Doxorubicin-loaded PEG-PCL copolymer micelles enhance cytotoxicity and intracellular accumulation of doxorubicin in adriamycin-resistant tumor cells

Yuan-Yuan Diao1,2,*, Hao-Ying Li3,*, Ying-Hua Fu4, Min Han1, Yu-Lan Hu1, Hong-Liang Jiang5, Yasuo Tsutsumi6, Qi-Chun Wei7, Da-Wei Chen2, Jian-Qing Gao1 1Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou; 2School of Pharmacy, Shenyang Pharmaceutical University, Shenyang; 3Biomanufacturing Research Centre, Department of Mechanical and Electrical Engineering, Soochow University, Suzhou; 4Department of Pharmaceutics, Jiaxing University College of Medicine, Jiaxing; 5Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China; 6Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; 7Department of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, People's Republic of China, *These authors contributed equally to this workBackground: Multidrug resistance remains a major obstacle to successful cancer chemotherapy. Some chemical multidrug resistance inhibitors, such as ciclosporin and verapamil, have been reported to reverse resistance in tumor cells. However, the accompanying side effects have limited their clinical application. In this study, we have developed a novel drug delivery system, ie, a polyethyleneglycol-polycaprolactone (PEG-PCL) copolymer micelle encapsulating doxorubicin, in order to circumvent drug resistance in adriamycin-resistant K562 tumor cells.Methods: Doxorubicin-loaded diblock copolymer PEG-PCL micelles were developed, and the physicochemical properties of these micelles, and accumulation and cytotoxicity of doxorubicin in adriamycin-resistant K562 tumor cells were studied.Results: Doxorubicin-loaded micelles were prepared using a solvent evaporation method with a diameter of 36 nm and a zeta potential of +13.8 mV. The entrapment efficiency of doxorubicin was 48.6% ± 2.3%. The micelles showed sustained release, increased up