Redox-triggered mitoxantrone prodrug micelles for overcoming multidrug-resistant breast cancer

Abstract

Multidrug resistance (MDR) severely hinders the efficient chemotherapeutic treatments of cancer. d-α-Tocopherol polyethylene 1000 succinate (TPGS) based drug delivery system holds the potential of re-sensitizing resistant cancer cells. In this study, a TPGS prodrug containing both TPGS and mitoxantrone (MTO) via a disulphide bond was synthesised and assembled into micelle (TSMm) with a monodispersed diameter of 46.50 ± 1.12 nm. The disulphide bonds within the micelles could be cleaved in response to a high concentration of intracellular glutathione (GSH) after entering the tumour cells, leading a rapid release of MTO. In vitro cytotoxicity study showed TSMm significantly inhibited the growth of resistant breast tumour cells MDA-MB-231/MDR comparing to either free MTO or disulphide-free prodrug micelle (TCMm). In addition, TSMm could sustain favourable intracellular retention and cause the depletion of ATP activity, leading to the preferential transportation of MTO into the nucleus and the reversal of MDR. In vivo imaging also verified that TSMm was specifically targeted to the tumour regions at 24 h post injection. Finally, TSMm has significantly stronger antitumor activity in xenograft nude mice with negligible side effects. Hence, TSMm can serve as promising prodrug candidates to strengthen the reversal of MDR in tumours with less side effects.

Keywords:

• Mitoxantrone
• prodrug micelles
• TPGS
• multidrug resistance
• redox-sensitive

Acknowledgements

The authors acknowledge financial support from the National Natural Science Foundation of China [81503259, 81273655], the Jiangsu Natural Science Foundation of China [BK20151002], the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions and Postgraduate Research & Practice Innovation Program of Jiangsu Province.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors acknowledge financial support from the National Natural Science Foundation of China [81503259, 81273655], the Jiangsu Natural Science Foundation of China [BK20151002], the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions and Postgraduate Research & Practice Innovation Program of Jiangsu Province.