Microfluidic Encapsulation of Sorafenib-Loaded ZIF-8 Nanoparticles in pH-Responsive Alginate Microparticles for Oral Chemotherapy of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality. Sorafenib is the current first-line oral therapy; however, its therapeutic efficacy is limited by poor aqueous solubility, low bioavailability, and gastrointestinal instability. This study aimed to develop a pH-responsive nano-in-microparticle delivery system using a single-step droplet-based microfluidic process to protect sorafenib in the gastric environment and achieve controlled release for enhanced oral chemotherapy. Sorafenib-loaded ZIF-8 nanoparticles (SZ NPs) were synthesized and characterized by scanning electron microscopy (SEM), Fourier-transform infrared (FTIR) spectroscopy, Energy-dispersive X-ray (EDX) spectroscopy, and X-ray diffraction (XRD), exhibiting a mean diameter of about 72 nm and a drug encapsulation efficiency of 76%. These SZ NPs were subsequently encapsulated in alginate to form pH-responsive nano-in-microparticles. Computational fluid dynamics (CFD) simulations were conducted to optimize flow dynamics and droplet formation within the microfluidic channels, and particle morphology and uniformity were assessed via bright-field microscopy, fluorescence microscopy, and SEM. The resulting nano-in-microparticles exhibited spherical morphology with hydrodynamic sizes ranging from 76 to 113 μm, depending on the flow rate ratio, demonstrating uniform SZ NP dispersion. Drug release studies in simulated gastric and intestinal fluids revealed that the nano-in-microparticles prevented premature drug release in acidic simulated gastric fluid (pH < 5.7), while facilitating a controlled and sustained release profile under simulated intestinal conditions (pH 7.4) over 24 h. Cytotoxicity assays against HepG2 liver cancer cells showed significant anticancer efficacy compared to free sorafenib. These findings highlight the potential of this pH-responsive platform as an effective oral delivery strategy for HCC therapy.