Natural epigallocatechin-3-gallocarboxylate nanoformulation loaded doxorubicin to construct a novel and low cardiotoxicity chemotherapeutic drug for high-efficiency breast cancer therapy

Abstract

Anthracycline doxorubicin (DOX) remains the first-line chemotherapeutic drug for the efficient treatment of breast cancer, but its severe cardiotoxicity limits its long-term application in clinical tumor chemotherapy. Until now, the pathogenesis mechanism of DOX-induced cardiotoxicity (DIC) is still not fully understood. According to current studies, the oxidative stress caused by the imbalance of reactive oxygen species (ROS) and reactive nitrogen species (RNS) production and mitochondrial dysfunction in myocardial cells are closely related to DIC. Presently, the usual technology to solve the DIC problem is to use a multifunctional nanoplatform to load DOX and obtain a new medicinal agent, thereby enhancing the efficacy of chemotherapeutic drugs and reducing toxic side effects.Herein, the present investigation employed the Mannich condensation reaction, initiated by L-cysteine and (-)-epigallocatechin-3-gallocarboxylate (EGCG), to synthesize EGCG&Cys nanoformulation with both anti-tumor and anti-oxidant properties. The EGCG&Cys were then employed as the DOX carrier to construct a novel chemotherapeutic drug, EGCG&Cys(DOX), for high-efficiency breast cancer treatment. The tumor growth inhibition index of EGCG&Cys(DOX) in tumor-bearing mice was 12.56% superior to the DOX group with the same concentration. Meanwhile, the anti-oxidant properties of EGCG can effectively eliminate a large amount of free radicals produced by DOX and significantly alleviate DIC by improving mitochondrial functional pathways. Ultrasound echocardiography (UCG) showed that the mean LVEF and LEFS values in the 5 mg/kg DOX treatment group were significantly reduced by 54.4% and 63.4%, and the EGCG&Cys(DOX) group mice were consistent with those of the non-chemotherapy group. Moreover, electrocardiogram, serum biochemical indicators, and histopathological analysis results also demonstrate that the cardiotoxicity of EGCG&Cys(DOX) novel chemotherapy drugs is significantly reduced. Consequently, this study presents a new technology for preparing highly efficient and safe nano-chemotherapeutic drugs and an in-depth evaluation of the antitumor efficacy and safety of the synthesized novel drugs, which gave fresh life to the development of nanomedicine in the clinical treatment of breast cancer.

Keywords: (-)-Epigallocatechin-3-Gallocarboxylate (EGCG); Antioxidant; Breast cancer; Chemotherapy; DOX-Induced cardiotoxicity (DIC); Doxorubicin.