A novel CD123-targeted therapeutic peptide loaded by micellar delivery system combats refractory acute myeloid leukemia
Shilin Xu 1, Meichen Zhang 1, Xiaocui Fang
2 3, Jie Meng 1, Haiyan Xing 4, Doudou Yan 1, Jian Liu 1, Yanlian Yang 2 3, Tao
Wen 1, Weiqi Zhang 1, Jianxiang Wang 5, Chen Wang 6 7, Haiyan Xu 8
J Hematol Oncol. 2021 Nov 13;14(1):193.
doi: 10.1186/s13045-021-01206-y.
PMID: 34774070
Abstract
Acute
myeloid leukemia (AML) is a common malignant heterogeneous hematopoietic
disease with very low average 5-year survival rate due to the refractory
feature and high rate of relapse. CD123 is highly expressed on multiple types
of AML cells, especially leukemia stem cells, and closely associated with the
poor prognosis of AML. Aiming to meet the urgent demand to targeted
therapeutics for the refractory AML patients, herein we synthesize a CD123
antagonistic peptide (PO-6) loaded in nanomicelles (mPO-6), and investigated
its therapeutic effect and pharmacokinetics on a lab-established refractory AML
mice model (AE & CKITD816V). It is shown that the PO-6 can effectively bind
to the CD123+ AML cells and the micellar formulation mPO-6 increases the
dissolution stability and the specific binding capacity. When injected
intravenously, mPO-6 significantly prolongs the survival of the refractory AML
mice by interfering CD123/IL-3 axis, evidenced by the down regulation of
phosphorylation of STAT5 and PI3K/AKT and the inhibition of activated NF-κB in
the nucleus, as well as by the analysis results of next generation
RNA-sequencing (RNA-seq) with the bone marrow of the AML mice. The antagonistic
effect leads to the significantly reduction of AML cells infiltration in the
bone marrow of the AML mice. In conclusion, mPO-6 could provide a potent
antagonistic therapeutic approach for targeted treatment of AML.