Tumor microenvironment improved by nanostructured lipid carriers co-deliverying paclitaxel and ubenimex to treat breast cancer

OBJECTIVE: The aim of this research was to design nanostructured lipid carriers co-delivering paclitaxel and ubenimex to improve the tumor microenvironment and enhance efficacy against breast cancer. SIGNIFICANCE: Nanostructured lipid carriers (NLC) offer unique advantages for co-delivery of anti-tumor drugs, including high drug-loading capacity, controlled-release performance, and facile functionalization. This study developed a nanostructured lipid carrier (NLC) co-loaded with paclitaxel and ubenimex to achieve synergistic therapeutic effects on breast cancer by improving the immunosuppressive tumor microenvironment. METHODS: Ubenimex (Uben) was conjugated to vitamin E polyethylene glycol succinate (TPGS) via ester bonds, after which the synthetic conjugate, paclitaxel, and lipid materials were formulated into the nanostructured lipid carrier (PTX/Uben-NLC) by the emulsified solvent evaporation-low-temperature curing method and subsequently characterized and evaluated for improved anti-tumor efficacy. RESULTS: The prepared PTX/Uben-NLC was approximately spherical with a negative potential and a particle size of about 161 nm. The formulation demonstrated sustained drug release. Uben exhibited pH-responsive release in the weakly acidic tumor microenvironment (TME) and induced immune cell activation and secretion of anti-tumor cytokines (IFN-γ, TNF-α, IL-12), while secretion of immunosuppressive cytokines (TGF-β and IL-10) was concurrently inhibited. PTX exerted direct anti-tumor effects on tumor cells. Consequently, the PTX/Uben-NLC alleviated TME immunosuppression and enhanced anti-breast-cancer activity. CONCLUSION: Dual-drug-loaded nanostructured lipid carriers alleviated TME immunosuppression to enhance synergistic anti-breast cancer therapy and provided a feasible solution for breast cancer treatment.