Dasatinib-Loaded Human Serum Albumin Nanoparticle-Impregnated Hydrogel for Localised Eradication of Residual Melanoma: Integrated In Silico , 3D Spheroid, and Dermatokinetic Evaluation

Abstract

The aim of this study is to investigate active targeting of residual melanoma cells. Melanoma is the most aggressive form of skin cancer for which the conventional therapies often fail to target post-surgical residual cells owing to challenges like chemoresistance, early metastasis, and recurrence. To mitigate the following issues, we repurposed Dasatinib (DAS), an antineoplastic drug approved for chronic myeloid leukaemia, and evaluated its potential in melanoma treatment through a safe, biomacromolecule-based topical delivery system. DAS-loaded human serum albumin nanoparticles (DNPs) were optimised via Box-Behnken design and incorporated into a hydrogel for localised delivery. The DNPs had a particle size of 125.6 ± 1.58 nm with a polydispersity index of 0.242 ± 0.008 and a zeta potential of –14.28 ± 0.22 mV. ATR-FTIR, PXRD, and DSC analyses demonstrated amorphisation of the drug in DNPs devoid of any chemical interactions. The loading and entrapment efficiencies of DAS in DNPs were estimated to be 7.49 ± 0.28 and 89.80 ± 1.52%, respectively. In vitro assays such as the MTT assay, scratch assay, transwell-based invasive assays, cell cycle assay, and 3D tumoroid-based assays demonstrated superior cytotoxic, anti-invasion, and antimigration properties of DNPs. Mechanistic studies demonstrated that DNPs induced apoptosis via caspase-7 upregulation and downregulation of PI3K, p-mTOR, VEGFR, and EGFR. Dermatokinetic analysis of DNPs-entrapped hydrogel confirmed DNPs accumulation in the epidermal and dermal layers near residual melanoma cells, highlighting their therapeutic potential in the management of residual disease.