Design and Evaluation of dendrimer/cyclodextrin conjugates as a novel siRNA carrier

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RNA interference (RNAi) is the mechanism of gene silencing-mediated messenger RNA degradation by small interference RNA (siRNA), which becomes a powerful tool for genetic analysis and novel gene therapy. However, one of the major obstacles for siRNA delivery is the difficulty to cross the biological membrane due to its hydrophilicity and high molecular weight. We evaluated the potential use of the starburst polyamidoamine dendrimer (generation 3) conjugate with α-cyclodextrin having an average degree of substitution of 2.4 (α-CDE conjugate) as a siRNA carrier for RNAi. The ternary complex composed of pGL2 control vector (pDNA)/pGL2 siRNA/α-CDE conjugate showed higher pGL2 siRNA sequence-specific gene silencing effects without off-target effects than those of commercial transfection reagents such as Lipofectamine^<TM>2000 (LP), TransFast^<TM> (TF) and Lipofectin^<TM> (LF). In the binary complex (siRNA/carrier) system, the similar inhibitory effects of α-CDE conjugate were observed without cytotoxicity. These superior RNAi effects of α-CDE conjugate to the other commercial transfection reagents could be attributed to stable complex formation and cytoplasmic distribution of siRNA after transfection. These results suggest that α-CDE conjugate has the potential to be a novel carrier for siRNA.