Acidic Environment-Responsive Metal Organic Framework-Mediated Dihydroartemisinin Delivery for Triggering Production of Reactive Oxygen Species in Drug-Resistant Lung Cancer

Abstract

Background

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.

Purpose

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.

Methods

D-ZIF was prepared by one-pot synthesis method using methylimidazole (MIM), Zn(NO₃)₂•6H₂O 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.

Results

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.

Conclusion

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.

Keywords:

• MOF
• drug delivery
• controlled release
• cancer therapy

Abbreviations

DHA, Dihydroartemisinin; ZIF, zeolitic imidazolate framework; D-ZIF, DHA-loaded ZIF; A549-TAX, TAX-resistant human lung adenocarcinoma; ROS, reactive oxygen species; HE, hematoxylin and eosin-stained.

Acknowledgments

We thank the Science and Technology Project of Education Department of Jiangxi Province of China (GJJ2200963), National Natural Science Foundation of China (22304065 and 32071390), Doctor Start-up Fund of Jiangxi University of Chinese Medicine (2022BSZR009), Jiangxi University of Chinese Medicine School-level Science and Technology Innovation Team Development Program (CXTD22005), and Jiangxi Administration of Traditional Chinese Medicine Science and Technology Program (2021B622).

Disclosure

The author reports no conflicts of interest in this work.