Abstract

Doxorubicin (DOX), a commonly used anti-cancer drug, is limited by its cardiotoxicity and multidrug resistance (MDR) of tumor cells. Epigallocatechin gallate (EGCG), a natural antioxidant component, can effectively reduce the cardiotoxicity of DOX. Meanwhile, EGCG can inhibit the expression of P-glycoprotein (P-gp) and reverse the MDR of tumor cells. In this study, DOX is connected with low molecular weight polyethyleneimine (PEI) via hydrazone bond to get the pH-sensitive PEI-DOX, which is then combined with EGCG to prevent the cardiotoxicity of DOX and reverse the MDR of cancer cells. In addition, folic acid (FA) modified polyethylene glycol (PEG) (PEG-FA) is added to get the targeted system PEI-DOX/EGCG/FA. The MDR reversal and targeting ability of PEI-DOX/EGCG/FA is performed by cytotoxicity and in vivo anti-tumor activity on multidrug resistant MCF-7 cells (MCF-7/ADR). Additionally, we investigate the anti-drug resistant mechanism by Western Blot. The ability of EGCG to reduce DOX cardiotoxicity is confirmed by cardiotoxicity assay. In conclusion, PEI-DOX/EGCG/FA can inhibit the expression of P-gp and reverse the MDR in tumor cells. It also shows the ability of remove oxygen free radicals effectively to prevent the cardiotoxicity of DOX.

摘要

阿霉素 (DOX) 是一种常用的抗癌药物，但受到其心脏毒性和肿瘤细胞的多药耐药性 (MDR) 的限制。表没食子儿茶素没食子酸酯 (EGCG) 是一种天然抗氧化成分，可有效降低 DOX 的心脏毒性。同时，EGCG可以抑制P-糖蛋白（P-gp）的表达，逆转肿瘤细胞的MDR。本研究将DOX与低分子量聚乙烯亚胺(PEI)通过腙键连接，得到pH敏感的PEI-DOX，再与EGCG结合，预防DOX的心脏毒性，逆转癌细胞的MDR。此外，加入叶酸（FA）修饰的聚乙二醇（PEG）（PEG-FA）得到靶向体系PEI-DOX/EGCG/FA。PEI-DOX/EGCG/FA 的 MDR 逆转和靶向能力是通过细胞毒性和体内进行的对多药耐药 MCF-7 细胞 (MCF-7/ADR) 的抗肿瘤活性。此外，我们通过 Western Blot 研究了抗药性机制。EGCG 降低 DOX 心脏毒性的能力通过心脏毒性测定得到证实。总之，PEI-DOX/EGCG/FA可以抑制P-gp的表达，逆转肿瘤细胞的MDR。它还显示出有效清除氧自由基以防止DOX心脏毒性的能力。