Melanoma remains a highly aggressive skin cancer with risks of chemoresistance, early metastasis, and local recurrence after surgery. The study aimed to address challenges in eradicating residual post-surgical melanoma cells by repurposing Dasatinib (DAS), a tyrosine kinase inhibitor approved for chronic myeloid leukemia, and delivering it locally using a biomacromolecule-based topical system. The authors proposed that targeted local delivery could concentrate drug at the site of residual disease while limiting systemic exposure.
Dasatinib was encapsulated in human serum albumin (HSA) nanoparticles (referred to as DNPs). Optimization of nanoparticle formulation parameters was performed using a Box-Behnken design. The optimized DNPs were then incorporated into a hydrogel matrix to enable topical, localized delivery to epidermal and dermal layers where residual melanoma cells are likely to persist after surgical excision.
Characterisation demonstrated that the optimized DNPs had a mean particle size of 125.6 ± 1.58 nm, a polydispersity index (PDI) of 0.242 ± 0.008, and a zeta potential of −14.28 ± 0.22 mV. Solid-state and chemical analyses — namely ATR-FTIR, powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC) — indicated amorphisation of Dasatinib within the nanoparticles and showed no evidence of chemical interactions between the drug and the albumin matrix. These findings suggest successful encapsulation with a change from crystalline to amorphous drug state within the carrier.
Quantitative formulation metrics reported in the study were a drug loading of 7.49 ± 0.28% and an entrapment efficiency of 89.80 ± 1.52% for Dasatinib in the HSA nanoparticles. These values indicate a high proportion of the administered drug was associated with the nanoparticulate carrier while the overall payload per mass of nanoparticles was modest.
A range of in vitro assays evaluated the cytotoxic and anti-invasive properties of the DNPs. These included MTT viability assays, scratch assays for cell migration, transwell assays for invasion, cell cycle analysis, and 3D tumoroid/spheroid assays. Across these models, the DNPs demonstrated superior cytotoxic, anti-invasion, and anti-migration effects relative to comparator conditions reported by the authors. Notably, 3D tumoroid-based testing was used to approximate more physiologically relevant tumor architecture compared with 2D cultures.
Mechanistic studies performed by the investigators linked the antitumor effects of DNPs to programmed cell death and modulation of key signaling pathways. Specifically, DNP treatment was associated with upregulation of caspase-7, consistent with activation of apoptotic execution pathways. Concurrently, the authors reported downregulation of several pro-survival and pro-angiogenic signaling proteins, including PI3K, phosphorylated mTOR (p-mTOR), VEGFR, and EGFR. These molecular changes provide a plausible mechanism for the observed reduction in cell viability, invasion, and migration.
Dermatokinetic analysis assessed distribution of the DNP-entrapped hydrogel within skin layers. Results indicated accumulation of nanoparticles in the epidermal and dermal compartments adjacent to residual melanoma cells, supporting the concept of localized retention of Dasatinib at clinically relevant tissue depths. The dermatokinetic data were presented by the authors as evidence that the hydrogel vehicle can deposit and retain DNPs in skin layers where microscopic residual disease would be expected.
The study demonstrates that a topical hydrogel containing Dasatinib-loaded HSA nanoparticles can be formulated with favorable physicochemical characteristics and high entrapment efficiency, and that this system exerts enhanced cytotoxic, anti-migration, and anti-invasion effects in vitro. Mechanistic data indicate apoptosis induction via caspase-7 and suppression of PI3K/p-mTOR, VEGFR, and EGFR signaling. Dermatokinetic findings show nanoparticle accumulation in epidermal and dermal layers, supporting potential for localized treatment of residual melanoma. The authors conclude that the DNP-entrapped hydrogel is a promising topical strategy to manage residual disease; detailed in vivo efficacy, safety, and clinical translation data were not reported in the abstract provided.