Discovery of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML), a malignant myeloproliferative disease characterized by abnormal activation of BCR-ABL fusion oncoprotein with protein tyrosine kinase (PTK) activity. However, the long-term treatment outcomes with TKIs are strongly limited by multiple drug resistances, resulting in relapse albeit with initial high response rate. Here, we reported a realgar (AsS) nanocrystal-based delivery system to reverse drug resistance for synergistic CML therapy. While AsS is extremely insoluble in water, bovine serum albumin (BSA) was rationally screened to effectively stabilize AsS nanocrystal with uniformed size of ~40 nm. Imatinib (IMA), a representative TKIs, can be readily loaded into the hydrophobic domain of BSA to develop AsS/IMA co-delivery system. Mechanistically, IMA inhibits PTK activity, while AsS degrades BCR-ABL1, which co-contribute to tumor suppression via complementary pathways for synergistic effect. Moreover, the nanosystem was modified with folic acid (FA) to enable tumor targetability, which has been demonstrated both in vitro and in vivo, resulting in robust tumor growth inhibition and significantly prolonged mice survival without any noticeable adverse effects. This work designed a synergistic nanoplatform for targeted CML therapy, provided a strategy to address the key limitation of AsS for biomedical applications, and highlighted the advantages of the combination between traditional Chinese and western medicine for diseases treatment.Copyright © 2021. Published by Elsevier B.V.
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