A promising strategy for overcoming MDR in tumor by magnetic iron oxide nanoparticles co-loaded with daunorubicin and 5-bromotetrandrin

Jian Cheng^1*, Jun Wang^2*, Baoan Chen¹, Guohua Xia¹, Xiaohui Cai¹, Ran Liu¹, Yanyan Ren¹, Wen Bao¹, Xuemei Wang^3
1Department of Hematology, Zhongda Hospital, Medical School, Southeast University, Nanjing, People's Republic of China; ²Department of Hematology and Oncology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, People's Republic of China; ³National Key Laboratory of Bioelectronics (Chien-Shiung Wu Laboratory), Southeast University, Nanjing, People's Republic of China
^*These authors have contributed equally to this work

Abstract: To overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from multidrug resistance (MDR) and minimize adverse effects of chemotherapy agents, a novel chemotherapy formulation of magnetic nanoparticles co-loaded with daunorubicin and 5-bromotetrandrin (DNR/BrTet-MNPs) was developed, and its effect on MDR leukemic cells was explored. After the DNR and Br were co-loaded onto a pluronic-stabilized and oleic acid-modified magnetic nanosystem, the physical characteristic and drug-loading capacity were evaluated. The cell toxicity of the self-prepared DNR/BrTet-MNPs formulation was then determined by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay; the cellular uptake of drug was demonstrated by fluorescent microscope. Lastly, the transcription of mdr1 and the expression of P-glycoprotein (P-gp) were detected by the reverse transcription reaction and western blotting assay, respectively. The results showed that the self-prepared DNR/BrTet-MNPs formulation possessed a sustained release of drug and displayed a dose-dependent antiproliferative activity on MDR leukemia K562/A02 cells. It also enhanced the accumulation of intracellular DNR in K562/A02 cells and downregulated the transcription of the mdr1 gene and the expression of P-gp. These findings suggest that the remarkable effect of the novel DNR/BrTet-MNPs formulation, acting as a drug depot system for the sustained release of the loaded DNR and BrTet, on multidrug resistance leukemia K562/A02 cells would be a promising strategy for overcoming MDR.

Keywords: multidrug resistance, targeting drug delivery system, leukemia