Uckun Fatih M, Dibirdik Ilker, Qazi Sanjive, Yiv Seang
Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA.
Arzneimittelforschung. 2010;60(4):210-7. doi: 10.1055/s-0031-1296275.
WHI-P131 (CAS 202475-60-3) is a dual-function inhibitor of JAK3 tyrosine kinase that demonstrated potent in vivo anti-inflammatory and anti-leukemic activity in several preclinical animal models. This is the first report of the development of nanoparticle (NP) constructs ofWHI-P131. Fourty-eight distinct NP formulations were prepared and WHI-P131 encapsulation efficiencies > 95% and intraliposomal WHI-P131 concentrations >10 mg/mL were achieved in lead NP formulations. The anti-cancer activity of WHI-P131-NP, a PEGylated lead formulation was tested in vitro and in vivo. Notably, WHI-P131-NP was capable of causing apoptotic death in primary leukemia cells from chemotherapy-resistant acute lymphoblastic leukemia (ALL) as well as chronic lymphocytic leukemia (CLL) patients. WHI-P131-NP was also active in the RS4;11 SCID mouse xenograft model of chemotherapy-resistant B-lineage ALL. The life table analysis showed that WHI-P131-NP was more effective than WHI-P131 (P = 0.01), vincristine (P < 0.0001), or vehicle (P < 0.0001). These experimental results demonstrate that the nanotechnology-enabled delivery of WHI-P131 shows therapeutic potential against leukemias with constitutive activation of the JAK3-STAT3/STAT5 molecular target.
WHI-P131（CAS 202475-60-3）是一种JAK3酪氨酸激酶的双功能抑制剂，在多种临床前动物模型中显示出强大的体内抗炎和抗白血病活性。这是关于WHI-P131纳米颗粒（NP）构建体研发的首次报告。制备了48种不同的NP制剂，在主要NP制剂中实现了WHI-P131包封效率>95%以及脂质体内WHI-P131浓度>10 mg/mL。对一种聚乙二醇化的主要制剂WHI-P131-NP的抗癌活性进行了体外和体内测试。值得注意的是，WHI-P131-NP能够使化疗耐药的急性淋巴细胞白血病（ALL）以及慢性淋巴细胞白血病（CLL）患者的原代白血病细胞发生凋亡性死亡。WHI-P131-NP在化疗耐药的B系ALL的RS4;11 SCID小鼠异种移植模型中也具有活性。生命表分析表明，WHI-P131-NP比WHI-P131（P = 0.01）、长春新碱（P < 0.0001）或赋形剂（P < 0.0001）更有效。这些实验结果表明，通过纳米技术递送WHI-P131对具有JAK3-STAT3/STAT5分子靶点组成性激活的白血病显示出治疗潜力。
