Oncotarget

Research Papers:

Folate-mediated mitochondrial targeting with doxorubicin-polyrotaxane nanoparticles overcomes multidrug resistance

He Wang, Henghui Yin, Fengjiao Yan, Mingna Sun, Lingran Du, Wei Peng, Qiuli Li, Yinghong Feng and Yi Zhou _

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Oncotarget. 2015; 6:2827-2842. https://doi.org/10.18632/oncotarget.3090

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Abstract

He Wang1,2,*, Henghui Yin3,*, Fengjiao Yan4, Mingna Sun2, Lingran Du2, Wei Peng2, Qiuli Li2, Yinghong Feng5 and Yi Zhou2

1 Department of Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

2 The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, China

3 Center of Breast Disease, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China

4 Department of Otorhinolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China

5 Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

* These authors contributed equally to this work

Correspondence:

Yi Zhou, email:

Keywords: Polyrotaxanes, Functional DOX nanoparticles, Multidrug resistance, Mitochondrial signaling pathway

Received: October 30, 2014 Accepted: December 25, 2014 Published: December 30, 2014

Abstract

Resistance to treatment with anticancer drugs is a significant obstacle and a fundamental cause of therapeutic failure in cancer therapy. Functional doxorubicin (DOX) nanoparticles for targeted delivery of the classical cytotoxic anticancer drug DOX to tumor cells, using folate-terminated polyrotaxanes along with dequalinium, have been developed and proven to overcome this resistance due to specific molecular features, including a size of approximately 101 nm, a zeta potential of 3.25 mV and drug-loading content of 18%. Compared with free DOX, DOX hydrochloride, DOX nanoparticles, and targeted DOX nanoparticles, the functional DOX nanoparticles exhibited the strongest anticancer efficacy in vitro and in the drug-resistant MCF-7/Adr (DOX) xenograft tumor model. More specifically, the nanoparticles significantly increased the intracellular uptake of DOX, selectively accumulating in mitochondria and the endoplasmic reticulum after treatment, with release of cytochrome C as a result. Furthermore, the caspase-9 and caspase-3 cascade was activated by the functional DOX nanoparticles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the antiapoptotic protein Bcl-2, thereby enhancing apoptosis by acting on the mitochondrial signaling pathways. In conclusion, functional DOX nanoparticles may provide a strategy for increasing the solubility of DOX and overcoming multidrug-resistant cancers.


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