Kaur Imit, Kosak Ken M, Terrazas Moises, Herron James N, Kern Steven E, Boucher Kenneth M, Shami Paul J
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, USA.
Pharm Res. 2015 Apr;32(4):1395-406. doi: 10.1007/s11095-014-1542-9. Epub 2014 Oct 18.
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.
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.
O(2)-(2,4-二硝基苯基)1-[(4-乙氧羰基)哌嗪-1-基]重氮-1,2-二醇盐（即JS-K）是一种具有前景的抗肿瘤活性的芳基重氮二醇盐类一氧化氮供体前药。JS-K具有挑战性的溶解性和稳定性。我们旨在对普朗尼克（®）P123配制的JS-K（P123/JS-K）与游离JS-K进行表征和比较。
我们测定了普朗尼克（®）P123的胶束大小、形状和临界胶束浓度。使用HL-60和U937细胞在体外评估疗效，并在NOD/SCID IL2Rγ（缺失）小鼠中使用HL-60细胞进行体内异种移植实验来评估疗效。我们比较了JS-K和P123/JS-K在不同介质中的稳定性。我们还比较了JS-K和P123/JS-K的血浆蛋白结合情况。我们测定了结合常数和斯特恩-沃尔默常数以及热力学参数。
球形的P123/JS-K胶束比空白P123更小。与游离JS-K相比，P123/JS-K制剂在缓冲盐水、全血、血浆和RPMI培养基中更稳定。P123影响了JS-K的蛋白结合特性。在HL-60和U937细胞中进行体外测试时，它与单独的JS-K疗效相当，并且在体内，与游离JS-K处理的NOD/SCID IL2Rγ（缺失）小鼠相比，P123/JS-K处理的NOD/SCID IL2Rγ（缺失）小鼠观察到更大程度的肿瘤消退。
普朗尼克（®）P123使JS-K增溶、稳定并影响其蛋白结合特性。P123/JS-K在体内显示出比游离JS-K更强的抗肿瘤活性。
