Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P. R. China.
Soochow College, Soochow University, Suzhou 215123, P. R. China.
Biomacromolecules. 2024 Jul 8;25(7):4569-4580. doi: 10.1021/acs.biomac.4c00561. Epub 2024 Jun 13.
Acute myeloid leukemia (AML) is often associated with poor prognosis and survival. Small molecule inhibitors, though widening the treatment landscape, have limited monotherapy efficacy. The combination therapy, however, shows suboptimal clinical outcomes due to low bioavailability, overlapping systemic toxicity and drug resistance. Here, we report that CXCR4-mediated codelivery of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor sorafenib (SOR) via T22 peptide-tagged disulfide cross-linked polymeric micelles (TM) achieves synergistic treatment of FLT3-ITD AML. TM-VS with a VEN/SOR weight ratio of 1/4 and T22 peptide density of 20% exhibited an extraordinary inhibitory effect on CXCR4-overexpressing MV4-11 AML cells. TM-VS at a VEN/SOR dosage of 2.5/10 mg/kg remarkably reduced leukemia burden, prolonged mouse survival, and impeded bone loss in orthotopic MV4-11-bearing mice, outperforming the nontargeted M-VS and oral administration of free VEN/SOR. CXCR4-mediated codelivery of BCL-2 and FLT3 inhibitors has emerged as a prospective clinical treatment for FLT3-ITD AML.
急性髓系白血病（AML）常伴有预后不良和生存率低。小分子抑制剂虽然拓宽了治疗范围，但单药治疗效果有限。然而，由于生物利用度低、系统毒性重叠和耐药性，联合治疗的临床效果并不理想。在这里，我们报告通过 T22 肽标记的二硫键交联聚合物胶束（TM）共递 CXCR4 介导的 BCL-2 抑制剂 venetoclax（VEN）和 FLT3 抑制剂 sorafenib（SOR），实现了协同治疗 FLT3-ITD AML。TM-VS 具有 VEN/SOR 重量比为 1/4 和 T22 肽密度为 20%，对过表达 CXCR4 的 MV4-11 AML 细胞具有非凡的抑制作用。TM-VS 以 VEN/SOR 剂量为 2.5/10 mg/kg 显著降低了白血病负担，延长了小鼠的生存时间，并抑制了荷瘤小鼠的骨质流失，优于非靶向 M-VS 和口服游离 VEN/SOR。BCL-2 和 FLT3 抑制剂的 CXCR4 介导共递已成为治疗 FLT3-ITD AML 的一种有前景的临床治疗方法。
