Successful therapeutic implementation of RNA interference critically depends on systems able to safely and efficiently deliver
small interfering RNA (
siRNA).
Dendrimers are emerging as appealing nanovectors for
siRNA delivery by virtue of their unique well-defined dendritic nanostructure within which is confined an intriguing cooperativity and multivalency. We have previously demonstrated that structurally flexible
triethanolamine (
TEA) core
poly(amidoamine) (PAMAM)
dendrimers of high generations are effective nanovectors for
siRNA delivery in vitro and in vivo. In the present study, we have developed
arginine-terminated
dendrimers with the aim of combining and harnessing the unique
siRNA delivery properties of the
TEA-core
PAMAM dendrimer and the cell-penetrating advantages of the
arginine-rich motif. A generation 4
dendrimer of this family (G4Arg) formed stable dendriplexes with
siRNA, leading to improved cell uptake of
siRNA by comparison with its nonarginine bearing
dendrimer counterpart. Moreover, G4Arg was demonstrated to be an excellent nanocarrier for
siRNA delivery, yielding potent gene silencing and anticancer effects in
prostate cancer models both in vitro and in vivo with no discernible toxicity. Consequently, importing an
arginine residue on the surface of a
dendrimer is an appealing option to improve delivery efficiency, and at the same time, the
dendrimer G4Arg constitutes a highly promising nanovector for efficacious
siRNA delivery and holds great potential for further therapeutic applications.