Quality by design-optimized EGCG-loaded cubosomal hydrogel for controlled dermal delivery: In vitro characterization and biological evaluation against melanoma

Epigallocatechin-3-gallate (EGCG), a potent antioxidant and anti-melanoma polyphenol, faces clinical limitations due to poor solubility, instability, and restricted skin permeation. To overcome these barriers, a nanostructured cubosomal hydrogel was developed to enhance EGCG’s dermal delivery and therapeutic efficacy. EGCG-loaded cubosomes were prepared using glycerol monooleate, Poloxamer 407, and Tween 80, and optimized via response surface methodology. The optimized system exhibited nanoscale dimensions (113.24 ± 0.21 nm), low polydispersity (0.16 ± 0.02), high entrapment efficiency (88.7 ± 0.42 %), and a strong negative zeta potential (–34.2 ± 0.27 mV). Incorporation into a xanthan gum hydrogel yielded a smooth, stable, and patient-compliant formulation. Electron microscopy confirmed spherical cubosomes with intact bicontinuous bilayer morphology, while RP-HPLC verified EGCG’s chemical stability post-formulation. The cubosomal hydrogel demonstrated sustained in vitrorelease (78.3 ± 3.6 % at 12 h) and significantly enhanced ex vivo permeation across excised goat skin (86.2 ± 3.2 %, flux 50.36 ± 2.15 µg/cm²/h) compared with the plain hydrogel. Cytotoxic evaluation in A375 melanoma cells revealed strong dose-dependent inhibition (IC₅₀ = 23.69 ± 2.78 µg/mL), supported by enhanced cellular uptake and mitochondrial localization on confocal imaging. Additionally, the formulation exhibited notable antioxidant activity (83.78 ± 1.85 % DPPH scavenging) and excellent physicochemical stability for 60 days under refrigerated and ambient conditions. Overall, EGCG-loaded cubosomal hydrogel provides a stable, biocompatible, and effective nanoplatform for sustained dermal delivery, offering significant potential for localized melanoma therapy.