Nanomedicine alleviates doxorubicin-induced cardiotoxicity and enhances chemotherapy synergistic chemodynamic therapy

Abstract

Doxorubicin (DOX) is widely used in clinic as a broad-spectrum chemotherapy drug, which can enhance the efficacy of chemodynamic therapy (CDT) by interfering tumor-related metabolize to increase H₂O₂ content. However, DOX can induce serious cardiomyopathy (DIC) due to its oxidative stress in cardiomyocytes. Eliminating oxidative stress would create a significant opportunity for the clinical application of DOX combined with CDT. To address this issue, we introduced sodium ascorbate (AscNa), the main reason is that AscNa can be catalyzed to produce H₂O₂ by the abundant Fe³⁺ in the tumor site, thereby enhancing CDT. While the content of Fe³⁺ in heart tissue is relatively low, so the oxidation of AscNa had tumor specificity. Meanwhile, due to its inherent reducing properties, AscNa could also eliminate the oxidative stress generated by DOX, preventing cardiotoxicity. Due to the differences between myocardial tissue and tumor microenvironment, a novel nanomedicine was designed. MoS₂ was employed as a carrier and CDT catalyst, loaded with DOX and AscNa, coating with homologous tumor cell membrane to construct an acid-responsive nanomedicine MoS₂-DOX/AscNa@M (MDA@M). In tumor cells, AscNa enhances the synergistic therapy of DOX and MoS₂. In cardiomyocytes, AscNa could effectively reduce the cardiomyopathy induced by DOX. Overall, this study enhanced the clinical potential of chemotherapy synergistic CDT.

Keywords: Chemodynamic therapy; Chemotherapy; DOX-induced cardiomyopathy; DOX-mediated oxidative stress; Sodium ascorbate.