Design and development of ultra-flexible combisomal gel for non-invasive delivery of 4-hydroxytamoxifen and hesperidin in breast cancer treatment

This study employs a systematic approach, beginning with molecular docking with estrogen receptors to establish a rational basis for combining 4-hydroxytamoxifen (4-OHT) and hesperidin in an ultra-flexible combisomal gel (UFCG) for transpapillary delivery to the breast ducts. The binding affinities of the ligands on the receptor protein were greater when combined than when interacting individually, indicating a synergistic effect. Ultra-flexible combisomes were prepared via reverse-phase evaporation and optimized using a Box-Behnken design using Design-Expert^® Software. Ultra-flexible combisomes yielded stable vesicle size (172.6 ± 5.82 nm) with appropriate polydispersity index (0.256 ± 0.071) and Zeta potential (−22.1 ± 1.64 mV). Encapsulation efficiencies were 67.25 ± 1.36% for 4-OHT and 94.36 ± 1.75% for hesperidin. FTIR studies confirmed drug-excipient compatibility, DSC indicated successful drug encapsulation, and TEM showed spherical morphology. UFCG showed sustained release over 24 h, best fitting Korsmeyer-Peppas and Higuchi models. UFCG demonstrated significantly higher permeation than conventional gels in skin and mammary papilla models, especially through porcine mammary papilla. The in vitro anti-cancer efficacy of individual and combined 4-OHT and hesperidin was evaluated on MCF-7 cells, showing that the combination loaded in ultra-flexible combisomes (UFC) exhibited enhanced cytotoxicity, achieving 50% cell death at lower concentrations than either drug alone. The non-invasive, direct delivery through the mammary papilla offers a promising approach to bypass skin barriers. Thus, UFCG could further improve breast cancer treatment efficacy with better patient compliance, warranting continued exploration of optimized drug delivery strategies. These preliminary findings demonstrate the potential of UFCG for transpapillary delivery, warranting further in vivo validation to confirm its therapeutic applicability.