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.

Recent Advances in Nanoparticle-Based Cancer Drug and Gene Delivery

“…These redox-sensitive TSMm showed significantly increased therapeutic effect in treatment-resistant MDA–MB-231/MDR breast tumor cells, compared with either free MTO or disulfide-free prodrug micelle (TCMm). Furthermore, TSMm has demonstrated significantly stronger antitumor activity in xenograft nude mice, without causing toxicity (Qiao et al, 2017). …”

The Effectiveness of Combined Drug Delivery Systems

“…Mitoxantrone is one anticancer agent that is already in use in the clinic since the past. Now, this is combined with covalent to improve efficiency [22][23][24][25] . Redox-triggered MTO prodrug performs a controlled drug release and improves the therapeutic effect.…”

“…This combination can maintain cytotoxicity and improve pharmacokinetic properties. The most promising inhibitor is tariquidar as this can sensitize those resistant cell lines and control the overexpression of P-gp 22,24,39,40 .…”

Peptide-based Drug Delivery for Curing Cancer

“…While the natural structure is advantageous, the mimetic version of RGD can improve stability and affinity. The other famous structure of RGD is cyclic which targets the ligands and binds its relationship with integrin [30][31][32][33] . In the field of biomedicine, many biologists face difficulties in the penetration of internal cells and this is feasible with the cell penetrating peptide in place.…”

“…This also improves the resistance of the affected patient and turns dormant cells invisible. Peptide treatment with the co-delivery of 5-Fu and Dox can promise a better choice of cancer therapy 30,32 .…”