Design and comparative evaluation of liposomes and ultra-flexible combisomes incorporating stratum corneum lipids for the delivery of 4-hydroxytamoxifen and thymoquinone

Ductal carcinoma in situ is characterized by abnormal epithelial proliferation in breast ducts. Standard therapy with tamoxifen is considered an overtreatment for this indolent condition, emphasizing the need for alternatives. This study aimed to explore a novel stratum corneum lipid-based ultra-flexible combisomal gel co-loaded with 4-hydroxytamoxifen and thymoquinone for transpapillary delivery in DCIS management. Comparative study was carried out against conventional liposomes lacking stratum corneum lipids and edge activators. Molecular docking confirmed synergistic binding of drugs to estrogen receptor (IL2J), supporting the rationale. Formulation was optimized using Design of Experiments (DoE). The optimized combisomes demonstrated vesicle size of 172.6 nm, zeta potential of –22.1 mV, and high thymoquinone entrapment efficiency (96.24 %). Characterization via DSC, FT-IR, and TEM also confirmed drug encapsulation. The combisomes showed a superior flexibility with high deformability index of 18.75 ± 0.526- compared to liposomes (1.20 ± 0.001). The combisomal gel achieved sustained super case II kinetics and improved permeation across the mammary papilla (98.37 % for 4-OHT, 99.03 % for TQN). Confocal microscopy validated deeper tissue penetration. In vitro cytotoxicity studies showed improved cellular uptake and synergistic efficacy. Overall, this study highlights the potential of the combisomal gel as a non-invasive, site-targeted therapeutic platform for effective DCIS treatment.