Pharmaceutical Research

, Volume 32, Issue 4, pp 1395–1406 | Cite as

Effect of a Pluronic® P123 Formulation on the Nitric Oxide-Generating Drug JS-K

  • Imit Kaur
  • Ken M. Kosak
  • Moises Terrazas
  • James N. Herron
  • Steven E. Kern
  • Kenneth M. Boucher
  • Paul J. Shami
Research Paper



O2-(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.


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.


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.


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.


acute myeloid leukemia (AML) glutathione JS-K nitric oxide O2-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] Pluronic® P123 



Alpha 1 acid glycoprotein


Acute myeloid leukemia


Area under the curve


Critical micelle concentration


Difference in the fluorescence in the absence and presence of JS-K or P123/JS-K at the concentration Q


Free energy


Enthalpy change


Entropy change


Quenched fluorescence


Fraction of initial fluorescence accessible to quencher


Fluorescence in the absence of external quencher




Hydrophilic-lipophilic balance


High performance liquid chromatography


Human serum albumin


Association binding constant


Potassium iodide


Quenching rate constant


Stern Volmer Constant






Nitric oxide


Poly(ethylene oxide)


Poly(propylene oxide)


Conc. of quencher/drug


Temperature in Kelvin


Transmission electron microscopy


Ultra performance liquid chromatography




Average lifetime of HSA molecule in absence of JS-K (quencher) or any other drug



This work was supported by grant RO1 CA129611 from the National Cancer Institute.

Paul Shami is Scientific Founder, Chief Medical Officer and Chairman of the Board of Directors of JSK Therapeutics Inc.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Imit Kaur
    • 1
  • Ken M. Kosak
    • 2
  • Moises Terrazas
    • 2
  • James N. Herron
    • 1
  • Steven E. Kern
    • 1
  • Kenneth M. Boucher
    • 3
  • Paul J. Shami
    • 1
    • 2
  1. 1.Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of UtahSalt Lake CityUSA
  2. 2.Division of Hematology and Hematologic Malignancies and Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  3. 3.Department of Oncological Sciences and Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA

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