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Synergistic and complete reversal of the multidrug resistance of mitoxantrone hydrochloride by three-in-one multifunctional lipid-sodium glycocholate nanocarriers based on simultaneous BCRP and Bcl-2 inhibition

Authors Ling G, Zhang T, Zhang P, Sun J, He Z

Received 5 September 2015

Accepted for publication 21 December 2015

Published 23 August 2016 Volume 2016:11 Pages 4077—4091


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Lei Yang

Guixia Ling,1 Tianhong Zhang,2 Peng Zhang,2 Jin Sun,1 Zhonggui He1

1Department of Pharmaceutics, 2Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China

Abstract: Multidrug resistance (MDR) is a severe obstacle to successful chemotherapy due to its complicated nature that involves multiple mechanisms, such as drug efflux by transporters (P-glycoprotein and breast cancer resistance protein, BCRP) and anti-apoptotic defense (B-cell lymphoma, Bcl-2). To synergistically and completely reverse MDR by simultaneous inhibition of pump and non-pump cellular resistance, three-in-one multifunctional lipid-sodium glycocholate (GcNa) nanocarriers (TMLGNs) have been designed for controlled co-delivery of water-soluble cationic mitoxantrone hydrochloride (MTO), cyclosporine A (CsA – BCRP inhibitor), and GcNa (Bcl-2 inhibitor). GcNa and dextran sulfate were incorporated as anionic compounds to enhance the encapsulation efficiency of MTO (up to 97.8%±1.9%) and sustain the release of cationic MTO by electrostatic interaction. The results of a series of in vitro and in vivo investigations indicated that the TMLGNs were taken up by the resistant cancer cells by an endocytosis pathway that escaped the efflux induced by BCRP, and the simultaneous release of CsA with MTO further efficiently inhibited the efflux of the released MTO by BCRP; meanwhile GcNa induced the apoptosis process, and an associated synergistic antitumor activity and reversion of MDR were achieved because the reversal index was almost 1.0.

Keywords: mitoxantrone hydrochloride, three-in-one multifunctional lipid-GcNa nanocarriers, sodium glycocholate, multidrug resistance, breast cancer resistance protein, B-cell lymphoma

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