Topical delivery of Vismodegib using fourth-generation PAMAM dendrimers: a potential treatment for Kaposi's sarcoma

The aim of this work was to develop dendrimer-based nanocarriers of Vismodegib (VDG) for the topical treatment of Kaposi's sarcoma (KS). Previous molecular docking studies have shown that VDG is capable of inhibiting cyclooxygenase-2 (COX-2), an enzyme transcriptionally induced by the viral oncoprotein vGPCR and critically involved in the angioproliferative phenotype of KS. In this study, VDG was complexed with generation 4 poly(amidoamine) (PAMAM) dendrimers bearing hydroxyl terminal groups (G4-OH), and surface-functionalized with folic acid (G4-FA). The resulting G4-OH@VDG and G4-FA@VDG complexes significantly enhanced the apparent aqueous solubility of VDG, achieving experimental stoichiometries of approximately 4 and 8 mol of VDG per mole of dendrimer, respectively. G4-OH@VDG displayed a hydrodynamic diameter of 225.1 ± 122.0 nm (PdI = 0.44 ± 0.02), while G4-FA@VDG exhibited a size of 210.5 ± 54.7 nm (PdI = 0.66 ± 0.08). Dendrimer-drug associations were confirmed by FT-IR spectroscopy, and in vitro release studies revealed distinct, pH-dependent release mechanisms. Cytotoxicity was evaluated using ex vivo (red blood cells) and in vitro (HaCaT keratinocytes) models, both relevant to topical KS treatment, and no cytotoxic effects were observed. Skin penetration studies using the Saarbrücken ex vivo model demonstrated that both systems were able to deliver VDG into the skin, with G4-OH@VDG achieving higher drug accumulation, particularly within the stratum corneum. Antitumoral activity was assessed in an in vitro KS model, where cytotoxic effects were observed at 48 h post-incubation. Notably, G4-OH@VDG exhibited the most favorable therapeutic profile, including significant reduction of cell viability and inhibition of cell migration at sublethal concentrations. Overall, these results demonstrate that the combination of drug repurposing and dendrimer-based nanotechnology for topical delivery enhances the therapeutic performance of VDG in in vitro models of Kaposi's sarcoma.