Development, Dermatokinetic and In Vivo Evaluation of Fluorouracil-Loaded Solid Lipid Nanoparticles for Enhanced Epidermal Targeting in Skin Cancer

Background: Topical chemotherapy for skin cancer is often limited by poor penetration of fluorouracil across the stratum corneum, resulting in inadequate drug localization within the epidermis and dermis. Solid lipid nanoparticles (SLNs) have emerged as promising nanocarriers for enhancing topical drug delivery and skin retention. Objective: This study aimed to develop and evaluate fluorouracil-loaded SLNs incorporated into a Carbopol gel to improve skin permeation, Dermatokinetic behavior, epidermal targeting, and local therapeutic efficacy. Methods: Fluorouracil-loaded SLNs were prepared using an optimized lipid–surfactant system and characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, drug loading, morphology, and solid-state properties. The optimized formulation was incorporated into a Carbopol 934 gel and evaluated for physicochemical properties, ex vivo skin permeation, Dermatokinetic parameters, confocal laser scanning microscopy (CLSM), FTIR and DSC-based permeation studies, in vitro cytotoxicity, skin irritation, and anti-inflammatory activity. Results: The optimized SLNs exhibited a particle size of 220 ± 0.9 nm, PDI of 0.419 ± 0.035, zeta potential of −18.5 ± 0.3 mV, entrapment efficiency of 88.3 ± 2.3%, and drug loading of 1.9 ± 0.3%. The SLN gel significantly enhanced epidermal and dermal drug deposition, achieving approximately 2.29-fold and 2.28-fold increases in Cskin, max, respectively, compared with the conventional gel. CLSM demonstrated deeper penetration (up to 60 μm) for the SLN gel, while FTIR and DSC analyses indicated lipid fluidization and structural modification of the stratum corneum. The formulation exhibited concentration-dependent cytotoxicity against B16 cells, produced no detectable skin irritation, and significantly reduced IL-1α and TNF-α levels compared with the conventional formulation (p < 0.001). Conclusion: Fluorouracil-loaded SLNs substantially improved topical delivery, skin retention, and anti-inflammatory activity while maintaining excellent dermal tolerability. These findings demonstrate that SLN-based topical delivery is a promising strategy for localized chemotherapy and epidermal targeting in skin cancer.