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Heme Oxygenase 1-Targeted Hybrid Nanoparticle for Chemo- and Immuno-Combination Therapy in Acute Myelogenous Leukemia.
Advanced Science ( IF 15.1 ) Pub Date : 2020-06-03 , DOI: 10.1002/advs.202000487
Seok-Beom Yong 1 , Jaehyun Kim 1 , Jee Young Chung 1 , Sehee Ra 1 , Seong Su Kim 1 , Yong-Hee Kim 1
Affiliation  

Acute myelogenous leukemia (AML) is a fatal blood cancer with high patient mortality. Daunorubicin and cytarabine are first‐line chemotherapy for AML, with bone marrow transplantation in most cases. Recently, cancer immunotherapy has been challenged in AML and leukemia‐niche myeloid cells are promising targets for the AML immunotherapy. Heme oxygenase 1 (HO1) is an antioxidative and cytoprotective enzyme inducing chemo‐resistant AML and has been focused as an immune checkpoint molecule in tumor microenvironments. Herein, lipid‐polymer hybrid nanoparticle (hNP) is loaded with tin mesoporphyrin (SnMP), a HO1‐inhibitor, and non‐covalently modified with an engineered antibody for leukemic cell‐targeted delivery. HO1‐inhibiting T‐hNP (T‐hNP/SnMP) enhances chemo‐sensitivity in human leukemia cells. In a human AML‐bearing orthotopic mouse model, intravenously injected T‐hNP not only actively targets to human leukemia cells but passively targets to CD11b+ myeloid cells in a bone marrow niche. The T‐hNP/SnMP enhances the chemo‐therapeutic effect of daunorubicin and boosts immune response by reprogramming bone marrow myeloid cells resulting from the recruitment of the monocyte‐lineage and induction of inflammatory genes. The ex vivo study demonstrates an enhanced immune response of HO1‐inhibited bone marrow CD11b+ myeloid cells against apoptotic leukemia cells. Collectively, HO1‐inhibiting dual cell‐targeted T‐hNP/SnMP has a strong potential as a novel therapeutic in AML.

中文翻译:

用于急性髓性白血病化疗和免疫联合治疗的血红素加氧酶 1 靶向混合纳米颗粒。

急性髓性白血病(AML)是一种致命的血液癌症,患者死亡率很高。柔红霉素和阿糖胞苷是 AML 的一线化疗药物,大多数情况下需要进行骨髓移植。最近,癌症免疫疗法在 AML 中受到挑战,白血病利基髓样细胞是 AML 免疫疗法的有希望的靶标。血红素加氧酶 1 (HO1) 是一种抗氧化和细胞保护酶,可诱导化疗耐药性 AML,并一直作为肿瘤微环境中的免疫检查点分子而受到关注。在此,脂质-聚合物混合纳米颗粒 (hNP) 负载有锡中卟啉 (SnMP)(一种 HO1 抑制剂),并用工程化抗体进行非共价修饰,用于白血病细胞靶向递送。HO1 抑制 T-hNP (T-hNP/SnMP) 增强人类白血病细胞的化疗敏感性。在人类 AML 原位小鼠模型中,静脉注射 T-hNP 不仅主动靶向人类白血病细胞,而且被动靶向骨髓微环境中的 CD11b+ 骨髓细胞。T-hNP/SnMP 可增强柔红霉素的化疗效果,并通过对单核细胞谱系募集和炎症基因诱导产生的骨髓骨髓细胞进行重编程来增强免疫反应。离体研究表明,HO1 抑制的骨髓 CD11b+ 骨髓细胞对凋亡白血病细胞的免疫反应增强。总的来说,HO1 抑制双细胞靶向 T-hNP/SnMP 具有作为 AML 新型疗法的巨大潜力。
更新日期:2020-07-08
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