Dual-targeted self-delivery micelle co-loading doxorubicin and artesunate for enhanced AML treatment via mitochondrial damage induction

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with high mortality rates and poor prognosis, largely due to the nonspecific drug distribution and suboptimal therapeutic efficacy. To address these challenges, here we proposed a CD44/Transferrin receptor dual targeted self-delivery micelle for the combination delivery of chemotherapeutic doxorubicin (DOX) and artesunate (ART), a natural product known for its ability of killing AML cells by inducing apoptosis. To improve AML targeting, the transferrin receptor targeting peptide T7 was conjugated with CD44 targeting hyaluronic acid (HA), followed by conjugation with hydrophobic ART to afford the amphiphilic polymer for DOX encapsulation (termed THAD). The resulting self-delivery micellar drug delivery system THAD significantly enhanced the cellular internalization of AML cells and facilitated in vivo tumor targeting. Compared with single drug treatment groups, the combination of ART and DOX showed a better tumor killing ability. Furthermore, THAD suppressed the tumor proliferation by 90.74%. Specifically, THAD induced significantly mitochondrial-dependent apoptosis via increasing mitochondrial membranes damage and subsequent G1 phase arrest, as evidenced by the decreased levels of pro-caspase-3 and Bcl-2, along with the increased levels of Bax and cleaved poly(ADP-ribose) polymerase (PARP). Furthermore, THAD inhibited protein kinase B (AKT) phosphorylation, leading to a decrease of c-Myc expression in response to a negative growth regulator. In the human acute myeloid leukemia cells (MOLM13) cell-bearing mouse model, THAD significantly inhibited AML cell infiltration and proliferation in both bone marrow and liver, effectively suppressing AML progression. Collectively, THAD demonstrated enhanced anti-AML effects by promoting apoptosis, offering a promising targeted self-delivery strategy for combination chemotherapy in AML treatment.