Smart and Generalizable Cytarabine Derivative-Triggered Nanoparticles for Synergistic Therapy of Relapsed/Refractory Acute Myeloid Leukemia

Abstract

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.

Recent Advances in Material Technology for Leukemia Treatments

“…To address the challenges of the short half‐life of cytarabine (10–20 min) and high‐dose administration‐induced toxicity, cytarabine and the B‐cell lymphoma‐2 ( BCL2 ) inhibitor venetoclax were loaded into albumin‐based carriers (known as AV‐NPs), which significantly extended drug circulation and exhibited increased antileukemic activity in vitro, improving safety within the hematopoietic system and ultimately resulting in enhanced therapeutic efficacy in an AML mouse model. [ 95 ]…”

n-Tuples on Scaffold Diversity Inspired by Drug Hybridisation to Enhance Drugability: Application to Cytarabine

“…It is known that the amine group of cytarabine increases the degradation ability in the human metabolism by involving the degradation process of rapid deamination by the liver enzyme cytidine deaminase [42,47]. Because of this, several works have been directed towards the synthesis of cytarabine derivatives by blocking that position [48,49]. Our goal in this direction was also to block this position in duples, producing new molecules with two substructures with an important biological and therapeutic activity that could produce synergies regarding the therapeutic effect.…”