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Prostate-targeted biodegradable nanoparticles loaded with androgen receptor silencing constructs eradicate xenograft tumors in mice
Yang, Jun Xie, Sheng-Xue Huang, Yiling Ling, Min Liu, Jihong Ran, Yali Wang, Yanlin Thrasher, J. Brantley Berkland, Cory J. Li, Benyi
Yang, Jun
Xie, Sheng-Xue
Huang, Yiling
Ling, Min
Liu, Jihong
Ran, Yali
Wang, Yanlin
Thrasher, J. Brantley
Berkland, Cory J.
Li, Benyi
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Abstract
BACKGROUND: Prostate cancer is the major cause of cancer death in men and the androgen receptor (AR) has been shown to play a critical role in the progression of the disease. Our previous reports showed that knocking down the expression of the AR gene using a siRNA-based approach in prostate cancer cells led to apoptotic cell death and xenograft tumor eradication. In this study, we utilized a biodegradable nanoparticle to deliver the therapeutic AR shRNA construct specifically to prostate cancer cells. MATERIALS & METHODS: The biodegradable nanoparticles were fabricated using a poly(dl-lactic-co-glycolic acid) polymer and the AR shRNA constructs were loaded inside the particles. The surface of the nanoparticles were then conjugated with prostate-specific membrane antigen aptamer A10 for prostate cancer cell-specific targeting. RESULTS: A10-conjugation largely enhanced cellular uptake of nanoparticles in both cell culture- and xenograft-based models. The efficacy of AR shRNA encapsulated in nanoparticles on AR gene silencing was confirmed in PC-3/AR-derived xenografts in nude mice. The therapeutic property of A10-conjugated AR shRNA-loaded nanoparticles was evaluated in xenograft models with different prostate cancer cell lines: 22RV1, LAPC-4 and LNCaP. Upon two injections of the AR shRNA-loaded nanoparticles, rapid tumor regression was observed over 2 weeks. Consistent with previous reports, A10 aptamer conjugation significantly enhanced xenograft tumor regression compared with nonconjugated nanoparticles. DISCUSSION: These data demonstrated that tissue-specific delivery of AR shRNA using a biodegradable nanoparticle approach represents a novel therapy for life-threatening prostate cancers.
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Date
2012-09
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Publisher
Future Medicine
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Research Projects
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Keywords
Androgen receptor, Aptamer, Nanoparticle, Prostate cancer, Prostate-specific membrane antigen, siRNA
Citation
Yang, J., Xie, S.-X., Huang, Y., Ling, M., Liu, J., Ran, Y., … Li, B. (2012). Prostate-targeted biodegradable nanoparticles loaded with androgen receptor silencing constructs eradicate xenograft tumors in mice. Nanomedicine (London, England), 7(9), 1297–1309. http://doi.org/10.2217/nnm.12.14