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Lipid nanoparticle siRNA systems for silencing the androgen receptor in human prostate cancer in vivo
- Source :
- International Journal of Cancer. 131:E781-E790
- Publication Year :
- 2012
- Publisher :
- Wiley, 2012.
-
Abstract
- 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 our 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 i.v. injection. To our knowledge, this is the first report demonstrating the feasibility of LNP delivery of siRNA for silencing AR gene expression in vivo.
- Subjects :
- Male
Cancer Research
Biology
Small hairpin RNA
Prostate cancer
In vivo
LNCaP
Gene expression
Androgen Receptor Antagonists
Tumor Cells, Cultured
medicine
Humans
Gene silencing
RNA, Small Interfering
Prostatic Neoplasms
medicine.disease
Lipids
Xenograft Model Antitumor Assays
Molecular biology
Gene Expression Regulation, Neoplastic
Androgen receptor
Oncology
Receptors, Androgen
Cell culture
Disease Progression
Nanoparticles
Subjects
Details
- ISSN :
- 00207136
- Volume :
- 131
- Database :
- OpenAIRE
- Journal :
- International Journal of Cancer
- Accession number :
- edsair.doi.dedup.....1f7eaea0c943129a7f221593b08547db