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Int J Pharm. 2017 Dec 20;534(1-2):368-377. doi: 10.1016/j.ijpharm.2017.10.036. Epub 2017 Oct 16.

Sequential therapy with redox-responsive glucolipid nanocarrier separately delivering siRNA and doxorubicin to overcome multidrug resistance.

Author information

1
Institute of Pharmaceutics, College of Pharmacy, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China.
2
Ocean College, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China.
3
Department of Pharmacy, School of Medicine Science, Jiaxing University, Zhejiang, 314001, People's Republic of China.
4
Institute of Pharmaceutics, College of Pharmacy, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, People's Republic of China. Electronic address: hufq@zju.edu.cn.

Abstract

P-glycoprotein (P-gp) is a major efflux transporter overexpressed on multidrug resistant tumor cells and responsible for pumping drugs out. If anti-tumor drugs are given when P-gp level is low, satisfactory treatment efficiency may be achieved. Thus, a P-gp down-regulating siRNA (siMDR1) and doxorubicin (DOX) were applied to eliminate multidrug resistant breast cancer cells (MCF-7/ADR). A redox-responsive glucolipid conjugate (CSO-ss-SA) was used to condense siRNA (CSO-ss-SA/siRNA) and encapsulate DOX (CSO-ss-SA/DOX) separately. They responded to the high reducing environment of tumor cells and fast released the payload. CSO-ss-SA/siMDR1 silenced MDR1 gene and resulted in a transient decrease of P-gp. Sequentially, DOX formulation (CSO-ss-SA/DOX or DOX·HCl) was delivered when P-gp was reduced to the lowest level. After pretreatment by CSO-ss-SA/siMDR1, cytotoxicity of CSO-ss-SA/DOX and DOX·HCl against MCF-7/ADR cells were 6.4 or 3.4-fold respectively of that treated by DOX·HCl alone, which exhibited increased cytotoxin sensitivity of drug resistant cells and maximized therapeutic outcomes. These results revealed that the sequential treatment strategy of CSO-ss-SA/siRNA and CSO-ss-SA/DOX hold potential in achieving an optimal overcoming multidrug resistance efficiency.

KEYWORDS:

Glucolipid conjugate micelles; Multidrug resistance; Redox-responsive; Sequential therapy; siRNA

PMID:
29051118
DOI:
10.1016/j.ijpharm.2017.10.036
[Indexed for MEDLINE]

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