chapter  7
20 Pages

Structurally Flexible and Amphiphilic Poly(Amidoamine) Dendrimers as Nonviral Vectors for siRNA Delivery

Among all the dendrimers, poly(amidoamine) dendrimers, also called PAMAM dendrimers, are the most extensively explored for siRNA delivery. PAMAM dendrimers bear primary amine terminals on the dendrimer surface, which are positively charged under physiological condition and ready to interact and condense with the negatively charged siRNA molecules through electrostatic interaction. These dendrimers also harbor tertiary amines in the interior, which are beneficial for the intracellular release of siRNA via the “proton sponge” effect.8,9 The released siRNA molecules will then eventually join the RNAi machinery to activate the gene silencing process. The first study on PAMAM dendrimers for siRNA delivery was reported in 2005 by Juliano and co-workers using commercially available ethylenediamine (EDA)-core PAMAM

dendrimer.10 Nevertheless, the employed PAMAM dendrimer and its related conjugates were not effective for functional siRNA delivery. In 2006, we reported the first successful dendrimerbased siRNA delivery11 using structurally flexible PAMAM dendrimers.12,13 These flexible dendrimers have a triethanolamine (TEA) core (Fig. 7.2) and are excellent vectors for the delivery of various RNAi molecules in vitro and in vivo.14,15 Recently, we have further explored amphiphilic dendrimers16-18 for siRNA delivery. Some of these amphiphilic dendrimers outperform the commercially available siRNA delivery agents and promote functional siRNA delivery in various cells including human primary and stem cells as well as in animal models. In this chapter, we will mainly focus on the structurally flexible and amphiphilic PAMAM dendrimers developed in our group and their siRNA delivery feature and potency.