Arginine-terminated generation 4 PAMAM dendrimer as an effective nanovector for functional siRNA delivery in vitro and in vivo.
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.
State Key Laboratory of Virology, College of Chemistry and Molecular Sciences, Wuhan University , Wuhan 430072, P. R. China.
Cheng
C
Liu
Xiaoxuan
X
Liu
Palma
P
Rocchi
Fanqi
F
Qu
Juan L
JL
Iovanna
Ling
L
Peng
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D049329:Nanostructures / Q000737:chemistry*; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D050091:Dendrimers; D004337:Drug Carriers; C531249:Poly(amidoamine); D011073:Polyamines; D034741:RNA, Small Interfering; D001120:Arginine