CXCR4-Mediated Codelivery of FLT3 and BCL-2 Inhibitors for Enhanced Targeted Combination Therapy of FLT3-ITD Acute Myeloid Leukemia.
Jiakun YangPeng ZhangYumin MaoRan ChenRu ChengJiaying LiHuanli SunChao DengZhiyuan ZhongPublished in: Biomacromolecules (2024)
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.
Keyphrases
- acute myeloid leukemia
- combination therapy
- allogeneic hematopoietic stem cell transplantation
- poor prognosis
- small molecule
- cancer therapy
- drug delivery
- bone loss
- long non coding rna
- body mass index
- type diabetes
- single cell
- randomized controlled trial
- induced apoptosis
- risk factors
- clinical trial
- cell death
- high resolution
- endoplasmic reticulum stress
- physical activity
- weight gain
- cell cycle arrest
- body weight
- study protocol
- replacement therapy
- protein protein
- pi k akt