Multifunctional magnetic Fe3O4 nanoparticles combined with chemotherapy and hyperthermia to overcome multidrug resistance

Abstract

Yanyan Ren1,2,*, Haijun Zhang1,2,*, Baoan Chen1, Jian Cheng1, Xiaohui Cai1, Ran Liu1, Guohua Xia1, Weiwei Wu1, Shuai Wang1, Jiahua Ding1, Chong Gao1, Jun Wang1, Wen Bao1, Lei Wang1, Liang Tian1, Huihui Song1, Xuemei Wang1,2 1Department of Hematology and Oncology, Key Medical Discipline, Jiangsu Province, Zhongda Hospital, and Faculty of Oncology, Medical School, Nanjing, 2State Key Laboratory of Bioelectronics, Southeast University, Nanjing, People's Republic of China*These authors contributed equally to this workBackground: Multidrug resistance in cancer is a major obstacle for clinical therapeutics, and is the reason for 90% of treatment failures. This study investigated the efficiency of novel multifunctional Fe3O4 magnetic nanoparticles (Fe3O4-MNP) combined with chemotherapy and hyperthermia for overcoming multidrug resistance in an in vivo model of leukemia.Methods: Nude mice with tumor xenografts were randomly divided into a control group, and the treatment groups were allocated to receive daunorubicin, 5-bromotetrandrine (5-BrTet) and daunorubicin, Fe3O4-MNP, and Fe3O4-MNP coloaded with daunorubicin and 5-bromotetrandrine (Fe3O4-MNP-DNR-5-BrTet), with hyperthermia in an alternating magnetic field. We investigated tumor volume and pathology, as well as P-glycoprotein, Bcl-2, Bax, and caspase-3 protein expression to elucidate the effect of multimodal treatment on overcoming multidrug resistance.Results: Fe3O4-MNP played a role in increasing tumor temperature during hyperthermia. Tumors became significantly smaller, and apoptosis of cells was observed in both the Fe3O4-MNP and Fe3O4-MNP-DNR-5-BrTet groups, especially in the Fe3O4-MNP-DNR-5-BrTet group, while tumor volumes in the other groups had increased after treatment for 12 days. Furthermore, Fe3O4-MNP-DNR-5-BrTet with hyperthermia noticeably decreased P-glycoprotein and Bcl-2 expression, and markedly increased Bax and caspase-3 expression.Conclusion: Fe3O4-MNP-DNR-5-BrTet with hyperthermia may be a potential approach for reversal of multidrug resistance in the treatment of leukemia.Keywords: magnetic nanoparticles, daunorubicin, 5-bromotetrandrine, multidrug resistance, hyperthermia