Co-loaded pH-Responsive AOT Nanovesicles for Combinatorial Chemotherapy: Structure, Stability, and Mechanism of Drug Release and Anti-Cancer Activity

Abstract Controlled and targeted drug delivery to the diseased site can significantly reduce systemic toxicity and improve therapeutic efficacy by enhancing cellular uptake. In this study, we report the development of biocompatible sodium bis(2-ethylhexyl) sulfosuccinate (AOT)-based nanovesicles for the co-delivery of hydrophilic and hydrophobic anti-cancer agents, doxorubicin and curcumin. These nanovesicles were thoroughly characterized by using FTIR, dynamic light scattering, transmission electron microscopy, and fluorescence lifetime spectroscopy to assess their physicochemical properties. The system exhibited high drug encapsulation efficiencies, excellent colloidal stability, and sustained pH-responsive drug release, which favored acidic environments that mimic tumor conditions. Cytotoxicity assays confirmed the biocompatibility of AOT vesicles and their enhanced anti-cancer efficacy upon drug loading. Consequently, the drug-loaded AOT vesicles showed induced apoptotic potential, interference in cell cycle progression, and significantly altered apoptosis-associated gene expression profiles. Atomistic molecular dynamics simulations provided insights into the spatial localization and interactions of both drugs within the nanovesicle, while umbrella sampling revealed the energetics of the drug release mechanisms. Together, these results highlight the potential of AOT-based nanovesicles as a cost-effective and multifunctional nanocarrier platform for combinatorial cancer therapy, offering a promising alternative to more intricate and expensive delivery methods.