Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance

Hai Wang; Zan Gao; Xuanyou Liu; Pranay Agarwal; Shuting Zhao; Daniel W Conroy; Guang Ji; Jianhua Yu; Christopher P Jaroniec; Zhenguo Liu; Xiongbin Lu; Xiaodong Li; Xiaoming He

doi:10.1038/s41467-018-02915-8

Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance

Nat Commun. 2018 Feb 8;9(1):562. doi: 10.1038/s41467-018-02915-8.

Authors

Hai Wang^{1

2

3}, Zan Gao⁴, Xuanyou Liu⁵, Pranay Agarwal^{1

3}, Shuting Zhao^{1

3}, Daniel W Conroy⁶, Guang Ji⁷, Jianhua Yu^{2

8}, Christopher P Jaroniec⁶, Zhenguo Liu^{3

5}, Xiongbin Lu⁹, Xiaodong Li¹⁰, Xiaoming He^{11

12

13

14}

Affiliations

¹ Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA.
² Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
³ Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA.
⁴ Department of Mechanical and Aerospace Engineering, University of Virginia, Charlottesville, VA, USA.
⁵ Division of Cardiovascular Medicine, Center for Precision Medicine, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
⁶ Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, 43210, USA.
⁷ Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
⁸ Division of Hematology, The Ohio State University, Columbus, OH, 43210, USA.
⁹ Department of Medical and Molecular Genetics and Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
¹⁰ Department of Mechanical and Aerospace Engineering, University of Virginia, Charlottesville, VA, USA. [email protected].
¹¹ Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
¹² Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
¹³ Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
¹⁴ Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA. [email protected].

Abstract

Multidrug resistance is a major challenge to cancer chemotherapy. The multidrug resistance phenotype is associated with the overexpression of the adenosine triphosphate (ATP)-driven transmembrane efflux pumps in cancer cells. Here, we report a lipid membrane-coated silica-carbon (LSC) hybrid nanoparticle that targets mitochondria through pyruvate, to specifically produce reactive oxygen species (ROS) in mitochondria under near-infrared (NIR) laser irradiation. The ROS can oxidize the NADH into NAD⁺ to reduce the amount of ATP available for the efflux pumps. The treatment with LSC nanoparticles and NIR laser irradiation also reduces the expression and increases the intracellular distribution of the efflux pumps. Consequently, multidrug-resistant cancer cells lose their multidrug resistance capability for at least 5 days, creating a therapeutic window for chemotherapy. Our in vivo data show that the drug-laden LSC nanoparticles in combination with NIR laser treatment can effectively inhibit the growth of multidrug-resistant tumors with no evident systemic toxicity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Adenosine Triphosphate / metabolism
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Doxorubicin / pharmacology
Drug Resistance, Multiple*
Drug Resistance, Neoplasm*
Humans
MCF-7 Cells
Mitochondria / drug effects
Mitochondria / metabolism*
NAD / metabolism
Nanoparticles / chemistry
Oxidation-Reduction
Reactive Oxygen Species / metabolism*
Silicon Dioxide / chemistry

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Reactive Oxygen Species
NAD
Silicon Dioxide
Doxorubicin
Adenosine Triphosphate

Abstract

Publication types

MeSH terms

Substances

Grants and funding