title: Nanomicellar TGX221 blocks xenograft tumor growth of prostate cancer in nude mice.
abstract: BACKGROUND
  Combination of androgen ablation along with early detection and surgery has made prostate cancer highly treatable at the initial stage. However, this cancer remains the second leading cause of cancer death among American men due to castration-resistant progression, suggesting that novel therapeutic agents are urgently needed for this life-threatening condition. Phosphatidylinositol 3-kinase p110β is a major cellular signaling molecule and has been identified as a critical factor in prostate cancer progression. In a recent report, we established a nanomicelle-based strategy to deliver p110β-specific inhibitor TGX221 to prostate cancer cells by conjugating the surface of nanomicelles with a RNA aptamer against prostate specific membrane antigen (PSMA) present in all clinical prostate cancers. In this study, we tested this nanomicellar TGX221 for its in vivo anti-tumor effect in mouse xenograft models.
  
  
  METHODS
  Prostate cancer cell lines LAPC-4, LNCaP, C4-2 and 22RV1 were used to establish subcutaneous xenograft tumors in nude mice. Paraffin sections from xenograft tumor specimens were used in immunohistochemistry assays to detect AKT phosphorylation, cell proliferation marker Ki67 and proliferating cell nuclear antigen (PCNA), as well as 5-bromo-2-deoxyuridine (BrdU) incorporation. Quantitative PCR assay was conducted to determine prostate-specific antigen (PSA) gene expression in xenograft tumors.
  
  
  RESULTS
  Although systemic delivery of unconjugated TGX221 significantly reduced xenograft tumor growth in nude mice compared to solvent control, the nanomicellar TGX221 conjugates completely blocked tumor growth of xenografts derived from multiple prostate cancer cell lines. Further analyses revealed that AKT phosphorylation and cell proliferation indexes were dramatically reduced in xenograft tumors received nanomicellar TGX221 compared to xenograft tumors received unconjugated TGX221 treatment. There was no noticeable side effect by gross observation or at microscopic level of organ tissue section.
  
  
  CONCLUSIONS
  These data strongly suggest that prostate cancer cell-targeted nanomicellar TGX221 is an effective anti-cancer agent for prostate cancer.
authors.affiliation: Department of Urology, The University of Kansas Medical Center, Kansas City, Kansas; Department of Urology, Tongji Hospital, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Ruibao
authors.initials: R
authors.lastname: Chen
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Yang
authors.forename: Xing
authors.initials: X
authors.lastname: Zeng
authors.forename: Wencong
authors.initials: W
authors.lastname: Jiang
authors.forename: Jihong
authors.initials: J
authors.lastname: Liu
authors.forename: J Brantley
authors.initials: JB
authors.lastname: Thrasher
authors.forename: M Laird
authors.initials: ML
authors.lastname: Forrest
authors.forename: Benyi
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000032:analysis; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D000954:Antigens, Surface; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011744:Pyrimidinones; C504718:TGX 221; D051057:Proto-Oncogene Proteins c-akt; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen
keywords: TGX221; cancer therapy; micelle; nanotechnology; p110β; prostate cancer