Theranostics 2019; 9(23):7033-7050. doi:10.7150/thno.35748 This issue Cite

Research Paper

Tumor acidity activated triphenylphosphonium-based mitochondrial targeting nanocarriers for overcoming drug resistance of cancer therapy

Hui Yu, Jia-Mi Li, Kai Deng, Wei Zhou, Cai-Xia Wang, Qian Wang, Kun-Heng Li, Hong-Yang Zhao, Shi-Wen Huang

Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University,Wuhan 430072, China

Citation:
Yu H, Li JM, Deng K, Zhou W, Wang CX, Wang Q, Li KH, Zhao HY, Huang SW. Tumor acidity activated triphenylphosphonium-based mitochondrial targeting nanocarriers for overcoming drug resistance of cancer therapy. Theranostics 2019; 9(23):7033-7050. doi:10.7150/thno.35748. https://www.thno.org/v09p7033.htm
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Abstract

Graphic abstract

The drug resistance in cancer treatment with DOX is mainly related to the overexpression of drug efflux proteins, residing in the plasma and nuclear membranes. Delivering DOX into the mitochondria, lacking drug efflux proteins, is an interesting method to overcome DOX resistance. To solve the problem of positively charged triphenylphosphonium (TPP) for mitochondrial targeting in vivo, a charge reversal strategy was developed.

Methods: An acidity triggered cleavable polyanion PEI-DMMA (PD) was coated on the surface of positively charged lipid-polymer hybrid nanoparticle (DOX-PLGA/CPT) to form DOX-PLGA/CPT/PD via electrostatic interaction. The mitochondrial localization and anticancer efficacy of DOX-PLGA/CPT/PD was evaluated both in vitro and in vivo.

Results: The surface negative charge of DOX-PLGA/CPT/PD prevents from rapid clearance in the blood and improved the accumulation in tumor tissue through the enhanced permeability and retention (EPR) effect. The hydrolysis of amide bonds in PD in weakly acidic tumor tissue leads to the conversion of DOX-PLGA/CPT/PD to DOX-PLGA/CPT. The positive charge of DOX-PLGA/CPT enhances the interaction with tumor cells, promotes the uptake and improves DOX contents in tumor cells. Once endocytosed by tumor cells, the exposed TPP in nanomedicine results in effective mitochondrial localization of DOX-PLGA/CPT. Afterward, DOX can release from the nanomedicine in the mitochondria, target mtDNA, induce tumor cells apoptosis and overcome DOX resistance of MCF-7/ADR breast cancer.

Conclusion: Tumor acidity triggered charge reversal of TPP-containing nanomedicine and activation of mitochondrial targeting is a simple and effective strategy for the delivery of DOX into the mitochondria of cancer cells and overcoming DOX resistance of MCF-7/ADR tumor both in vitro and in vivo, providing new insight in the design of nanomedicines for cancer chemotherapy.

Keywords: tumor acidity, charge reversal, mitochondrial targeting, resistance, cancer therapy


Citation styles

APA
Yu, H., Li, J.M., Deng, K., Zhou, W., Wang, C.X., Wang, Q., Li, K.H., Zhao, H.Y., Huang, S.W. (2019). Tumor acidity activated triphenylphosphonium-based mitochondrial targeting nanocarriers for overcoming drug resistance of cancer therapy. Theranostics, 9(23), 7033-7050. https://doi.org/10.7150/thno.35748.

ACS
Yu, H.; Li, J.M.; Deng, K.; Zhou, W.; Wang, C.X.; Wang, Q.; Li, K.H.; Zhao, H.Y.; Huang, S.W. Tumor acidity activated triphenylphosphonium-based mitochondrial targeting nanocarriers for overcoming drug resistance of cancer therapy. Theranostics 2019, 9 (23), 7033-7050. DOI: 10.7150/thno.35748.

NLM
Yu H, Li JM, Deng K, Zhou W, Wang CX, Wang Q, Li KH, Zhao HY, Huang SW. Tumor acidity activated triphenylphosphonium-based mitochondrial targeting nanocarriers for overcoming drug resistance of cancer therapy. Theranostics 2019; 9(23):7033-7050. doi:10.7150/thno.35748. https://www.thno.org/v09p7033.htm

CSE
Yu H, Li JM, Deng K, Zhou W, Wang CX, Wang Q, Li KH, Zhao HY, Huang SW. 2019. Tumor acidity activated triphenylphosphonium-based mitochondrial targeting nanocarriers for overcoming drug resistance of cancer therapy. Theranostics. 9(23):7033-7050.

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