Nanomicelles co-loading CXCR4 antagonist and doxorubicin combat the refractory acute myeloid leukemia
Meichen Zhang 1, Yangyang Ge 1, Shilin Xu
1, Xiaocui Fang 2, Jie Meng 1, Lanlan Yu 1, Chenxuan Wang 1, Jian Liu 1, Tao
Wen 1, Yanlian Yang 2, Chen Wang 3, Haiyan Xu 4
Pharmacol Res. 2022 Oct 12;185:106503. doi:
10.1016/j.phrs.2022.106503. Online ahead of print.
PMID: 36241000
Abstract
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.