Phenylalanine-Coated PLGA Nanoparticles for Targeted Delivery of Silibinin in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, characterized by rapid progression and poor prognosis. Silibinin (SIL), the main active constituent of milk thistle, inhibits proliferation, induces apoptosis, and suppresses metastasis of HCC. However, its clinical use is limited by poor water solubility and low oral bioavailability. Nanoencapsulation offers an effective strategy to overcome these drawbacks, enabling selective targeting of tumor cells. This work aimed to design, develop, and characterize silibinin-loaded PLGA nanoparticles coated with phenylalanine (Phe-SIL-Nps) to enhance SIL delivery to HCC cells. An L4 Taguchi design was used to optimize the formulation. PVA concentration was the most influential factor, significantly affecting particle size, drug loading, and encapsulation efficiency, while sonication time had a statistically significant effect on the PDI. The optimized formulation (SIL-Nps), prepared with 3% PVA, a sonication time of 8 min, and a sonicator amplitude of 75%, exhibited a particle size ≈250 nm, a PDI ≈0.2, a zeta potential of -26 mV, a drug loading of ≈450 μg SIL/10 mg Nps, and a high encapsulation efficiency (≈96%). Phenylalanine coating increased particle size up to 275 nm and shifted the zeta potential to more negative values (-35 mV). Both SIL-Nps and Phe-SIL-Nps showed a spherical shape and exhibited a controlled release profile for 7 days. Phe-SIL-Nps displayed higher cytotoxicity than free SIL and SIL-Nps, as well as greater ROS production in Hep3B cells. This enhanced effect is attributed to their higher internalization via LAT transporters, which are overexpressed in HCC cells. These results suggest that LAT-targeted nanoparticles represent a promising technological approach to enhance the antitumor efficacy of antineoplastic agents in hepatocellular carcinoma.