Thermosensitive Block Copolymer Hydrogel with Embedded Catanionic Vesicles as a Localized Doxorubicin Delivery...

Skin cancer, particularly melanoma, remains a major therapeutic challenge due to its high metastatic potential and limited efficacy of systemic chemotherapy. Localized and controlled delivery of chemotherapeutic agents such as doxorubicin (DOX) represents a promising alternative to systemic treatments and costly immunotherapies. Hybrid hydrogels that integrate polymeric scaffolds with embedded nanostructures (e.g., vesicles, micelles, or nanoparticles) have emerged as particularly effective platforms for enhancing therapeutic performance. Herein, we report the development of a thermosensitive hybrid hydrogel for potential melanoma drug delivery applications, obtained by dispersing DOX-loaded, pH-sensitive 12-2-12/SLSar catanionic vesicles within a poloxamer 237 (F87) scaffold. The system was comprehensively characterized in terms of rheological behavior, biocompatibility, drug-release kinetics, and in vitro anti-melanoma activity in 2D monolayer cell cultures and 3D spheroids. In parallel, molecular-level interactions between the F87 matrix and the surfactant-based vesicles were investigated. Strong polymer-surfactant interactions were observed, leading to the formation of mixed polymer/surfactant micelles and vesicles, and inducing significant modifications in aggregate physicochemical properties, particularly surface charge. These interactions were found to be thermally driven and strongly dependent on the polymer-to-surfactant ratio. The catanionic vesicles exhibited high DOX encapsulation efficiency and remained stably dispersed within the F87 scaffold. The resulting hybrid hydrogel demonstrated controlled release kinetics, offering potential advantages for localized drug delivery compared with vesicle-only formulations. Moreover, the hybrid system demonstrated excellent biocompatibility and significantly outperformed neat F87 hydrogels in enhancing DOX internalization and inducing melanoma cell death in vitro. Overall, this work presents a versatile and tunable strategy for integrating catanionic vesicles into thermosensitive polymeric scaffolds, providing a promising platform for localized melanoma drug delivery.