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

作者：Zhidi He, Fang Chen, Honglan Liu, Tingting Liu, Dan He, Yashi Wang, Jiaxin Li, Dong Chen, Zhipeng Tian, Man Li, Rong Guo, Qin He · 发表于：Nano Research · 年份：2025 · DOI：10.26599/nr.2025.94907663 · 被引用次数：2 · 研究领域：Nanoplatforms for cancer theranostics、Nanoparticle-Based Drug Delivery、Dendrimers and Hyperbranched Polymers

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 AKT phosphorylation, leading to a decrease of c-Myc expression in response to a negative...