Efficient delivery of small interfering RNA into cancer cells using dodecylated dendrimers

Polyamidoamine (PAMAM) dendrimers are promising nonviral gene vectors due to their well-defined molecular structure, low immune response and ease of modification. High generation PAMAM dendrimers are reported with relatively high efficacy in the delivery of small interfering RNA (siRNA), but are suffering from several drawbacks such as severe cytotoxicity and high cost of manufacturing. Here, we report several efficient siRNA vectors based on low generation dendrimers. Dodecylated G2, G3 and G4 PAMAM dendrimers show dramatically increased gene silencing efficiency with negligible cytotoxicity on several cell lines compared to unmodified dendrimers. The increased gene silencing efficacy is mainly attributed to the hydrophobic modification on the dendrimer surface which significantly increases the cellular uptake of dendrimer/siRNA complexes. In addition, the most efficient polymer G4-23C12 can also efficiently deliver Bcl-2 siRNA into cancer cells, specifically inhibit the expression of target gene in vitro, and further lead to cell apoptosis. This study reveals the structure-function relationship of lipid-modified dendrimers in siRNA delivery and provides valuable insight to guide the development of efficient and non-toxic siRNA vectors.