Synthetic CXCR4 Antagonistic Peptide Assembling with Nanoscaled Micelles Combat Acute Myeloid Leukemia.,Small

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Synthetic CXCR4 Antagonistic Peptide Assembling with Nanoscaled Micelles Combat Acute Myeloid Leukemia.
Small ( IF 13.0 ) Pub Date : 2020-06-30 , DOI: 10.1002/smll.202001890
Jie Meng ₁ , Yangyang Ge ₁ , Haiyan Xing ₂ , Hui Wei ₂ , Shilin Xu ₁ , Jian Liu ₁ , Doudou Yan ₁ , Tao Wen ₁ , Min Wang ₂ , Xiaocui Fang _{3,

4} , Lilusi Ma _{3,

4} , Yanlian Yang _{3,

4} , Chen Wang _{3,

4} , Jianxiang Wang ₂ , Haiyan Xu ₁

Affiliation

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.

中文翻译：

纳米级胶束合成的CXCR4拮抗肽与急性髓细胞白血病作斗争。

急性髓细胞性白血病（AML）是最常见的成人急性白血病，由于耐药性和高复发率，因此存活率非常低。C‐X‐C趋化因子受体4（CXCR4）在AML细胞中高度表达，并积极介导化学耐药性和复发。本文将化学合成的CXCR4拮抗肽E5制成胶束制剂（M-E5），并应用于难治性AML小鼠，并对其治疗效果和药代动力学进行了研究。结果表明，M‐E5可以有效阻断从骨髓（BM）和脾脏分离的白血病细胞中的表面CXCR4，并抑制C‐X‐C趋化因子配体12介导的迁移。皮下注射M‐E5可以明显抑制白血病细胞在脾脏和BM中的植入，并动员残留的白血病细胞进入外周血，减少器官负担，并显着延长AML小鼠的生存期。M-E5还可以提高高纯harringtonine和阿霉素结合方案的疗效。核糖核酸测序表明，治疗作用是通过抑制增殖，增强细胞凋亡和分化来实现的，所有这些都与CXCR4信号传导阻滞有关。M-E5在给药后2小时达到浓度峰值，血液中半衰期为14.5小时。总之，M-E5是难治性AML治疗的一种新型有前途的治疗候选药物。核糖核酸测序表明，治疗作用是通过抑制增殖，增强细胞凋亡和分化来实现的，所有这些都与CXCR4信号传导阻滞有关。M-E5在给药后2小时达到浓度峰值，血液中半衰期为14.5小时。总之，M-E5是难治性AML治疗的一种新型有前途的治疗候选药物。核糖核酸测序表明，治疗作用是通过抑制增殖，增强细胞凋亡和分化来实现的，所有这些都与CXCR4信号传导阻滞有关。M-E5在给药后2小时达到浓度峰值，血液中半衰期为14.5小时。总之，M-E5是难治性AML治疗的一种新型有前途的治疗候选药物。

更新日期：2020-08-06

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