A cascade nanoplatform for the regulation of the tumor microenvironment and combined cancer therapy.

Abstract

Recently, disulfiram (DSF), an anti-alcoholism drug, has attracted increasing biomedical interest due to its anticancer effects. However, the anticancer activity of DSF is Cu(II)-dependent and it is extremely unstable, which severely hinders its clinical translation. Herein, we report the fabrication of a multifunctional nanoplatform (MCDGF) that can improve the stability of diethyldithiocarbamate (DTC), a main metabolite of DSF, by modifying the aryl boronic ester group to form a prodrug (DQ), and also realize the in situ generation of Cu(DTC)2, which relies on a cascade reaction. The delivered Cu/DQ induces immunogenic cell death (ICD) and powerfully enhances immune responses of cytotoxic T lymphocytes (CTLs) and the infiltration of dendritic cells as well as T cells. Furthermore, the grafted glucose oxidase (GOx) decomposes glucose, thus "starving" the cancer cells and providing H2O2 for the production of Cu(DTC)2. More importantly, H2O2 significantly promotes the polarization of macrophages to the anti-tumor subtype. The nano-carrier "mesoporous polydopamine (MPDA)" also displays a good photothermal therapeutic effect. The nanoplatform-integrated chemotherapy, starvation therapy, photothermal therapy, and immunotherapy synergistically stimulated CTL activation and M1 macrophage polarization. Taken together, the as-prepared nanoplatform could regulate the tumor immune microenvironment and eliminate cancer with combined cancer therapy, which will offer a promising strategy for cancer treatment and promote the clinical application of DSF in breast cancer.