The polycomb repressive complex 1 (PRC1) protein, Bmi1 is overexpressed in acute myeloid leukemia and mediates histone H2A monoubiquitination through its ubiquitin (E3) ligase activity. The 2-pyridine-3-yl-methylene-indan-1,3-dione (PRT4165) inhibits PRC1-mediated H2A monoubiquitination but the poor aqueous solubility, and physiological instability limit its application. In current study, the encapsulation of PRT4165 in human serum albumin nanoparticles (HSANPs) improved its therapeutic efficacy as evident through the enhanced apoptosis, sub-G1 cell cycle arrest, depolarized mitochondrial membrane, reactive oxygen species generation and caspase 3 activation. The nanoformulation repressed Bmi1 through ubiquitin-proteasome pathway (UPP) and regulated H2AK119 ubiquitination in AML cells. Co-immunoprecipitation studies revealed the direct interaction of Bmi1 and C-Myb, a crucial regulator of AML pathogenesis. Moreover, PRT4165 encapsulated HSANPs showed improved in vivo biodistribution, better dispersibility and biocompatibility, and exhibited enhanced suppression of leukemia stem cell marker, CD45⁺ and activation of myeloid monocytes differentiation marker, CD11b⁺ in AML xenograft mouse model.

在急性粒细胞白血病中，多梳抑制复合物1（PRC1）蛋白Bmi1过表达，并通过其泛素（E3）连接酶活性介导组蛋白H2A单泛素化。2-吡啶-3-基-亚甲基-茚满-1,3-二酮（PRT4165）抑制PRC1介导的H2A单泛素化，但水溶性差，并且生理不稳定，限制了其应用。在当前的研究中，PRT4165在人血清白蛋白纳米颗粒（HSANP）中的封装改善了其治疗效果，这通过增强的细胞凋亡，亚G1细胞周期阻滞，线粒体膜去极化，活性氧生成和caspase 3活化来证明。纳米制剂通过泛素-蛋白酶体途径（UPP）抑制Bmi1，并调节AML细胞中的H2AK119泛素化。免疫共沉淀研究揭示了Bmi1和C-Myb的直接相互作用，C-Myb是AML发病机理的关键调节因子。此外，PRT4165封装的HSANP表现出改进体内生物分布，更好的分散性和生物相容性，并在AML异种移植小鼠模型中显示出对白血病干细胞标志物CD45 ^+的抑制作用增强，以及髓样单核细胞分化标志物CD11b ^+的激活。