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 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.
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Authors | Imit Kaur, Ken M Kosak, Moises Terrazas, James N Herron, Steven E Kern, Kenneth M Boucher, Paul J Shami |
Journal | Pharmaceutical research
(Pharm Res)
Vol. 32
Issue 4
Pg. 1395-406
(Apr 2015)
ISSN: 1573-904X [Electronic] United States |
PMID | 25330743
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antineoplastic Agents
- Azo Compounds
- Blood Proteins
- Drug Carriers
- Micelles
- Nitric Oxide Donors
- O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate
- Piperazines
- Prodrugs
- pluronic block copolymer P123
- Poloxalene
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Topics |
- Animals
- Antineoplastic Agents
(administration & dosage, pharmacokinetics, therapeutic use)
- Azo Compounds
(administration & dosage, pharmacokinetics, therapeutic use)
- Blood Proteins
(metabolism)
- Cell Survival
(drug effects)
- Drug Carriers
(chemistry)
- Drug Stability
- HL-60 Cells
- Humans
- Mice, Inbred NOD
- Mice, SCID
- Micelles
- Molecular Structure
- Nitric Oxide Donors
(administration & dosage, pharmacokinetics, therapeutic use)
- Particle Size
- Piperazines
(administration & dosage, pharmacokinetics, therapeutic use)
- Poloxalene
(chemistry)
- Prodrugs
(administration & dosage, pharmacokinetics)
- Protein Binding
- Surface Properties
- U937 Cells
- Xenograft Model Antitumor Assays
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