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

Abstract

Chemotherapy based on small molecule drugs, hormones, cycline kinase inhibitors, and monoclonal antibodies 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 monotherapies targeting biochemical cues or physical cues in the TME have been developed, none of them can cope with the complex TME, while mechanochemical combination therapy remains largely to be explored. Herein, a combination therapy strategy based on an extracellular matrix (ECM) modulator and TME‐responsive drug for the first attempt of mechanochemically synergistic treatment of breast cancer is developed. Specifically, based on overexpressed NAD(P)H quinone oxidoreductase 1 (NQO1) in breast cancer, a TME‐responsive drug (NQO1‐SN38) is designed and it is combined with the inhibitor (i.e., β‐Aminopropionitrile, BAPN) for Lysyl oxidases (Lox) that contributes to the tumor stiffness, for mechanochemical therapy. It is demonstrated that NQO1 can 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 reduces collagen deposition and enhances drug penetration in tumor heterospheroids in vitro. It is further demonstrated that the mechanochemical therapy showed outstanding therapeutic efficacy in vivo, providing a promising approach for breast cancer therapy.

Matrix stiffness affects tumor-associated macrophage functional polarization and its potential in tumor therapy

“…BAPN is the first pan-inhibitor of the LOX family with the features of non-specificity and irreversibility [ 141 ]. Although BAPN showed an antitumor effect by suppressing LOX activity in many preclinical studies [ 142 – 144 ], no clinical trials have been conducted for BAPN due to the lack of suitable chemical modification sites as well as the non-tumorigenic toxicity and teratogenic effect [ 139 , 145 , 146 ]. PXS compounds are a new generation of oral pan-LOX inhibitors, including PXS-S1A, PXS-S2A, PXS-S1C, PXS-5153A, and PXS-5505.…”