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

## TL;DR

This study develops a pH-responsive delivery system to improve oral chemotherapy for liver cancer by encapsulating sorafenib in nanoparticles within microparticles.

## Contribution

A novel pH-responsive nano-in-microparticle system is developed for controlled oral delivery of sorafenib to treat hepatocellular carcinoma.

## Key findings

- The nano-in-microparticles prevented premature drug release in acidic gastric conditions and enabled sustained release in intestinal conditions.
- Cytotoxicity assays showed enhanced anticancer efficacy against HepG2 liver cancer cells compared to free sorafenib.
- The system achieved uniform dispersion of nanoparticles with spherical morphology and controlled size distribution.

## Abstract

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.