Imatinib co-loaded targeted realgar nanocrystal for synergistic therapy of chronic myeloid leukemia

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 (As4S4) nanocrystal-based delivery system to reverse drug resistance for synergistic CML therapy. While As4S4 is extremely insoluble in water, bovine serum albumin (BSA) was rationally screened to effectively stabilize As4S4 nanocrystal with uniformed size of similar to 40 nm. Imatinib (IMA), a representative TKIs, can be readily loaded into the hydrophobic domain of BSA to develop As4S4/IMA co-delivery system. Mechanisti-cally, IMA inhibits PTK activity, while As4S4 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 As4S4 for biomedical applications, and highlighted the advantages of the combination between traditional Chinese and western medicine for diseases treatment.

Automated summary

The discovery of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has greatly transformed chronic myeloid leukemia (CML) therapy. This study introduced a realgar nanocrystal-based delivery system to reverse drug resistance for synergistic CML treatment, showing significant tumor growth inhibition and prolonged survival in mice. The nanosystem was also modified with folic acid for tumor targetability, highlighting the benefits of combining traditional Chinese and western medicine for disease treatment.