Journal
ADVANCED SCIENCE
Volume 10, Issue 8, Pages -Publisher
WILEY
DOI: 10.1002/advs.202204866
Keywords
acute myeloid leukemia; BCL2 inhibitor; B-N coordination; boronic ester bond; MCL1 inhibitor; synergetic therapy
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This study adopts phenylboronic acid-functionalized polypeptide nanovehicles for co-delivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors to achieve synergistic and potent treatment of AML. The nanovehicles exhibit efficient and robust drug coencapsulation using dynamic boronic ester bonds, B-N coordination, and pi-pi stacking. In both mouse and cell models, the nanoparticles show significant anti-tumor activity and hold great potential for AML treatment.
Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid-functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. Leveraging the dynamic boronic ester bonds, B-N coordination, and pi-pi stacking, the nanovehicles reveal remarkably efficient and robust drug coencapsulation. ABT199 can induce a series of pro-apoptotic reactions by promoting the dissociation of the pro-apoptotic protein Bim from BCL2, while the released Bim is often captured by MCL1 protein overexpressed in AML. TW37 has a strong inhibitory ability to MCL1, thereby can restrain the depletion of Bim protein. Dual inhibitor-loaded nanoparticles (NPAT) reveal excellent stability, acid/enzyme/H2O2-triggered drug release, and significant cytotoxicity toward MOLM-13-Luc and MV-411 AML cells with low half maximal inhibitory concentrations of 1.15 and 7.45 ng mL(-1), respectively. In mice bearing MOLM-13-Luc or MV-411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid-functionalized smart nanodrugs hold remarkable potential for AML treatment.
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