期刊
MOLECULAR PHARMACEUTICS
卷 9, 期 3, 页码 470-481出版社
AMER CHEMICAL SOC
DOI: 10.1021/mp2006104
关键词
dendrimer; sticky siRNA; siRNA delivery; gene silencing; Hsp27; prostate cancer
资金
- international ERA-Net EURONANOMED
- National Natural Science Foundation of China [20572081]
- National Mega Project on Major Drug Development [2009ZX0930-014]
- Association Francaise contre les Myopathies [13074, 10793]
- Wuhan University
- CNRS
- INSERM
- European COST Action [TD0802]
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.
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