A novel CD123-targeted therapeutic peptide loaded by micellar delivery system combats refractory acute myeloid leukemia

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.

CD123 Antagonistic Peptides Assembled with Nanomicelles Act as Monotherapeutics to Combat Refractory Acute Myeloid Leukemia

“…It has been well-documented that IL-3 can trigger the activation of NF-κB by the signaling pathway of STATs and PI3K/AKT, which mediated activation of multiple genes linked to cell proliferation and anti-apoptosis expressions. ,, It has been known that m PO-6 could competitively bind to the extracellular N-terminal domain of CD123 on the CD123 + AML cells, which is the important site for influencing IL-3-mediated signaling pathways . In this study, experimental results showed that m PO-6 played a CD123 antagonistic role to the MOLM-13 cells by inhibiting IL-3-mediated the phosphorylation of STAT5 and PI3K as well as the activation of NF-κB in the nucleus (Figure A,B).…”

“…In the current work, the AML mouse model was established by intravenously injecting AE and CKIT D816V cells into C57Bl/6 mice followed by X-ray irradiation at a dose of 450 cGy. The AML mice are refractory because they are not able to benefit from cytarabine, one of the first-line chemotherapeutics due to the gene mutation feature . We examined whether m PO-6 could prolong the survival of the mice following the schematic regimens (Figure A).…”

“…Lyophilized FITC-labeled or unlabeled peptide PO-6 (DDDYDTRAQGTDIGCDFRRISDDD) used in this study was identified by the cell-based selection process, which has been introduced in detail in our previous studies, and the peptides were synthesized and purchased from Guoping Pharmaceutical Co., Ltd. (Anhui, China). ,, A stock solution of PO-6 was dissolved in sterile PBS solution and stored at −80 °C.…”

“…Compared with antibodies, synthetic peptides have advantages including synthesis feasibility and lower cost. Previously, we had chemically synthesized novel antagonistic peptides targeting CD123 and CXCR4 by using a lab-developed cell-based selection process of a fragmental screening method, which prolonged the survival of the refractory AML animal model. , In these investigations, nanomicelles are applied that plays several important roles: one is to inhibit the self-aggregation tendency of the free peptides in the physiological environment, and another is that the micelles can act as carriers so that many of the peptide molecules could be assembled in the micelles, which increases the binding amount of PO-6 to the AML cells. In the present study, we systematically investigated the fabrication of nanomicelles loaded with the CD123 antagonistic peptide as well as the therapeutic effects, pharmacokinetics, and biodistribution.…”

Targeting macrophages in hematological malignancies: recent advances and future directions

“…CD123 is highly expressed on AML blasts and leukemic stem cells (LSCs) and demonstrates only a moderate expression on normal HSCs, suggesting that CD123 is a promising target antigen [ 190 ]. SIRPα receptors on macrophages interact with CD47 to inhibit phagocytosis.…”