Efficient delivery of sticky siRNA and potent gene silencing in a prostate cancer model using a generation 5 triethanolamine-core PAMAM dendrimer.
Successful achievement of RNA interference in therapeutic applications requires safe and efficient vectors for siRNA delivery. In the present study, we demonstrate that a triethanolamine (TEA)-core PAMAM dendrimer of generation 5 (G(5)) is able to deliver sticky siRNAs bearing complementary A(n)/T(n) 3'-overhangs effectively to a prostate cancer model in vitro and in vivo and produce potent gene silencing of the heat shock protein 27, leading to a notable anticancer effect. The complementary A(n)/T(n) (n = 5 or 7) overhangs characteristic of these sticky siRNA molecules help the siRNA molecules self-assemble into "gene-like" longer double-stranded RNAs thus endowing a low generation dendrimer such as G(5) with greater delivery capacity. In addition, the A(n)/T(n) (n = 5 or 7) overhangs act as protruding molecular arms that allow the siRNA molecule to enwrap the dendrimer and promote a better interaction and stronger binding, ultimately contributing toward the improved delivery activity of G(5). Consequently, the low generation dendrimer G(5) in combination with sticky siRNA therapeutics may constitute a promising gene silencing-based approach for combating castration-resistant prostate tumors or other cancers and diseases, for which no effective treatment currently exists.
Département de Chimie, Centre Interdisciplinaire de Nanoscience de Marseille, CNRS UMR 7325, Aix-Marseille Université, 163 avenue de Luminy, 13288 Marseille, France.
Xiaoxuan
X
Liu
Cheng
C
Liu
Erik
E
Laurini
Paola
P
Posocco
Sabrina
S
Pricl
Fanqi
F
Qu
Palma
P
Rocchi
Ling
L
Peng
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry*; D004983:Ethanolamines / Q000737:chemistry*; D005434:Flow Cytometry; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D050091:Dendrimers; D004983:Ethanolamines; C104700:PAMAM Starburst; D034741:RNA, Small Interfering; C009546:triethanolamine