Department of Biochemistry and Molecular Biology at the University of British Columbia, Vancouver, British Columbia, Canada.
The androgen receptor (AR) plays a critical role in the progression of prostate cancer. Silencing this protein using short hairpin RNA (shRNA) has been correlated with tumor growth inhibition and decreases in serum prostate specific antigen (PSA). In this study we have investigated the ability of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA) to silence AR in human prostate tumor cell lines in vitro and in LNCaP xenograft tumors following intravenous (i.v.) injection. In vitro screening studies using a panel of cationic lipids showed that LNPs containing the ionizable cationic lipid 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA) exhibited the most potent AR silencing effects in LNCaP cells. This is attributed to an optimized ability of DLin-KC2-DMA-containing LNP to be taken up into cells and to release the siRNA into the cell cytoplasm following endocytotic uptake. DLin-KC2-DMA LNPs were also effective in silencing the AR in a wild-type AR expressing cell line, LAPC-4, and a variant AR expressing cell line, CWR22Rv1. Importantly, it is demonstrated that LNP AR-siRNA systems containing DLin-KC2-DMA can silence AR gene expression in distal LNCaP xenograft tumors and decrease serum PSA levels following intravenous injection. To our knowledge, this is the first report demonstrating the feasibility of LNP delivery of siRNA for silencing AR gene expression in vivo.
Written by:
Lee JB, Zhang K, Tam YY, Tam YK, Belliveau NM, Sung VY, Lin PJ, Leblanc E, Ciufolini MA, Rennie PS, Cullis PR. Are you the author?
Reference: Int J Cancer. 2011 Nov 16. Epub ahead of print.
doi: 10.1002/ijc.27361
PubMed Abstract
PMID: 22095615
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