Optimized Beta-Sitosterol Transethosomal Gel OutperformsTransferosomes for Enhanced Transdermal Delivery and Cytotoxicity inBreast Cancer Therapy

Background: Beta-sitosterol, a plant-derived phytosterol with potent anticancer and pro-apoptotic properties, suffers from poor oral bioavailability due to its classification as a BCS Class II compound. To overcome this limitation, a transdermal delivery system was explored using vesicular carriers, transethosomes, and transferosomes. The central hypothesis proposed that transethosomal gels, due to their ethanol content and enhanced membrane fluidity, would demonstrate superior drug entrapment, permeation, and anticancer efficacy compared to transferosomal gels. Methods: Transethosomal and transferosomal formulations containing beta-sitosterol were developed and optimized using a Box–Behnken Design. The optimized vesicles were characterized for particle size, zeta potential, and entrapment efficiency, followed by incorporation into Carbopol 934-based gels. These gels were then evaluated for in vitro release, ex vivo skin permeation, cytotoxicity against MCF-7 breast cancer cells, and antibacterial activity. Results: Among the formulations, transethosomes exhibited the most desirable properties, including a vesicle size of 180 nm, an entrapment efficiency of 80.55%, and a zeta potential of −26 mV, indicating stability and enhanced penetration. The optimized transethosomal gel (ET4G3) showed 84.85% drug release, 75.4% ex vivo skin permeation, significant cytotoxicity toward MCF-7 cells, and notable antibacterial activity. Discussion: The ethanol content in transethosomes improved membrane flexibility and skin permeability, resulting in better performance than transferosomes. The release followed Higuchi kinetics, indicating a diffusion-controlled, sustained delivery. Conclusion: The superior efficacy of ET4G3 highlights its potential as a promising transdermal nanocarrier for targeted and sustained breast cancer therapy, offering an effective alternative to conventional oral delivery systems.