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A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier

Glioblastoma multiforme (GBM) is the most common and lethal central nervous system tumor. Recently, atovaquone has shown inhibition of signal transducer and activator transcription 3, a promising target for GBM therapy. However, it is currently unable to achieve therapeutic drug concentrations in th...

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Autores principales: Takabe, Hiroyuki, Warnken, Zachary N., Zhang, Yajie, Davis, Daniel A., Smyth, Hugh D. C., Kuhn, John G., Weitman, Steve, Williams III, Robert O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027483/
https://www.ncbi.nlm.nih.gov/pubmed/29783757
http://dx.doi.org/10.3390/pharmaceutics10020060
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author Takabe, Hiroyuki
Warnken, Zachary N.
Zhang, Yajie
Davis, Daniel A.
Smyth, Hugh D. C.
Kuhn, John G.
Weitman, Steve
Williams III, Robert O.
author_facet Takabe, Hiroyuki
Warnken, Zachary N.
Zhang, Yajie
Davis, Daniel A.
Smyth, Hugh D. C.
Kuhn, John G.
Weitman, Steve
Williams III, Robert O.
author_sort Takabe, Hiroyuki
collection PubMed
description Glioblastoma multiforme (GBM) is the most common and lethal central nervous system tumor. Recently, atovaquone has shown inhibition of signal transducer and activator transcription 3, a promising target for GBM therapy. However, it is currently unable to achieve therapeutic drug concentrations in the brain with the currently reported and marketed formulations. The present study sought to explore the efficacy of atovaquone against GBM as well as develop a formulation of atovaquone that would improve oral bioavailability, resulting in higher amounts of drug delivered to the brain. Atovaquone was formulated as an amorphous solid dispersion using an optimized formulation containing a polymer and a spontaneously emulsifying component (SEC) with greatly improved wetting, disintegration, dispersibility, and dissolution properties. Atovaquone demonstrated cytotoxicity against GBM cell lines as well as provided a confirmed target for atovaquone brain concentrations in in vitro cell viability studies. This new formulation approach was then assessed in a proof-of-concept in vivo exposure study. Based on these results, the enhanced amorphous solid dispersion is promising for providing therapeutically effective brain levels of atovaquone for the treatment of GBM.
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spelling pubmed-60274832018-07-13 A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier Takabe, Hiroyuki Warnken, Zachary N. Zhang, Yajie Davis, Daniel A. Smyth, Hugh D. C. Kuhn, John G. Weitman, Steve Williams III, Robert O. Pharmaceutics Article Glioblastoma multiforme (GBM) is the most common and lethal central nervous system tumor. Recently, atovaquone has shown inhibition of signal transducer and activator transcription 3, a promising target for GBM therapy. However, it is currently unable to achieve therapeutic drug concentrations in the brain with the currently reported and marketed formulations. The present study sought to explore the efficacy of atovaquone against GBM as well as develop a formulation of atovaquone that would improve oral bioavailability, resulting in higher amounts of drug delivered to the brain. Atovaquone was formulated as an amorphous solid dispersion using an optimized formulation containing a polymer and a spontaneously emulsifying component (SEC) with greatly improved wetting, disintegration, dispersibility, and dissolution properties. Atovaquone demonstrated cytotoxicity against GBM cell lines as well as provided a confirmed target for atovaquone brain concentrations in in vitro cell viability studies. This new formulation approach was then assessed in a proof-of-concept in vivo exposure study. Based on these results, the enhanced amorphous solid dispersion is promising for providing therapeutically effective brain levels of atovaquone for the treatment of GBM. MDPI 2018-05-19 /pmc/articles/PMC6027483/ /pubmed/29783757 http://dx.doi.org/10.3390/pharmaceutics10020060 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Takabe, Hiroyuki
Warnken, Zachary N.
Zhang, Yajie
Davis, Daniel A.
Smyth, Hugh D. C.
Kuhn, John G.
Weitman, Steve
Williams III, Robert O.
A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier
title A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier
title_full A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier
title_fullStr A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier
title_full_unstemmed A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier
title_short A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier
title_sort repurposed drug for brain cancer: enhanced atovaquone amorphous solid dispersion by combining a spontaneously emulsifying component with a polymer carrier
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027483/
https://www.ncbi.nlm.nih.gov/pubmed/29783757
http://dx.doi.org/10.3390/pharmaceutics10020060
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