Fabrication and Optimization of Sesamol-Loaded Nanoemulgel for Skin Cancer: Insights from Molecular Modeling, In Vitro and In Vivo Studies

<title>Abstract</title> <p> <bold>Purpose</bold> The current investigation aimed to develop nanoemulgel based topical delivery system for Sesamol (SES) and evaluate its therapeutic efficacy against skin cancer supported by in silico ADME profiling, molecular modeling,in vitro and in vivo assessments. <bold>Methods</bold> The human BRAF serine/threonine-protein kinase is a key component of the MAPK signaling pathway implicated in melanoma progression. To explore the probable binding of SES with this enzyme molecular docking studies were performed. SES's pharmacokinetic/toxicity profile was predicted via PharmoADMET using its SMILES structure. SES loaded nanoemulsions (SES-NE) was made by aqueous titration, optimized with a Central Composite Design, subsequently formulated into Carbopol based SES-nanoemulgel (SES-NEG) and evaluated for physicochemical properties, A375-melanoma cytotoxicity, dermal toxicity, and skin irritation in Wistar rats. <bold>Results</bold> Molecular docking studies of SES exhibited strong binding affinity of -10.7 kcal/mol by interacting with crucial residues Asp143 &amp; Thr81 of BRAF followed by Pharmoscore of 90/100 explaining good prediction confidence and excellent ADMET profile of candidate. Optimized SES-NE produced globules averaging 215 ± 1.3 nm in size, a polydispersity index of 0.273 ± 0.013, a zeta potential of − 22 ± 0.016 mV, and an entrapment efficiency of 81.8 ± 0.52%. SES-NEG exhibited suitable pH (5.9 ± 0.024), viscosity (257.97 ± 12.32 cps), and spreadibility (28.17 ± 0.015 g·cm/s) for topical application. SES-NEG exhibited significantly higher cytotoxicity against A375-melanoma cells compared to pristine SES with an IC₅₀ of 23.21 ± 0.09 µg/mL, while exhibiting no systemic toxicity or irritation. <bold>Conclusion</bold> The optimistic results of the current study showed that SES-NEG is a safe, stable, and effective topical delivery system that significantly enhances anticancer efficacy, making it a potential approach for topical delivery in the management of skin carcinoma. </p>