The First Dongguan Affiliated Hospital, Guangdong Medical University, 523710, Dongguan, China; School of Pharmacy, Guangdong Medical University, Dongguan 523808, China.
School of Pharmacy, Guangdong Medical University, Dongguan 523808, China.
Eur J Pharm Biopharm. 2023 Sep;190:284-293. doi: 10.1016/j.ejpb.2023.07.014. Epub 2023 Aug 1.
Artesunate (ART) has potent anticancer activity but it suffers from poor stability and low bioavailability in vivo due to the special endoperoxide moiety in the molecules. In this work, we fabricated programmable enzyme/reactive oxygen species (ROS) responsive ART complex carriers with size and charge adaptive regulation in order to improve stability and overcome biochemical hurdles of solid tumor. The complex carries (ART/AA-PAMAM@HA) were created by electrostatic interaction between dendrimer-ART/arachidonic acid (AA) (ART/AA-PAMAM) and hyaluronic acid (HA), which can proactively penetrate deeply into tumors and selective drug release. Specifically, ART induced Fenton reaction and produced a mass of ROS and lipid peroxides (LPO), leading to the depressing of GSH level and glutathione peroxidase 4 (GPX4) activity. Meanwhile, exogenous AA further promoted the accumulation of LPO by cascade regulating ferroptosis pathway. In the anti-tumor efficacy in vivo, the tumor inhibition ratio was achieved to 46.92%. This work shows a new anti-tumor strategy triggering ferroptosis via regulating redox homeostasis.
青蒿琥酯（ART）具有很强的抗癌活性，但由于分子中的特殊过氧化物部分，其在体内的稳定性和生物利用度较差。在这项工作中，我们设计了可编程酶/活性氧（ROS）响应的 ART 复合载体，具有大小和电荷自适应调节的能力，以提高稳定性并克服实体瘤的生化障碍。该复合物载体（ART/AA-PAMAM@HA）是通过树状大分子-ART/花生四烯酸（AA）（ART/AA-PAMAM）与透明质酸（HA）之间的静电相互作用形成的，能够主动深入肿瘤并进行选择性药物释放。具体来说，ART 诱导芬顿反应并产生大量的 ROS 和脂质过氧化物（LPO），导致 GSH 水平和谷胱甘肽过氧化物酶 4（GPX4）活性降低。同时，外源性 AA 通过级联调节铁死亡途径进一步促进 LPO 的积累。在体内抗肿瘤疗效中，肿瘤抑制率达到 46.92%。这项工作展示了一种通过调节氧化还原平衡触发铁死亡的新的抗肿瘤策略。
