Ultradeformable liposomal delivery of vismodegib modulates its biological activity in melanoma cells.

Introduction: Vismodegib (VDG), a Smoothened inhibitor approved for basal cell carcinoma, has potential for repurposing in other tumors in which Hedgehog (Hh) signaling contributes to malignancy. However, systemic VDG treatment is associated with relevant adverse effects, and its effective delivery to cutaneous targets remains challenging, supporting the exploration of drug delivery systems for its administration. Methods: Here, we first screened the response to VDG across four murine tumor cell lines-B16 melanoma, 4T1 mammary carcinoma, Colon-26 colon carcinoma, and LLC1 Lewis lung carcinoma-and then evaluated whether nanocarrier-based delivery could modify its activity in melanoma cells. Results: Free VDG produced moderate effects across the screened models, with B16 emerging as the most responsive model showing evidence of growth inhibition together with modulation of Hh-related markers. In this setting, encapsulation of VDG into ultradeformable liposomes (UDL), specially designed for topical application, significantly changed the biological response to treatment, producing a stronger cytotoxic response, concentration-dependent inhibition of cell population expansion, and increased accumulation of dead cells compared with the free drug. An exploratory PAMAM G4.5 dendrimer-based formulation did not show detectable biological effects at the tested concentration, which was constrained by the need to maintain subtoxic dendrimer levels. Although no significant transcriptional changes were detected at the analyzed time point, reduced Gli-1 expression at higher concentrations suggested some degree of Hh pathway modulation by UDL-VDG. However, the enhanced biological effect of UDL-VDG could not be explained solely by canonical Hh inhibition, and responses varied across melanoma models. Discussion: Overall, these results show that ultradeformable liposomal delivery potentiates the in vitro anti-melanoma activity of VDG and supports its further exploration as a repurposing strategy for candidate non-metastatic cutaneous melanoma. More broadly, these findings support the rationale for topical nanocarrier-based delivery as an approach that could potentially improve local drug availability while helping to reduce some of the limitations associated with systemic administration.