Rational Design and Characterization of 5-Fluorouracil-Loaded Lipid-Polymer Hybrid Nanoparticles for Enhanced...

Effective management of skin cancer remains challenging due to limited transdermal drug penetration, systemic toxicity, and therapeutic resistance. In this study, 5-fluorouracil (5-FU)-loaded lipid-polymer hybrid nanoparticles (LPHNPs) were rationally engineered as a next-generation nanocarrier system to overcome these barriers. The hybrid design synergistically combines the structural integrity of polymers with the biocompatibility and permeability-enhancing attributes of lipids. Using a central composite design, formulation parameters were optimized to achieve favorable physicochemical characteristics, yielding nanoparticles with a mean diameter of 256.7 nm, a polydispersity index (PDI) of 0.2711, and a positive zeta potential of +25.47 mV, indicative of excellent colloidal stability. In vitro release and ex vivo permeation studies revealed a sustained drug release profile and significantly improved dermal penetration compared to conventional formulations. Moreover, the Hen's egg test-chorioallantoic membrane (HET-CAM) irritation assay confirmed the biocompatibility and reduced irritation potential of the developed system. Overall, the optimized 5-FU-loaded LPHNPs present a promising platform for localized, controlled transdermal chemotherapy, potentially minimizing systemic exposure and improving therapeutic efficacy in skin cancer management.