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

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ABSTRACT

Purpose

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.

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 IL2Rγnull 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 IL2Rγnull mice when compared to free JS-K-treated NOD/SCID IL2Rγnull 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.

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Abbreviations

AGP:

Alpha 1 acid glycoprotein

AML:

Acute myeloid leukemia

AUC:

Area under the curve

CMC:

Critical micelle concentration

dF:

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

dG:

Free energy

dH:

Enthalpy change

dS:

Entropy change

F:

Quenched fluorescence

f:

Fraction of initial fluorescence accessible to quencher

Fo:

Fluorescence in the absence of external quencher

GSH:

Glutathione

HLB:

Hydrophilic-lipophilic balance

HPLC:

High performance liquid chromatography

HSA:

Human serum albumin

Ka:

Association binding constant

KI:

Potassium iodide

Kq:

Quenching rate constant

Ksv:

Stern Volmer Constant

mL:

Milliliter

mM:

Milimolar

NO:

Nitric oxide

PEO:

Poly(ethylene oxide)

PPO:

Poly(propylene oxide)

Q:

Conc. of quencher/drug

T:

Temperature in Kelvin

TEM:

Transmission electron microscopy

UPLC:

Ultra performance liquid chromatography

μM:

Micromolar

τo :

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

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ACKNOWLEDGMENTS AND DISCLOSURES

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.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, USA

    Imit Kaur, James N. Herron, Steven E. Kern & Paul J. Shami

  2. Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Suite 2100, 2000 Circle of Hope, Salt Lake City, Utah, 84112, USA

    Ken M. Kosak, Moises Terrazas & Paul J. Shami

  3. Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

    Kenneth M. Boucher

Authors
  1. Imit Kaur
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  2. Ken M. Kosak
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Correspondence to Paul J. Shami.

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Kaur, I., Kosak, K.M., Terrazas, M. et al. Effect of a Pluronic® P123 Formulation on the Nitric Oxide-Generating Drug JS-K. Pharm Res 32, 1395–1406 (2015). https://doi.org/10.1007/s11095-014-1542-9

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  • DOI: https://doi.org/10.1007/s11095-014-1542-9

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