Reversal of doxorubicin resistance in breast cancer by mitochondria-targeted pH-responsive micelles

Pengcheng Yu; Haijun Yu; Chengyue Guo; Zhirui Cui; Xianzhi Chen; Qi Yin; Pengcheng Zhang; Xiangliang Yang; Honggang Cui; Yaping Li

doi:10.1016/j.actbio.2014.12.001

Reversal of doxorubicin resistance in breast cancer by mitochondria-targeted pH-responsive micelles

Acta Biomater. 2015 Mar:14:115-24. doi: 10.1016/j.actbio.2014.12.001. Epub 2014 Dec 9.

Authors

Pengcheng Yu¹, Haijun Yu², Chengyue Guo³, Zhirui Cui³, Xianzhi Chen³, Qi Yin³, Pengcheng Zhang⁴, Xiangliang Yang⁵, Honggang Cui⁶, Yaping Li⁷

Affiliations

¹ National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hjyu@simm.ac.cn.
³ State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Department of Chemical and Biomolecular Engineering, Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, USA.
⁵ National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China. Electronic address: yangxl@hust.edu.cn.
⁶ Department of Chemical and Biomolecular Engineering, Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, USA.
⁷ National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ypli@simm.ac.cn.

PMID: 25498306
DOI: 10.1016/j.actbio.2014.12.001

Abstract

Chemotherapy is an important approach for clinical cancer treatment. However, the success of chemotherapy is usually hindered by the occurrence of intrinsic or acquired multidrug resistance of cancer cells. Herein, we reported an effective approach to overcome doxorubicin (DOX) resistance in MCF-7/ADR breast cancer using DOX-loaded pH-responsive micelles. The micelles were prepared from a pH-responsive diblock copolymer, poly(ethylene glycol)-block-poly(2-(diisopropylamino)ethyl methacrylate) (PEG-b-PDPA), and a vitamin E derivate (D-α-tocopheryl polyethylene glycol 1000 succinate, TPGS) (denoted as PDPA/TPGS micelles). At neutral pH of 7.4, DOX was loaded into the hydrophobic core of PDPA/TPGS micelles via a film sonication method. After cellular uptake, the DOX payload was released in early endosomes by acidic pH-triggered micelle dissociation. Meanwhile, the TPGS component synergistically improved the cytotoxicity of DOX by targeting mitochondrial organelles and reducing the mitochondrial transmembrane potential. In vitro cell culture experiments using DOX-resistant MCF-7/ADR cells demonstrated that PDPA/TPGS micelles reduced the IC50 of DOX by a sixfold magnitude. In vivo animal studies showed that DOX-loaded PDPA/TPGS micelles (PDPA/TPGS@DOX) inhibited tumor growth more efficiently than free DOX in a nude mouse model bearing orthotopic MCF-7/ADR tumor. All these results imply that the mitochondria-targeted pH-responsive PDPA/TPGS micelles have significant potential for efficiently combating DOX resistance in breast cancer cells.

Keywords: Breast cancer; Doxorubicin; Mitochondria; Multidrug resistance; pH-responsive.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Breast Neoplasms / drug therapy*
Breast Neoplasms / pathology
Cell Cycle / drug effects
Cell Death / drug effects
Cell Proliferation / drug effects
Doxorubicin / pharmacokinetics
Doxorubicin / pharmacology*
Doxorubicin / therapeutic use
Drug Resistance, Neoplasm / drug effects*
Endocytosis / drug effects
Female
Humans
Hydrogen-Ion Concentration
MCF-7 Cells
Membrane Potential, Mitochondrial / drug effects
Mice, Inbred BALB C
Mice, Nude
Micelles*
Microscopy, Electron, Transmission
Mitochondria / drug effects
Mitochondria / metabolism*
Polymethacrylic Acids / chemistry
Rats, Sprague-Dawley
Tissue Distribution / drug effects
Vitamin E / chemistry

Substances

Micelles
Polymethacrylic Acids
poly(2-(diisopropylamino)ethyl methacrylate)
Vitamin E
Doxorubicin
tocophersolan