pH-Responsive Delivery of Nonsteroidal Anti-Inflammatory Drugs by ZIF-8 Metal-Organic Frameworks for Cancer Treatment

Nonsteroidal anti-inflammatory drugs (NSAIDs) have attracted increasing attention as potential anticancer agents due to their ability to inhibit cyclooxygenase-mediated inflammatory pathways involved in tumor progression. However, their clinical use in oncology remains limited by poor tumor selectivity and systemic toxicity. In this work, we investigate zeolitic imidazolate framework-8 (ZIF-8) nanoparticles as pH-responsive carriers for the delivery of different NSAIDs with potential anticancer activity. A loading strategy based on the conversion of the drugs into their sodium salts, followed by ultrasound-assisted encapsulation, was developed to preserve the structural integrity of the MOF while achieving efficient drug incorporation. Structural and textural characterization by XRPD, SEM, ATR-MIR spectroscopy, and nitrogen physisorption confirmed the formation of ZIF-8 nanoparticles with an average size of about 150 nm and the successful encapsulation of the drugs within the porous framework. High-performance liquid chromatography revealed drug-loading efficiencies exceeding 80% for selected formulations. Release studies demonstrated a pronounced pH-dependent behavior, with significantly faster drug release under mildly acidic conditions that mimic the tumor microenvironment. The biological activity of selected formulations was evaluated in prostate-derived cell models (BPH, LNCaP, and DU145), revealing enhanced cytotoxicity toward cancer cells under acidic conditions compared to physiological pH. In particular, naproxen@ZIF-8 showed a marked reduction in DU145 cell viability at low concentrations and under mildly acidic conditions. These results highlight the potential of ZIF-8 as a versatile nanoplatform for the controlled and tumor-responsive delivery of anti-inflammatory drugs with an anticancer activity.