Kushwaha Avinash Chandra, Mrunalini Boddu, Malhotra Pankaj, Karmakar Surajit, Roy Choudhury Subhasree
Epigenetics Research Laboratory, Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab 140306, India.
Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab 140306, India.
ACS Appl Mater Interfaces. 2025 Jan 8;17(1):711-724. doi: 10.1021/acsami.4c18737. Epub 2024 Dec 22.
The heterogeneous form of malignancy in the myeloid lineage of normal hematopoietic stem cells (HSCs) is characterized as acute myeloid leukemia (AML). The t(9;11) reciprocal translocation (p22;q23) generates MLL-AF9 oncogene, which results in myeloid-based monoblastic AML with frequent relapse and poor survival. MLL-AF9 binds with the C-Myb promoter and regulates AML onset, maintenance, and survival. The bone marrow microenvironment (BMM) protects leukemia stem cells (LSCs) from therapeutic agents, which can lead to relapsed condition. Targeting leukemia BMM can be a viable therapeutics approach for AML treatment, wherein bone homing bisphosphonate, ibandronic acid (IBD), can localize to the BMM. In order to target the BMM of AML, C-Myb siRNA was entrapped in Vitamin D nanoemulsion-functionalized with BMM-targeted IBD, which exhibited binding with bone slices and localization into mice bone marrow. IBD functionalization and C-Myb siRNA nanotherapy enhanced the suppression of LSCs (c-Kit) and the upregulation of myeloid differentiation markers CD11b and Gr-1 in peripheral blood and bone marrow of athymic nude mice and patient-derived xenograft models. IBD functionalization enhanced the downregulation of C-Myb and C-Myb-Survivin cross talk in bone marrow and spleen tissue responsible for AML onset, maintenance, and pathogenesis. Further C-Myb binding to Survivin promoter was abrogated by the present bone-marrow-targeted nanotherapy, signifying its translational potential for AML therapeutics.
正常造血干细胞（HSCs）髓系中的异质性恶性肿瘤形式被表征为急性髓系白血病（AML）。t(9;11)相互易位（p22;q23）产生MLL-AF9癌基因，这导致基于髓系的单核细胞性AML，具有频繁复发和低生存率。MLL-AF9与C-Myb启动子结合并调节AML的发生、维持和生存。骨髓微环境（BMM）保护白血病干细胞（LSCs）免受治疗药物的影响，这可能导致复发情况。靶向白血病BMM可能是一种可行的AML治疗方法，其中骨靶向双膦酸盐伊班膦酸（IBD）可定位于BMM。为了靶向AML的BMM，将C-Myb siRNA包裹在经BMM靶向IBD功能化的维生素D纳米乳剂中，其显示出与骨切片结合并定位于小鼠骨髓中。IBD功能化和C-Myb siRNA纳米疗法增强了对无胸腺裸鼠和患者来源异种移植模型外周血和骨髓中LSCs（c-Kit）的抑制以及髓系分化标志物CD11b和Gr-1的上调。IBD功能化增强了骨髓和脾脏组织中负责AML发生、维持和发病机制的C-Myb和C-Myb-生存素相互作用的下调。目前的骨髓靶向纳米疗法进一步消除了C-Myb与生存素启动子的结合，表明其在AML治疗中的转化潜力。
