Development of a FU/TA ethosome-based polymeric nanocomposite film for sustained, non-invasive hypertrophic scar therapy: from bench to clinic.

The current first-line treatment for hypertrophic scars (HS) involves multiple intralesional injections of 5-fluorouracil (5-Fu) and triamcinolone acetonide (TA), which can be extremely painful due to the dense nature of scar tissue and is often poorly tolerated by patients. Advances in nanotechnology have opened new avenues for effective and non-invasive therapies for various skin conditions, including HSs. In this study, ethosomes co-loaded with 5-Fu and TA (FU/TA-E) were developed and subsequently incorporated into a three-dimensional polymeric film matrix (FU/TA-EF), formed through Schiff-base linkages between gelatin (G) and oxidized tragacanth gum (OTG). This nanocomposite film was designed to facilitate ease of application and provide sustained drug release. The FU/TA-E nanoparticles exhibited a spherical morphology, an average size of 149.3 ± 36.15 nm, a zeta potential of -0.5 ± 6.02 mV, and high encapsulation efficiencies, 96 ± 2.3 % for 5-Fu and 98 ± 1.8 % for TA. In vitro release and skin penetration studies demonstrated prolonged drug release profiles and effective permeation through dense scar tissue. H&E and Masson's trichrome staining of rabbit scar models treated with FU/TA-EF revealed reduced fibroblast proliferation, disrupted collagen fiber alignment, and a lowered Scar Elevation Index (SEI). A 12-week clinical study on patients further validated the formulation's safety and efficacy, showing no adverse skin reactions. Vancouver Scar Scale (VSS) assessments indicated notable improvements, including decreased scar height and enhanced skin pliability. These preliminary findings highlight the potential of FU/TA-EF as a promising, non-invasive therapeutic strategy for HS treatment.