kDa polyethyleneglycol (PEG), or with 1 equivalent of PEG plus 8 molar equivalents of dimethylmaleic anhydride (DMMAn) – modified melittin peptide to enhance endosomal escape. Polymers were characterized in their capability of siRNA complex formation, cytotoxicity, and luciferase reporter gene silencing activity. Succinylation of OEI-HD-1 at 12% of nitrogens strongly reduced siRNA binding and silencing activity. All other OEI-HD-1 derivates displayed improved in vitro biocompatibility and siRNA mediated luciferase gene knockdown in Neuro2A/eGFPLuc cells. Succinylation at 7% of nitrogens strongly reduced cytotoxicity of the polymer and extended the functional window between gene silencing and cytotoxicity. Incorporation of DMMAn-Mel and PEG into OEI-HD-1 generated a pH-responsive lytic polymer conjugate with the highest potency in siRNA mediated gene knockdown and largest functional activity/biocompatibility window.
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