title: Effect of a Pluronic(®) P123 formulation on the nitric oxide-generating drug JS-K.
abstract: OBJECTIVE
  O(2)-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] or JS-K is a nitric oxide-producing prodrug of the arylated diazeniumdiolate class with promising anti-tumor activity. JS-K has challenging solubility and stability properties. We aimed to characterize and compare Pluronic(®) P123-formulated JS-K (P123/JS-K) with free JS-K.
  
  
  METHODS
  We determined micelle size, shape, and critical micelle concentration of Pluronic(®) P123. Efficacy was evaluated in vitro using HL-60 and U937 cells and in vivo in a xenograft in NOD/SCID IL2Rγ (null) mice using HL-60 cells. We compared JS-K and P123/JS-K stability in different media. We also compared plasma protein binding of JS-K and P123/JS-K. We determined the binding and Stern Volmer constants, and thermodynamic parameters.
  
  
  RESULTS
  Spherical P123/JS-K micelles were smaller than blank P123. P123/JS-K formulation was more stable in buffered saline, whole blood, plasma and RPMI media as compared to free JS-K. P123 affected the protein binding properties of JS-K. In vitro it was as efficacious as JS-K alone when tested in HL-60 and U937 cells and in vivo greater tumor regression was observed for P123/JS-K treated NOD/SCID IL2Rγ (null) mice when compared to free JS-K-treated NOD/SCID IL2Rγ (null) mice.
  
  
  CONCLUSIONS
  Pluronic(®) P123 solubilizes, stabilizes and affects the protein binding characteristics of JS-K. P123/JS-K showed more in vivo anti-tumor activity than free JS-K.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Imit
authors.initials: I
authors.lastname: Kaur
authors.forename: Ken M
authors.initials: KM
authors.lastname: Kosak
authors.forename: Moises
authors.initials: M
authors.lastname: Terrazas
authors.forename: James N
authors.initials: JN
authors.lastname: Herron
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kern
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boucher
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shami
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001391:Azo Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001798:Blood Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D018922:HL-60 Cells; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008823:Micelles; D015394:Molecular Structure; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010316:Particle Size; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011060:Poloxalene / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011485:Protein Binding; D013499:Surface Properties; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D001798:Blood Proteins; D004337:Drug Carriers; D008823:Micelles; D020030:Nitric Oxide Donors; C474958:O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate; D010879:Piperazines; D011355:Prodrugs; C464484:pluronic block copolymer P123; D011060:Poloxalene