224 NANOPARTICLE-BASED PROSTATE CANCER CELL-SPECIFIC DELIVERY OF ANDROGEN RECEPTOR SIRNA INDUCES RAPID TUMOR REGRESSION IN NUDE MICE

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2012224 NANOPARTICLE-BASED PROSTATE CANCER CELL-SPECIFIC DELIVERY OF ANDROGEN RECEPTOR SIRNA INDUCES RAPID TUMOR REGRESSION IN NUDE MICE Stephen M. Graham, Jeffrey M. Holzbeierlein, Jun Yang, Sheng-xue Xie, Cory Berkland, J. Brantley Thrasher, and Benyi Li Stephen M. GrahamStephen M. Graham Kansas City, KS More articles by this author , Jeffrey M. HolzbeierleinJeffrey M. Holzbeierlein Kansas City, KS More articles by this author , Jun YangJun Yang Kansas City, KS More articles by this author , Sheng-xue XieSheng-xue Xie Lawrence, KS More articles by this author , Cory BerklandCory Berkland Lawrence, KS More articles by this author , J. Brantley ThrasherJ. Brantley Thrasher Kansas City, KS More articles by this author , and Benyi LiBenyi Li Kansas City, KS More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.278AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Medical treatment for metastatic prostate cancer (CaP) has relied heavily on androgen ablation, but unfortunately, almost all patients progress to more aggressive castration-resistant cancers. Recent studies suggest that androgen receptor (AR) signaling is required for hormone-refractory progression. We have previously demonstrated that ablation of AR protein by small interfering ribonucleic acid (siRNA)-mediated gene silencing led to profound apoptotic cell death in AR-native CaP cells. We also found that injection of a viral vector bearing the AR siRNA expression cassette into mice xenograft tumors of human CaP resulted in significant tumor suppression. In this study, we combined nanoparticle delivery with siRNA technology to determine its effectiveness in AR silencing in an in vivo model of CaP. METHODS We conjugated PLGA [poly-DL-lactic-co-glycolic acid] nanoparticles with A10 PSMA (prostate-specific membrane antigen) aptamer for CaP cell-specific targeting, loaded with ARHP8 shRNA (short hairpin RNA) vector or an empty GFP vector (negative control). Three different CaP cell lines including 22RV1, LAPC-4, and LNCaP were used to generate xenografts in nude mice for testing the tumor suppression effect of the ARHP8 nanoparticles in vivo. RESULTS The results revealed that injection of a 200 microliter nanoparticle solution containing 4 microgram ARHP shRNA plasmid DNA induced a dramatic AR gene silencing. Upon two injections of the ARHP8 nanoparticles, regardless of PSMA aptamer conjugation, a significant suppression of tumor growth was observed. Most importantly, PSMA aptamer conjugation significantly enhanced tumor eradication of the xenografts compared to non-conjugated nanoparticles. CONCLUSIONS We developed a nanoparticle-based approach for targeted delivery of the AR siRNA molecules for treatment of advanced CaP. Our data demonstrates that tissue-specific delivery of AR siRNA eliminated CaP xenografts that are dependent on AR for survival, representing a novel therapy or even a cure for this health-threatening disease. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byAtala A (2018) Re: Anisamide-Targeted Cyclodextrin Nanoparticles for siRNA Delivery to Prostate Tumours in MiceJournal of Urology, VOL. 190, NO. 1, (357-357), Online publication date: 1-Jul-2013. Volume 187Issue 4SApril 2012Page: e93 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Stephen M. Graham Kansas City, KS More articles by this author Jeffrey M. Holzbeierlein Kansas City, KS More articles by this author Jun Yang Kansas City, KS More articles by this author Sheng-xue Xie Lawrence, KS More articles by this author Cory Berkland Lawrence, KS More articles by this author J. Brantley Thrasher Kansas City, KS More articles by this author Benyi Li Kansas City, KS More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...