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<p>The present study aimed to develop and optimize a rosmarinic acid (RA)–loaded cubosomal hydrogel using a Quality by Design (QbD) approach for enhanced dermal delivery and melanoma therapy. Critical formulation and process parameters were identified through design-of-experiments, yielding optimized cubosomes with desirable physicochemical attributes. The optimized RA nanoparticles (RA–NPs) exhibited a mean particle size of 121.4&#xa0;nm, a negative zeta potential of − 21.8 mV, and a high encapsulation efficiency of 89.4%. Scanning and transmission electron microscopy confirmed the formation of uniformly spherical cubosomes with a well-defined internal cubosomal architecture and intact lipid bilayer organization. The nanoparticles were incorporated into a xanthan gum-based hydrogel with suitable pH and viscosity for dermal application. In vitro diffusion studies demonstrated a biphasic release profile, with the cubosomal hydrogel achieving significantly higher cumulative drug release at 12&#xa0;h (79.2 ± 2.6%) compared with the plain RA hydrogel (64.7 ± 2.9%). Ex vivo skin permeation studies further revealed markedly enhanced transdermal transport, with cumulative permeation of 87.9 ± 2.8% for the cubosomal hydrogel versus 66.6 ± 3.1% for the plain hydrogel, corresponding to an enhancement factor of ~ 1.35. The cubosomal hydrogel also exhibited a significantly higher steady-state flux (52.14 ± 2.52&#xa0;µg/cm²/h) and apparent permeability coefficient (81.74 ± 0.41 × 10⁻⁶ cm/s) compared to the reference gel. Cytotoxicity studies in A-375 human melanoma cells demonstrated potent antiproliferative activity (IC₅₀ = 18.14 ± 2.62&#xa0;µg/mL), while confocal microscopy confirmed efficient cellular uptake and mitochondrial localization. Antioxidant assays indicated additional radical-scavenging activity, and stability studies predicted a shelf life of approximately 12 months under refrigerated conditions. Overall, the QbD-enabled RA-loaded cubosomal hydrogel offers superior drug release, enhanced skin permeation, and selective anticancer activity, highlighting its promise as an advanced nanocarrier system for topical melanoma therapy. Future in vivo and preclinical studies are warranted to validate its therapeutic efficacy, safety, and translational applicability.</p>

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Design and Optimization of Rosmarinic Acid-Loaded Cubosomal Hydrogel for Enhanced Melanoma Therapy: Physicochemical Characterization and In Vitro Biological Evaluation

  • 期刊论文

  • 发表日期：

    2026年2月26日

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  • Rahul Koli,
  • V. S. Mannur

摘要

The present study aimed to develop and optimize a rosmarinic acid (RA)–loaded cubosomal hydrogel using a Quality by Design (QbD) approach for enhanced dermal delivery and melanoma therapy. Critical formulation and process parameters were identified through design-of-experiments, yielding optimized cubosomes with desirable physicochemical attributes. The optimized RA nanoparticles (RA–NPs) exhibited a mean particle size of 121.4 nm, a negative zeta potential of − 21.8 mV, and a high encapsulation efficiency of 89.4%. Scanning and transmission electron microscopy confirmed the formation of uniformly spherical cubosomes with a well-defined internal cubosomal architecture and intact lipid bilayer organization. The nanoparticles were incorporated into a xanthan gum-based hydrogel with suitable pH and viscosity for dermal application. In vitro diffusion studies demonstrated a biphasic release profile, with the cubosomal hydrogel achieving significantly higher cumulative drug release at 12 h (79.2 ± 2.6%) compared with the plain RA hydrogel (64.7 ± 2.9%). Ex vivo skin permeation studies further revealed markedly enhanced transdermal transport, with cumulative permeation of 87.9 ± 2.8% for the cubosomal hydrogel versus 66.6 ± 3.1% for the plain hydrogel, corresponding to an enhancement factor of ~ 1.35. The cubosomal hydrogel also exhibited a significantly higher steady-state flux (52.14 ± 2.52 µg/cm²/h) and apparent permeability coefficient (81.74 ± 0.41 × 10⁻⁶ cm/s) compared to the reference gel. Cytotoxicity studies in A-375 human melanoma cells demonstrated potent antiproliferative activity (IC₅₀ = 18.14 ± 2.62 µg/mL), while confocal microscopy confirmed efficient cellular uptake and mitochondrial localization. Antioxidant assays indicated additional radical-scavenging activity, and stability studies predicted a shelf life of approximately 12 months under refrigerated conditions. Overall, the QbD-enabled RA-loaded cubosomal hydrogel offers superior drug release, enhanced skin permeation, and selective anticancer activity, highlighting its promise as an advanced nanocarrier system for topical melanoma therapy. Future in vivo and preclinical studies are warranted to validate its therapeutic efficacy, safety, and translational applicability.