A modular lipid-based oral drug delivery system for precision combination chemotherapy in breast cancer

Breast cancer is the third leading cause of cancer-related deaths among women in the United States. Treatment options often include chemotherapy, which involves the use of highly potent but toxic medications that can cause severe adverse reactions, further worsening the patient's condition and, in some cases, leading to fatal outcomes. Additionally, oral delivery of chemotherapeutic agents is limited by poor bioavailability, arising from the harsh acidic and enzymatic environment of the gastrointestinal tract, low oral absorption, and extensive hepatic first pass metabolism, which contribute to the significant toxicity and reduce therapeutic efficiency associated with conventional chemotherapies. This study aimed to develop and evaluate a mannosamine modified, freeze-dried self-emulsifying drug delivery system (SEDDS) capable of co-delivering chemotherapeutic agents to enhance oral absorption and improve targeted delivery for breast cancer treatment Methods: Four SEDDS formulations were optimized and prepared using varying ratios of Labrasol, Capryol 90, Labrafac PG, and Gellucire 44/14. Primary water-in-oil emulsions containing doxorubicin and ellipticine were dispersed into an external aqueous phase containing mannosamine to form water-in-oil-in-water double emulsions under passive mixing. Formulations were subsequently freeze dried to yield solid, dispersible SEDDS. The formulations were characterized for particle size, polydispersity index, stability, and morphology (SEM). Thermal behavior (DSC, XRD), drug release profile (In vitro Dissolution), permeation (MDCK cell line), and cellular uptake (MDA MB-231 and MDA MB-468 cell lines) were also assessed. Results: Optimized surfactant-to-oil ratios (1:9 and 2:8 aqueous: oil phase ratios) produced stable primary and double emulsions suitable for SEDDS development. Microscopy confirmed triphasic w/o/w structures with internal aqueous droplets encapsulated within a lipid phase and surrounded by an external aqueous phase. SEDDS demonstrated particle sizes between 190-587 nm and PDI values of 0.005-0.336. Thermal analyses of freeze dried SEDDS indicated the formation of amorphous mixtures with sustained release kinetics. Fluorescence imaging showed efficient cellular uptake of the dual drug loaded formulations. Conclusion: A mannosamine modified SEDDS was successfully developed, enabling dual loading of doxorubicin and ellipticine with favorable stability, sustained release, and efficient cellular uptake. This work demonstrates the potential of this lipid-based, modular oral delivery platform to enable mono and combination chemotherapy with improved bioavailability and reduced toxicity. By integrating innovative formulation science with targeted drug delivery, this work contributes to broader efforts at designing safe and effective treatments for cancer.