title: Prostate-targeted biodegradable nanoparticles loaded with androgen receptor silencing constructs eradicate xenograft tumors in mice.
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.
  
  
  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.
  
  
  CONCLUSIONS
  These data demonstrated that tissue-specific delivery of AR shRNA using a biodegradable nanoparticle approach represents a novel therapy for life-threatening prostate cancers.
authors.affiliation: Department of Urology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Sheng-Xue
authors.initials: SX
authors.lastname: Xie
authors.forename: Yiling
authors.initials: Y
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Ling
authors.forename: Jihong
authors.initials: J
authors.lastname: Liu
authors.forename: Yali
authors.initials: Y
authors.lastname: Ran
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.forename: J Brantley
authors.initials: JB
authors.lastname: Thrasher
authors.forename: Cory
authors.initials: C
authors.lastname: Berkland
authors.forename: Benyi
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000737:chemistry; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D015316:Genetic Therapy; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D011944:Receptors, Androgen / Q000235:genetics*; D014183:Transplantation, Heterologous
chemical_list: D052157:Aptamers, Nucleotide; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D017430:Prostate-Specific Antigen