Enhanced Prevention of Breast Tumor Metastasis by Nanoparticle-Delivered Vitamin E in Combination with Interferon-Gamma

Preventing cancer metastasis is one of the remaining challenges in cancer therapy. As an efficient natural product, alpha-tocopheryl succinate (alpha-TOS), the most effective form of vitamin E, holds great anticancer potential. To improve its efficacy and bioavailability, lipid-coated calcium carbonate/phosphate (LCCP) nanoparticles (NPs) with folic acid and PEG modification are synthesized for efficient delivery of alpha-TOS to 4T1 cancer cells. The optimized LCCP-FA NPs (NP-TOS15) show an alpha-TOS loading efficiency of around 60%, and enhanced uptake by 4T1 metastatic cancer cells. Consequently, NP-TOS15 significantly enhance the anticancer effect in combination with interferon-gamma (IFN-gamma) in terms of apoptosis facilitation and migration inhibition. Importantly, NP-TOS15 upregulate the anticancer immunity via downregulating program death ligand 1 (PD-L1) expression that is initially induced by IFN-gamma, and remarkably prevent the lung metastasis, particularly in combination with IFN-gamma. Further investigation reveals that this combination therapy also modulates the cytotoxic lymphocyte infiltration into the tumor microenvironment for tumor elimination. Taken together, the NP delivery of alpha-TOS in combination with IFN-gamma provides an applicable strategy for cancer therapy.