Acute myeloid leukemia (AML) is rapidly
progressed hematologic
malignancy with relapsed and refractory characteristics. Cytarabine
combined with the BCL2 inhibitor venetoclax showed impressive response
rates in the treatment of relapsed/refractory acute myeloid leukemia
(R/R AML), while it requires complicated administration regimens and
brings added toxicity. In this work, we synthesized a mercaptopropionic
acid-substituted derivative of Ara-C (Ara-SH) and used it as the trigger
to fabricate a smart cytarabine and venetoclax-coloaded nanoparticle
(AV-NP) through self-assembly. The AV-NP characterized with redox-responsive
drug release, rapid uptake by leukemia cells, and long retention in
circulation had the potential to accumulate in leukemia-enriched sites.
It generated a remarkable synergistic effect with higher antileukemia
activity in vitro and better safety in the hematologic system compared
with free drugs and significantly improved the therapeutic effect
on orthotopic AML mice in vivo. These similar results were also confirmed
in primary cells from R/R-AML patients. Besides, the AV-NP has the
superiority of facile fabrication and generalizability, rendering
it easy for clinical translation.
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