Combination Therapy of Lox Inhibitor and Stimuli-Responsive Drug for Mechanochemically Synergistic Breast Cancer Treatment.

Chemotherapy based on small molecule drugs, hormone, cycline kinase inhibitor and monoclonal antibody has been widely used for breast cancer treatment in the clinic but with limited efficacy, due to the poor specificity and tumor microenvironment (TME) caused diffusion barrier. Although mono-therapy targeting biochemical cues or physical cues in the TME have been developed, neither of them can cope with the complex TME, while mechanochemical combination therapy remains largely to be explored. Herein, we developed a combination therapy strategy based on ECM modulator and TME-responsive drug for the first attempt of mechanochemically synergistic treatment of breast cancer. Specifically, based on overexpressed NAD(P)H quinone oxidoreductase 1 (NQO1) in breast cancer, we designed a TME-responsive drug (NQO1-SN38) and combined it with the inhibitor (i.e., β-Aminopropionitrile, BAPN) for Lysyl oxidases (Lox) that contributes to the tumor stiffness, for mechanochemical therapy. We demonstrated that NQO1 could trigger the degradation of NQO1-SN38 and release SN38, showing nearly twice tumor inhibition efficiency compared with SN38 treatment in vitro. Lox inhibition with BAPN significantly reduced collagen deposition and enhanced drug penetration in tumor heterospheroids in vitro. We further demonstrated that the mechanochemical therapy showed outstanding therapeutic efficacy in vivo, providing a promising approach for breast cancer therapy. This article is protected by copyright. All rights reserved.