Astragaloside IV-loaded zeolitic imidazolate framework-8 based on supercritical fluid as anti-solvent technology to improve bioavailability and anti-tumor activity against non-small cell lung cancer

Yang et al. Cancer Cell International (2025) 25:386 https://doi.org/10.1186/s12935-025-04028-x Cancer Cell International Open Access RESEARCH Astragaloside IV-loaded zeolitic imidazolate framework-8 based on supercritical fluid as anti-solvent technology to improve bioavailability and anti-tumor activity against non-small cell lung cancer Gang Yang1†, Ji-Yuan Chen1†, Chun-Ai Gong1†, Rong Wang1, Lu Han1, Jing Wang1, Min-Yan Chen1 and Yong-Fang Yuan1* Abstract Astragaloside (AST) has shown therapeutic potential against non-small cell lung cancer (NSCLC). However, its poor water solubility and low bioavailability limit its clinical application. To overcome these challenges, we developed an AST-loaded zeolitic imidazolate framework-8 (AST@ZIF) using supercritical fluid carbon dioxide (SCF-CO2) technology. This approach aimed to enhance the solubility, bioavailability, and anti-tumor efficacy of AST. Notably, this is the first study to employ SCF-CO2 as an anti-solvent through solution-enhanced dispersion by supercritical fluids (SEDS) for preparing drug-loaded ZIF-8. The resulting AST@ZIF-SEDS displayed a uniform hexagonal or cubic morphology, with AST transitioning from a crystalline to an amorphous state. Compared to AST@ZIF prepared using traditional methods (one-pot synthesis and solvent adsorption), AST@ZIF-SEDS demonstrated superior drug loading capacity, dispersibility, reduced residual solvent content, and improved stability. As a novel carrier, ZIF-8 effectively enhanced the solubility and bioavailability of AST while maintaining favorable biosecurity. In vivo studies further confirmed that AST@ZIF-SEDS significantly improved tumor inhibition compared with AST powder. In conclusion, SEDS technology represents a promising strategy for maximizing the therapeutic potential of ZIF-8 as a drug carrier. AST@ZIF-SEDS exhibited strong anti-tumor activity and holds potential as an effective treatment for NSCLC. Keywords Astragaloside IV, Zeolitic imidazolate framework-8, Solution-enhanced dispersion by supercritical fluids, Solubility, Non-small cell lung cancer † Gang Yang, Ji-Yuan Chen and Chun-Ai Gong contributed equally to this work. *Correspondence: Yong-Fang Yuan Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Yang et al. Cancer Cell International (2025) 25:386 Page 2 of 21 Graphical abstract Introduction Lung cancer is a malignant tumor with the highest morbidity and mortality rates in the world. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 80–85% of the total cases. Owing to the rapid progression and metastasis of NSCLC, most patients are already in the middle to late stages at the time of diagnosis, resulting in limited surgical opportunities and a high postoperative recurrence rate [1, 2]. Radiotherapy, chemotherapy, and immunotherapy are the primary treatments for NSCLC [3–5]. Currently, the dual-drug cisplatin regimen, including gemcitabine and vinorelbine [6, 7], is the standard regimen for the first-line of advanced NSCLC treatment, whereas docetaxel and pemetrexed monotherapy are used as the second-line treatment [8, 9]. However, these interventions targeting the different stages of NSCLC may still result in treatment failure owing to tumor micrometastasis, decreased patient compliance from toxicity and side effects, and the development of acquired drug resistance. The 5-year survival rate of patients with advanced NSCLC remains less than 15% [10, 11]. Therefore, the search for new chemotherapeutic drugs is a major issue that urgently needs to be addressed for the treatment of NSCLC. Astragalus is a traditional Chinese medicine widely used for treating diseases such as diabetes, angiocardiopathy, and various cancers [12]. Modern pharmacology reveals its role in enhancing immunity, organ protection, reducing blood sugar, and exerting anti-tumor effects [13]. Astragaloside IV (AST), its primary active component, exhibits anti-inflammatory, antioxidant, and immunomodulatory properties. Notably, AST has shown efficacy against several cancers, including ovarian, liver, breast, colorectal, and lung cancers [14], by inhibiting tumor growth and metastasis, promoting apoptosis, enhancing immune function, and preventing drug resistance. It regulates critical pathways involved in epithelial–mesenchymal transformation and autophagy, such as the phosphoinositide‑3‑kinase/protein kinase B, Wnt/β‑catenin, mitogen‑activated protein kinase/ extracellular regulated protein kinase, and transforming growth factor‑β/SMAD pathways [15]. Additionally, AST impedes lung cancer progression by curtailing tumor growth, invasion, migration, and angiogenesis, primarily through its influence on macrophage M2 polarization via the AMPK signaling pathway [16]. However, AST exhibits poor water solubility and low bioavailability following oral administration and gets distributed across multiple tissues and organs without specific tissue targeting, which limits its clinical application [17]. In recent years, researchers have developed different AST delivery systems, such as nanoparticles, liposomes, and hydrogels, to improve the water solubility and bioavailability of AST [18–20]. However, the drug loading efficiency of these delivery systems remains unsatisfactory, typically below 15%. Therefore, it is crucial to seek new delivery carriers to enhance the drug loading and water solubility of AST, consequently increasing its therapeutic efficacy. Recently, metal-organic frameworks (MOFs) have attracted much attention as novel hybrid porous materials owing to their high specific surface area, abundant pore structures, structural and compositional diversity, and the ease of tailoring their pores as well as their Yang et al. Cancer Cell International (2025) 25:386 physicochemical properties [21]. Zeolitic imidazolate framework-8 (ZIF-8), a subclass of MOFs, in addition to t (...truncated)