Design of tadalafil-loaded gelatin/zein films: functional and biopharmaceutical characterization, photoprotection and pro-angiogenic activities

Chronic wounds require advanced therapeutic strategies to promote adequate healing. The dressings should ideally be biocompatible, absorb exudates, control the permeability and stimulate cell proliferation. Tadalafil, a phosphodiesterase-5 inhibitor, has been proposed to enhance the wound repairing through its pro-angiogenic effects. Although its poor water solubility limits the topical application and bioavailability. This study aimed to design a tadalafil-loaded gelatin/zein film as a potential wound dressing material and evaluate its functional biopharmaceutical and biological performances. The films were prepared by the casting method using a screening-design guided formulation. They were characterized regarding their physical properties, drug release kinetics, and in ovo angiogenic potential. Scanning electron microscopy revealed that tadalafil's incorporation fundamentally altered the film's internal microstructure, from a dense, phase-separated matrix of the blank films into a highly porous, interconnected network. This change resulted in desirable functional properties for an adequate wound dressing, including a threefold increase in water sorption (288.3% vs. 95.2%), hydrophilicity (contact angle 35.6° vs. 52.0°) and anisotropic swelling behavior compared to blank films. Despite the microstructural alterations, the films maintained a high photoprotective capacity combined with a suitable vapor permeability. The selected tadalafil loaded-film, according to the best functional performance, provided a sustained, biphasic release of tadalafil (∼75% over 150 hours). The release kinetic was predominantly driven by a Fickian diffusion mechanism. Crucially, in the in ovo yolk sac membrane assay, the loaded film demonstrated a potent pro-angiogenic activity, increasing significantly the formation of new blood vessels to a similar level of arginine (p > 0.05). In conclusion, tadalafil acted not only as a therapeutic agent but also as a structural pore forming agent, creating a gelatin/zein film with superior functional behavior, sustained drug release, and validated pro-angiogenic effects. Accordingly, the tadalafil loaded-zein films could be addressed as a promising strategy for wound healing applications.