Nanomicelles co-loading CXCR4 antagonist and doxorubicin combat the refractory acute myeloid leukemia

髓系白血病 阿霉素 CXCR4型 骨髓 癌症研究 药理学 心脏毒性 趋化因子受体 白血病 CXCR4拮抗剂 趋化因子 医学 脾脏 化疗 受体 免疫学 内科学
作者
Meichen Zhang,Yangyang Ge,Shilin Xu,Xiaocui Fang,Jie Meng,Lanlan Yu,Chenxuan Wang,Jian Liu,Tao Wen,Yanlian Yang,Chen Wang,Haiyan Xu
出处
期刊:Pharmacological Research [Elsevier]
卷期号:185: 106503-106503 被引量:5
标识
DOI:10.1016/j.phrs.2022.106503
摘要

Acute myeloid leukemia (AML) is featured with poor prognosis and high mortality, because chemo-resistance, nonspecific distribution and dose-limiting toxicity lead to a high rate of relapse and a very low 5-year survival percentage of less than 25%. CXCR4 is a highly expressed chemokine receptor in multiple types of AML cells and closely associated with the drug resistance and relapse. In this work, we integrate a chemically synthesized CXCR4 antagonistic peptide and doxorubicin using DSPE-mPEG2000 micelles (referred to as M-E5-Dox) that is applied to a very challenging refractory AML mouse model as well as human AML cell lines. Results showed that M-E5-Dox can effectively bind to the CXCR4-expressing AML cells, downregulating the signaling proteins mediated by CXCR4/CXCL12 axis and increasing the cellular uptake of Dox. Importantly, M-E5-Dox remarkably decreases the leukemic cells in the peripheral blood and bone marrow, as well as their infiltration in the spleen and liver of the AML mice, which in turn prolongs the survival significantly. Meanwhile, M-E5-Dox did not increase the cardiotoxicity of Dox. In conclusion, M-E5-Dox harnesses the functions of CXCR4 specific binding and CXCR4 antagonism of the peptide and the tumor cell killing capacity of Dox, which displays significant therapeutic effects and promising translational potentials for the treatment of refractory AML.
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