The hypoxic microenvironment is presumed to be a sanctuary for myeloid leukemia cells that causes relapse following chemotherapy, but the underlying mechanism remains elusive. Using a zebrafish xenograft model, we observed that the hypoxic hematopoietic tissue preserved most of the chemoresistant leukemic cells following the doxorubicin (Dox) treatment. And hypoxia upregulated TFEB, a master regulator of lysosomal biogenesis, and increased lysosomes in leukemic cells. Specimens from relapsed myeloid leukemia patients also harbored excessive lysosomes, which trapped Dox and prevented drug nuclear influx leading to leukemia chemoresistance. Pharmaceutical inhibition of lysosomes enhanced Dox-induced cytotoxicity against leukemic cells under hypoxia circumstance. To overcome lysosome associated chemoresistance, we developed a pH-sensitive dextran-doxorubicin nanomedicine (Dex-Dox) that efficiently released Dox from lysosomes and increased drug nuclear influx. More importantly, Dex-Dox treatment significantly improved the chemotherapy outcome in the zebrafish xenografts transplanted with cultured leukemic cells or relapsed patient specimens. Overall, we developed a novel lysosome targeting nanomedicine that is promising to overcome the myeloid leukemia chemoresistance.

中文翻译：

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一种以溶酶体为靶点的葡聚糖-阿霉素纳米药物克服了阿霉素诱导的髓性白血病化疗耐药

缺氧微环境被认为是导致化疗后复发的髓性白血病细胞的避难所，但其潜在机制仍然难以捉摸。使用斑马鱼异种移植模型，我们观察到在多柔比星 (Dox) 治疗后，缺氧的造血组织保留了大部分化学抗性白血病细胞。缺氧上调了 TFEB（溶酶体生物发生的主要调节剂），并增加了白血病细胞中的溶酶体。来自复发性粒细胞白血病患者的标本也含有过多的溶酶体，这些溶酶体捕获了 Dox 并阻止了导致白血病化疗耐药的药物核内流。在缺氧情况下，溶酶体的药物抑制增强了 Dox 诱导的对白血病细胞的细胞毒性。为了克服溶酶体相关的化学抗性，我们开发了一种对 pH 敏感的葡聚糖-阿霉素纳米药物 (Dex-Dox)，它可以有效地从溶酶体中释放 Dox 并增加药物核内流。更重要的是，Dex-Dox 治疗显着改善了移植了培养的白血病细胞或复发患者标本的斑马鱼异种移植物的化疗结果。总体而言，我们开发了一种新型溶酶体靶向纳米药物，有望克服髓细胞白血病的化学抗性。