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

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

Wang H1,2,3, Gao Z4, Liu X5, Agarwal P1,3, Zhao S1,3, Conroy DW6, Ji G7, Yu J2,8, Jaroniec CP6, Liu Z3,5, Lu X9, Li X10, He X11,12,13,14.

Author information

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. xl3p@virginia.edu.
11
Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA. shawnhe@umd.edu.
12
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. shawnhe@umd.edu.
13
Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA. shawnhe@umd.edu.
14
Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA. shawnhe@umd.edu.

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.

PMID:
29422620
PMCID:
PMC5805731
DOI:
10.1038/s41467-018-02915-8
[Indexed for MEDLINE]
Free PMC Article

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