Chen Mengting, Fang Xiaocui, Du Rong, Meng Jie, Liu Jingyi, Liu Mingpeng, Yang Yanlian, Wang Chen
CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Pharmaceutics. 2023 Sep 12;15(9):2305. doi: 10.3390/pharmaceutics15092305.
Chronic myeloid leukemia (CML) is recognized as a classic clonal myeloproliferative disorder. Given the limited treatment options for CML patients in the accelerated phase (AP) and blast phase (BP), there is an evident need to develop new therapeutic strategies. This has the potential to improve outcomes for individuals in the advanced stages of CML. A promising therapeutic target is Wilms' tumor 1 (WT1), which is highly expressed in BP-CML cells and plays a crucial role in CML progression. In this study, a chemically synthesized nucleus-targeting WT1 antagonistic peptide termed WIP2W was identified. The therapeutic implications of both the peptide and its micellar formulation, M-WIP2W, were evaluated in WT1 BP-CML cell lines and in mice. The findings indicate that WIP2W can bind specifically to the WT1 protein, inducing cell cycle arrest and notable cytotoxicity in WT1 BP-CML cells. Moreover, subcutaneous injections of M-WIP2W were observed to significantly enhance intra-tumoral accumulation and to effectively inhibit tumor growth. Thus, WIP2W stands out as a potent and selective WT1 inhibitor, and the M-WIP2W nanoformulation appears promising for the therapeutic treatment of refractory CML as well as other WT1-overexpressing malignant cancers.
慢性髓性白血病（CML）被认为是一种典型的克隆性骨髓增殖性疾病。鉴于加速期（AP）和急变期（BP）的CML患者治疗选择有限，显然需要开发新的治疗策略。这有可能改善CML晚期患者的预后。一个有前景的治疗靶点是威尔姆斯瘤1（WT1），它在BP-CML细胞中高度表达，在CML进展中起关键作用。在本研究中，鉴定了一种化学合成的靶向细胞核的WT1拮抗肽，称为WIP2W。在WT1 BP-CML细胞系和小鼠中评估了该肽及其胶束制剂M-WIP2W的治疗意义。研究结果表明，WIP2W可以特异性结合WT1蛋白，诱导WT1 BP-CML细胞的细胞周期停滞和显著的细胞毒性。此外，观察到皮下注射M-WIP2W可显著增强肿瘤内蓄积并有效抑制肿瘤生长。因此，WIP2W是一种有效的选择性WT1抑制剂，M-WIP2W纳米制剂对于难治性CML以及其他WT1过表达的恶性肿瘤的治疗似乎很有前景。
