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Synthetic CXCR4 Antagonistic Peptide Assembling with Nanoscaled Micelles Combat Acute Myeloid Leukemia
Author(s) -
Meng Jie,
Ge Yangyang,
Xing Haiyan,
Wei Hui,
Xu Shilin,
Liu Jian,
Yan Doudou,
Wen Tao,
Wang Min,
Fang Xiaocui,
Ma Lilusi,
Yang Yanlian,
Wang Chen,
Wang Jianxiang,
Xu Haiyan
Publication year - 2020
Publication title -
small
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.785
H-Index - 236
eISSN - 1613-6829
pISSN - 1613-6810
DOI - 10.1002/smll.202001890
Subject(s) - myeloid leukemia , cxcr4 , spleen , pharmacology , chemokine receptor , bone marrow , cancer research , chemokine , leukemia , homoharringtonine , medicine , myeloid , immunology , receptor
Acute myeloid leukemia (AML) is the most common adult acute leukemia with very low survival rate due to drug resistance and high relapse rate. The C‐X‐C chemokine receptor 4 (CXCR4) is highly expressed by AML cells, actively mediating chemoresistance and reoccurrence. Herein, a chemically synthesized CXCR4 antagonistic peptide E5 is fabricated to micelle formulation (M‐E5) and applied to refractory AML mice, and its therapeutic effects and pharmacokinetics are investigated. Results show that M‐E5 can effectively block the surface CXCR4 in leukemic cells separated from bone marrow (BM) and spleen, and inhibit the C‐X‐C chemokine ligand 12‐mediated migration. Subcutaneous administration of M‐E5 significantly inhibits the engraftment of leukemic cells in spleen and BM, and mobilizes residue leukemic cells into peripheral blood, reducing organs’ burden and significantly prolonging the survival of AML mice. M‐E5 can also increase the efficacy of combining regime of homoharringtonine and doxorubicin. Ribonucleic acid sequencing demonstrates that the therapeutic effect is contributed by inhibiting proliferation and enhancing apoptosis and differentiation, all related to the CXCR4 signaling blockade. M‐E5 reaches the concentration peak at 2 h after administration with a half‐life of 14.5 h in blood. In conclusion, M‐E5 is a novel promising therapeutic candidate for refractory AML treatment.