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Issue 3, 2015
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The energy blocker inside the power house: mitochondria targeted delivery of 3-bromopyruvate

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Abstract

A key hallmark of many aggressive cancers is accelerated glucose metabolism. The enzymes that catalyze the first step of glucose metabolism are hexokinases. Elevated levels of hexokinase 2 (HK2) are found in cancer cells, but only in a limited number of normal tissues. Metabolic reprogramming of cancer cells using the energy blocker 3-bromopyruvate (3-BP), which inhibits HK2, has the potential to provide tumor-specific anticancer agents. However, the unique structural and functional characteristics of mitochondria prohibit selective subcellular targeting of 3-BP to modulate the function of this organelle for therapeutic gain. A mitochondria-targeted gold nanoparticle (T-3-BP-AuNP), decorated with 3-BP and delocalized lipophilic triphenylphosphonium cations to target the mitochondrial membrane potential (Δψm), was developed for delivery of 3-BP to cancer cell mitochondria by taking advantage of the higher Δψm in cancer cells compared to normal cells. In vitro studies demonstrated an enhanced anticancer activity of T-3-BP-AuNPs compared to the non-targeted construct NT-3-BP-AuNP or free 3-BP. The anticancer activity of T-3-BP-AuNPs was further enhanced upon laser irradiation by exciting the surface plasmon resonance band of AuNP and thereby utilizing a combination of 3-BP chemotherapeutic and AuNP photothermal effects. The lower toxicity of T-3-BP-NPs in normal mesenchymal stem cells indicated that these NPs preferentially kill cancer cells. T-3-BP-AuNPs showed an enhanced ability to modulate cancer cell metabolism by inhibiting glycolysis as well as demolishing mitochondrial oxidative phosphorylation. Our findings demonstrate that concerted chemo-photothermal treatment of glycolytic cancer cells with a single NP capable of targeting mitochondria, mediating simultaneous release of a glycolytic inhibitor and photothermal ablation, may have promise as a new anticancer therapy.

Graphical abstract: The energy blocker inside the power house: mitochondria targeted delivery of 3-bromopyruvate

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Supplementary files

Article information


Submitted
01 Jul 2014
Accepted
24 Oct 2014
First published
27 Oct 2014

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2015,6, 1832-1845
Article type
Edge Article
Author version available

The energy blocker inside the power house: mitochondria targeted delivery of 3-bromopyruvate

S. Marrache and S. Dhar, Chem. Sci., 2015, 6, 1832
DOI: 10.1039/C4SC01963F

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    [Original citation] - Published by The Royal Society of Chemistry.

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