Multichannel Ca²⁺ Generator for Synergistic Tumor Therapy via Intracellular Ca²⁺ Overload and Chemotherapy

Ca²⁺ overload has attracted an increasing attention due to its benefit of precise cancer therapy, but its efficacy is limited by the strong Ca²⁺ excretion of cancer cells. Moreover, monotherapy of Ca²⁺ overload usually fails to treat tumors satisfactorily. Herein, we develop a multifunctional nanosystem that could induce Ca²⁺ overload by multipathway and simultaneously produce chemotherapy for synergistic tumor therapy. The nanosystem (CaMSN@CUR) is prepared by synthesizing a Ca-doped mesoporous silica nanoparticle (CaMSN) followed by loading the anticancer drug curcumin (CUR). CaMSN serves as the basis Ca²⁺ generator to induce Ca²⁺ overload directly in the intracellular environment by acid-triggered Ca²⁺ release, while CUR could not only exhibit chemotherapy but also facilitate Ca²⁺ release from the endoplasmic reticulum to the cytoplasm and inhibit Ca²⁺ efflux out of cells to further enhance Ca²⁺ overload. The in vitro and in vivo results show that CaMSN@CUR could exhibit a remarkable cytotoxicity against 4T1 cells and significantly inhibit tumor growth in 4T1 tumor-bearing mice via the synergy of Ca²⁺ overload and CUR-mediated chemotherapy. It is expected that the designed CaMSN@CUR has a great potential for effective tumor therapy.