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

Objective The aim of this research was to design nanostructured lipid carriers (NLCs) co-delivering paclitaxel (PTX) and ubenimex (Uben) to improve the tumor microenvironment (TME) and enhance efficacy against breast cancer.Significance Nanostructured lipid carriers 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 NLC co-loaded with PTX and Uben to achieve synergistic therapeutic effects on breast cancer by improving the immunosuppressive TME.Methods Ubenimex was conjugated to vitamin E polyethylene glycol succinate (TPGS) via ester bonds, after which the synthetic conjugate, PTX, 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 TME and induced immune cell activation and secretion of anti-tumor cytokines (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-12 (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 NLCs alleviated TME immunosuppression to enhance synergistic anti-breast cancer therapy and provided a feasible solution for breast cancer treatment.