Academician Workstation, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, People's Republic of China.
Department of Transfusion, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
Int J Nanomedicine. 2024 Apr 29;19:3847-3859. doi: 10.2147/IJN.S451042. eCollection 2024.
Dihydroartemisinin (DHA) has emerged as a promising candidate for anticancer therapy. However, the application of DHA in clinics has been hampered by several limitations including poor bioavailability, short circulation life, and low solubility, significantly restricting its therapeutic efficacy and leading to notable side effects during the treatment.
We present DHA-loaded zeolitic imidazolate framework-8 (D-ZIF) with controllable and targeted DHA release properties, leading to enhanced antitumor effects while reducing potential side effects.
D-ZIF was prepared by one-pot synthesis method using methylimidazole (MIM), Zn(NO)•6HO and DHA. We characterized the physical and chemical properties of D-ZIF by TEM, DLS, XRD, FT-IR, and TG. We measured the drug loading efficiency and the cumulative release of DHA in different pH conditions. We evaluated the cytotoxicity of D-ZIF on renal cell carcinoma (RCC786-O), glioma cells (U251), TAX-resistant human lung adenocarcinoma (A549-TAX) cells by CCK8 in vitro. We explored the possible antitumor mechanism of D-ZIF by Western blot. We evaluated the biocompatibility and hemolysis of D-ZIF and explored the in vivo antitumor efficiency in mice model by TUNEL testing and blood biomarker evaluations.
D-ZIF showed rhombic dodecahedral morphology with size of 129±7.2 nm and possessed a noticeable DHA encapsulation efficiency (72.9%). After 48 hours, D-ZIF released a cumulative 70.0% of the loaded DHA at pH 6.5, and only 42.1% at pH 7.4. The pH-triggered programmed release behavior of D-ZIF could enhance anticancer effect of DHA while minimizing side effects under normal physiological conditions. Compared with the free DHA group with 31.75% of A549-TAX cell apoptosis, the percentage of apoptotic cells was approximately 76.67% in the D-ZIF group. D-ZIF inhibited tumor growth by inducing tumor cell apoptosis through the mechanism of ROS production and regulation of Nrf2/HO-1 and P38 MAPK signaling pathways. D-ZIF showed potent effects in treating tumors with high safety in vivo.
This pH-responsive release mechanism enhanced the targeting efficiency of DHA towards tumor cells, thereby increasing drug concentration in tumor sites with negligible side effects. Herein, D-ZIF holds great promise for curing cancers with minimal adverse effects.
二氢青蒿素（DHA）已成为癌症治疗的有前途的候选药物。然而，DHA 在临床上的应用受到多种限制，包括生物利用度差、循环寿命短和溶解度低，这极大地限制了其治疗效果，并导致治疗过程中出现明显的副作用。
我们提出了载有二氢青蒿素的沸石咪唑酯骨架-8（D-ZIF），具有可控和靶向的二氢青蒿素释放特性，在提高抗肿瘤效果的同时降低潜在的副作用。
采用一锅合成法，以甲基咪唑（MIM）、Zn（NO）•6HO 和 DHA 为原料制备 D-ZIF。通过 TEM、DLS、XRD、FT-IR 和 TG 对 D-ZIF 的物理化学性质进行了表征。我们测量了不同 pH 值条件下 DHA 的载药效率和累积释放。我们通过 CCK8 在体外评价了 D-ZIF 对肾癌细胞（RCC786-O）、神经胶质瘤细胞（U251）、TAX 耐药人肺腺癌细胞（A549-TAX）的细胞毒性。我们通过 Western blot 探讨了 D-ZIF 的可能抗肿瘤机制。我们评价了 D-ZIF 的生物相容性和溶血作用，并通过 TUNEL 检测和血液生物标志物评估在小鼠模型中的体内抗肿瘤效果。
D-ZIF 呈十二面体形态，粒径为 129±7.2nm，具有显著的 DHA 包封效率（72.9%）。48 小时后，在 pH6.5 条件下，D-ZIF 累积释放 70.0%的负载 DHA，而在 pH7.4 条件下仅释放 42.1%。D-ZIF 的 pH 触发的程序释放行为可以在正常生理条件下增强 DHA 的抗癌作用，同时最小化副作用。与游离 DHA 组 31.75%的 A549-TAX 细胞凋亡相比，D-ZIF 组的凋亡细胞百分比约为 76.67%。D-ZIF 通过诱导肿瘤细胞凋亡，通过 ROS 产生和调节 Nrf2/HO-1 和 P38 MAPK 信号通路发挥抑制肿瘤生长的作用。D-ZIF 在体内具有高效治疗肿瘤的作用，安全性高。
这种 pH 响应释放机制提高了 DHA 对肿瘤细胞的靶向效率，从而在肿瘤部位增加了药物浓度，同时副作用极小。因此，D-ZIF 有望成为治疗癌症的有效方法，副作用极小。
