Naringenin Nanocrystals Containing Pluronic® F127 Hydrogel for Skin Cancer Treatment

Naringenin (NRG), a poorly water-soluble flavonoid with anticancer potential, suffers from limited bioavailability due to low aqueous solubility and poor membrane permeation. In this study, NRG nanocrystals (NRG-NCs) were developed using an optimized antisolvent precipitation–probe sonication method and incorporated into a 20% (w/w) Pluronic® F127 hydrogel for enhanced delivery. The optimized NRG-NCs exhibited a mean particle size of ~195 ± 5 nm, polydispersity index of ~0.20 ± 0.02, and zeta potential of −24 ± 3 mV. Percentage yield and drug loading capacity were 88.6 ± 2.3% and 78.4 ± 1.8%, respectively. Nanocrystal formation resulted in ~9-fold enhancement in saturation solubility compared to raw NRG. The NRG-NCs gel demonstrated rapid dissolution (~90% release within 120 min) and ~2.5-fold higher ex vivo permeation across the Strat-M® membrane relative to pure NRG. The hydrogel exhibited suitable physicochemical properties (viscosity ~12,850 cP; pH 6.2 ± 0.1; spreadability 5.8 ± 0.3 cm) and maintained >92% drug content after 30 days of refrigerated storage. Mechanistic studies revealed dose-dependent cytotoxicity, characterized by increased intracellular ROS, mitochondrial membrane depolarization, and elevated caspase-3 activity, confirming ROS-mediated apoptosis. In conclusion, the nanocrystal–hydrogel platform significantly enhances the solubility, permeation, and pro-apoptotic efficacy of NRG, demonstrating its potential for skin cancer treatment.