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

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.

• Authors: Pengcheng Yu, Haijun Yu, Chengyue Guo, Zhirui Cui, Xianzhi Chen, Qi Yin, Pengcheng Zhang, Xiangliang Yang, Honggang Cui, Yaping Li
• Journal: Acta biomaterialia (Acta Biomater) Vol. 14 Pg. 115-24 (Mar 2015) ISSN: 1878-7568 [Electronic] England
• PMID: 25498306 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Cell Cycle (drug effects)
• Cell Death (drug effects)
• Cell Proliferation (drug effects)
• Doxorubicin (pharmacokinetics, pharmacology, 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, metabolism)
• Polymethacrylic Acids (chemistry)
• Rats, Sprague-Dawley
• Tissue Distribution (drug effects)
• Vitamin E (chemistry)