Formulation, Development and Evaluation of Lycopene–Phosphatidylcholine Phytosomes for Improved Bioavailability and Anticancer Efficacy in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with limited treatment options and poor prognosis in advanced stages. Natural bioactive compounds such as lycopene, a carotenoid predominantly found in tomatoes, have shown significant anticancer and antioxidant activities. However, its therapeutic application is restricted by poor solubility, instability, and limited bioavailability. To overcome these limitations, phytosome-based drug delivery systems have emerged as a promising approach to enhance absorption and target-specific delivery. In the present study, a lycopene–phosphatidylcholine phytosome was developed and characterized to improve its physicochemical stability, solubility, and anticancer efficacy against hepatocellular carcinoma. The phytosome was prepared using the solvent evaporation method and optimized for drug-to-lipid ratio, particle size, and entrapment efficiency. Characterization studies using dynamic light scattering, zeta potential analysis, Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) confirmed successful phytosome formation and strong drug–lipid interactions. Transmission electron microscopy (TEM) revealed uniform spherical morphology with nanoscale dimensions. In vitro release studies demonstrated a sustained and enhanced dissolution profile compared to free lycopene. Cytotoxicity assays on HepG2 and Huh7 cell lines revealed that lycopene phytosomes induced greater apoptotic cell death, reduced colony formation, and modulated oxidative stress markers more effectively than pure lycopene. Mechanistic investigations indicated significant regulation of apoptosis-related proteins, including upregulation of Bax and p53 and downregulation of Bcl-2 and NF-κB signaling pathways. In vivo studies in a diethylnitrosamine (DEN)-induced HCC rat model further demonstrated improved therapeutic efficacy, as evidenced by reduced tumor burden, restoration of liver function biomarkers, and histological improvements. Overall, the findings suggest that phytosome-based delivery markedly enhances the bioavailability and anticancer activity of lycopene, making it a potential adjuvant or alternative therapeutic option for hepatocellular carcinoma.