CXCR4-directed liposomal co-delivery of cytarabine and AMD3100 for redox-associated chemosensitization in acute...

Acute myeloid leukemia (AML) cells can be protected from chemotherapy through CXCR4-associated interactions with the bone marrow microenvironment and adaptive redox buffering. Here, we developed CTCE-9908-functionalized, cytarabine (Ara-C) and the CXCR4 antagonist AMD3100-coloaded liposomes (C-AM@Lipo) for integrating CXCR4-directed uptake enhancement with redox-associated chemosensitization. CTCE-9908 functionalization increased cellular uptake in HL-60 and C1498 leukemia cells, while scrambled peptide modification and competitive inhibition reduced this advantage, supporting the involvement of CTCE-9908/CXCR4-associated interactions. Compared with free drugs and non-functionalized liposomes, C-AM@Lipo induced greater apoptosis and more pronounced redox disturbance, characterized by reduced GSH/GSSG ratios, increased mitochondrial superoxide generation, lipid peroxidation, and γH2AX-associated DNA damage. In a disseminated C1498-Luc-GFP leukemia model, C-AM@Lipo reduced systemic and bone marrow leukemia burden and prolonged survival. DiR-based biodistribution analysis showed enhanced femoral accumulation, while extended safety evaluation demonstrated preserved bone marrow cellularity and no evident hematological or hepatorenal toxicity. Collectively, this study establishes a coordinated liposomal strategy linking CXCR4-associated uptake enhancement with Ara-C/AMD3100 co-delivery and redox-associated chemosensitization for improved AML therapy.