title: Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells.
abstract: BACKGROUND
  We report pharmacokinetic (PK) data, evaluation of modifications for increased stability, evaluation for cellular uptake, and mediation of regression of breast cancer for the aptamer OPN-R3.
  
  
  METHODS
  The OPN-R3 aptamer was assessed for PK data in vivo with additional comparison of IV and subcutaneous dosing. Five aptamer variants were generated by differential 2'-O-methylation for comparison with parent. OPN-R3-Cy3 was incubated with MDA-MB231 cells and cellular uptake evaluated under confocal microscopy. Mice were treated with OPN-R3, mutant, or saline 3 weeks after inoculation with MDA-MB231 cells and tumor size was evaluated.
  
  
  RESULTS
  OPN-R3 PK data were: t(1/2) 7.76 hours, T(max) 3 hours, C(max) 13.2 mmol/L, mean residence time 9 hours, AUC (0-t) 161.9 mmol/hr/L, and K(d) 57.2 nmol/L. The half-life was higher when given intravenously versus subcutaneously (E(1/2) 7.93 vs 0.74 hours). The 2' methylation of all available bases increased unmodified aptamer stability and affinity (t(1/2) 6.2 hours; K(d) 520 nmol/L), but this did not improve on parent aptamer (t(1/2) 7.78 hours, K(d) 18 nmol/L). The aptamer remained extracellular. OPN-R3 caused regression of tumor to levels seen at 1 week after tumor inoculation.
  
  
  CONCLUSIONS
  We show the efficacy of OPN-R3 for reversing growth of breast cancer cells with adequate PK stability for clinical application.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA.
authors.forename: Lindsay Jones
authors.initials: LJ
authors.lastname: Talbot
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Mi
authors.forename: Syamal Dave
authors.initials: SD
authors.lastname: Bhattacharya
authors.forename: Victoria
authors.initials: V
authors.lastname: Kim
authors.forename: Hongtao
authors.initials: H
authors.lastname: Guo
authors.forename: Paul C
authors.initials: PC
authors.lastname: Kuo
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D053495:Osteopontin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D052157:Aptamers, Nucleotide; D053495:Osteopontin