Enhanced therapeutic efficacy of doxorubicin against multidrug-resistant breast cancer with reduced cardiotoxicity
Tianyu Zhang,
Nuannuan Li,
Ru Wang,
Yiying Sun,
Xiaoyan He,
Xiaoyan Lu,
Liuxiang Chu,
Kaoxiang Sun
Affiliations
Tianyu Zhang
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, China
Nuannuan Li
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, China
Ru Wang
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, China
Yiying Sun
Yantai Saipute Analyzing Service Co. Ltd, Yantai, Shandong Province, China
Xiaoyan He
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, China
Xiaoyan Lu
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, China
Liuxiang Chu
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, China
Kaoxiang Sun
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, China
AbstractDoxorubicin (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.
