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

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 xenog raft 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.

JS‐K induces reactive oxygen species‐dependent anti‐cancer effects by targeting mitochondria respiratory chain complexes in gastric cancer

“…12 In addition, JS-K also significantly inhibits the growth of HL-60 and OPM1 multiple myeloma cells inoculated subcutaneously in mice. 3,6,29 Therefore, JS-K exhibits significant anti-cancer activity in both solid tumours and blood malignancies. However, the role of JS-K in the treatment of orthotopic tumours is controversial because JS-K inhibited the growth of human hepatoma JM-1 cells implanted intrahepatically in nude rats 2 ; however, it did not result in tumour growth retardation or extend survival within tracranial U87 rat glioma.…”

“…In compliance with our results, JS‐K suppresses the growth of some solid tumour cells subcutaneously implanted into the flank of nude mice, including human prostate cancer (PPC‐1) and NSCLC (H1703 and H1944) cells . In addition, JS‐K also significantly inhibits the growth of HL‐60 and OPM1 multiple myeloma cells inoculated subcutaneously in mice . Therefore, JS‐K exhibits significant anti‐cancer activity in both solid tumours and blood malignancies.…”

Glutathione <em>S</em>-transferase &pi;: a potential role in antitumor therapy

“…While JS-K has been shown to be advantageous in treating cancer, its clinical use has been hindered with reports of poor solubility. Structural modification of JS-K is able to prolong its half-life, and combining JS-K with special nanoparticles can greatly improve its solubility and stability, 103 , 113 further improving its prospects for clinical applications. JS-K and many other NO prodrugs represent an innovative biological approach in the development of anticancer therapeutics.…”

Organometallic Ruthenium Nitrosyl Obtained by C–H Bond Activation – Photoinduced Delivery of Nitric Oxide and NO‐Mediated Antiproliferation Activity Studies

“…The idea for the present study originated from some recent reports on nitric oxide and its antitumor activity studies. Shami and co‐workers reported that NO has a direct cytotoxic effect on tumor cells. They mentioned that NO leads to the apoptosis of tumor cells through the posttranslational modification of several important proteins.…”