Structural and Functional Tuning of ZIF-8 Nanoparticles Via Zinc Salt Variation and Ligand Ratio for Enhanced Drug Delivery

Abstract

The clinical application of doxorubicin (DOX), a widely used chemotherapeutic agent, is limited by systemic toxicity, rapid clearance, and the development of multidrug resistance. Metal-organic frameworks (MOFs), particularly zeolitic imidazolate frameworks (ZIFs), have emerged as promising nanocarriers to overcome these limitations due to their high drug-loading capacity, pH-responsive release profiles, and favorable biocompatibility. Among them, ZIF-8 is especially attractive for its ability to selectively release drugs in acidic tumor microenvironments. However, the physicochemical and biological properties of ZIF-8 are highly sensitive to synthesis parameters, particularly the choice of zinc salt precursor and the Zn2+:ligand molar ratio. In this study, we systematically investigated the effects of four zinc salts (zinc nitrate, zinc acetate, zinc chloride, and zinc bromide) and three Zn2+:2-methylimidazole molar ratios (1:35, 1:70, and 1:200) on the synthesis, drug-loading efficiency, release behavior, and anticancer activity of DOX-loaded ZIF-8 (DOX@ZIF-8) nanoparticles. The resulting nanocarriers were characterized using scanning electron microscopy (SEM), dynamic light scattering (DLS), energy-dispersive X-ray spectroscopy (EDX), inductively coupled plasma optical emission spectroscopy (ICP-OES), thermogravimetric analysis (TGA), and Brunauer-Emmett-Teller (BET) surface area analysis. pH-responsive DOX release was evaluated under physiological (pH 7.4) and acidic (pH 5.0) conditions. Cytotoxicity was assessed in A549 lung cancer cells via the MTT assay. Additionally, in vitro time-lapse live-cell imaging and wound healing assays were conducted to evaluate intracellular drug uptake and cellular responses. Our findings highlight the critical influence of zinc salt selection and ligand ratio on the structure-property-function relationships of ZIF-8, providing valuable insights for the rational design of MOF-based nanocarriers in targeted cancer therapy.