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

• Published in: Pharmaceutical research 2015-04, Vol.32 (4), p.1395-1406
• Main Authors: Kaur, Imit, Kosak, Ken M., Terrazas, Moises, Herron, James N., Kern, Steven E., Boucher, Kenneth M., Shami, Paul J.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Azo Compounds - administration & dosage; Azo Compounds - pharmacokinetics; Azo Compounds - therapeutic use; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood Proteins - metabolism; Cell Survival - drug effects; Drug Carriers - chemistry; Drug Stability; HL-60 Cells; Humans; Medical Law; Mice, Inbred NOD; Mice, SCID; Micelles; Molecular Structure; Nitric Oxide Donors - administration & dosage; Nitric Oxide Donors - pharmacokinetics; Nitric Oxide Donors - therapeutic use; Particle Size; Pharmacology/Toxicology; Pharmacy; Piperazines - administration & dosage; Piperazines - pharmacokinetics; Piperazines - therapeutic use; Poloxalene - chemistry; Prodrugs - administration & dosage; Prodrugs - pharmacokinetics; Protein Binding; Research Paper; Surface Properties; U937 Cells; Xenograft Model Antitumor Assays
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-014-1542-9

ABSTRACT Purpose 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 IL2R γ 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 IL2R γ null mice when compared to free JS-K-treated NOD/SCID IL2R γ 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.