Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel

Marion Paolini,1,2 Laurence Poul,1 Céline Berjaud,1 Matthieu Germain,1 Audrey Darmon,1 Maxime Bergère,1 Agnès Pottier,1 Laurent Levy,1 Eric Vibert2 1Nanobiotix, Paris, 2UMR-S 1193 INSERM/Paris-Sud University, Centre Hépato-Biliaire, Hôpital Paul...

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Autores principales: Paolini M, Poul L, Berjaud C, Germain M, Darmon A, Bergère M, Pottier A, Levy L, Vibert E
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Publicado: Dove Medical Press 2017
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spelling oai:doaj.org-article:d495815586474c7caa4136da95f209012021-12-02T07:23:00ZNano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel1178-2013https://doaj.org/article/d495815586474c7caa4136da95f209012017-08-01T00:00:00Zhttps://www.dovepress.com/nano-sized-cytochrome-p450-3a4-inhibitors-to-block-hepatic-metabolism--peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Marion Paolini,1,2 Laurence Poul,1 Céline Berjaud,1 Matthieu Germain,1 Audrey Darmon,1 Maxime Bergère,1 Agnès Pottier,1 Laurent Levy,1 Eric Vibert2 1Nanobiotix, Paris, 2UMR-S 1193 INSERM/Paris-Sud University, Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France Abstract: Most drugs are metabolized by hepatic cytochrome P450 3A4 (CYP3A4), resulting in their reduced bioavailability. In this study, we present the design and evaluation of biocompatible nanocarriers trapping a natural CYP3A4-inhibiting compound. Our aim in using nanocarriers was to target the natural CYP3A4-inhibiting agent to hepatic CYP3A4 and leave drug-metabolizing enzymes in other organs undisturbed. In the design of such nanocarriers, we took advantage of the nonspecific accumulation of small nanoparticles in the liver. Specific targeting functionalization was added to direct nanocarriers toward hepatocytes. Nanocarriers were evaluated in vitro for their CYP3A4 inhibition capacity and in vivo for their biodistribution, and finally injected 24 hours prior to the drug docetaxel, for their ability to improve the efficiency of the drug docetaxel. Nanoparticles of poly(lactic-co-glycolic) acid (PLGA) with a hydrodynamic diameter of 63 nm, functionalized with galactosamine, showed efficient in vitro CYP3A4 inhibition and the highest accumulation in hepatocytes. When compared to docetaxel alone, in nude mice bearing the human breast cancer, MDA-MB-231 model, they significantly improved the delay in tumor growth (treated group versus docetaxel alone, percent treated versus control ratio [%T/C] of 32%) and demonstrated a major improvement in overall survival (survival rate of 67% versus 0% at day 55). Keywords: hepatic metabolism, CYP3A4, PLGA nanoparticles, hepatocyte targeting, galactosaminePaolini MPoul LBerjaud CGermain MDarmon ABergère MPottier ALevy LVibert EDove Medical Pressarticlehepatic metabolismCYP3A4PLGA nanoparticleshepatocyte targetingdocetaxelgalactosamineMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 5537-5556 (2017)
institution DOAJ
collection DOAJ
language EN
topic hepatic metabolism
CYP3A4
PLGA nanoparticles
hepatocyte targeting
docetaxel
galactosamine
Medicine (General)
R5-920
spellingShingle hepatic metabolism
CYP3A4
PLGA nanoparticles
hepatocyte targeting
docetaxel
galactosamine
Medicine (General)
R5-920
Paolini M
Poul L
Berjaud C
Germain M
Darmon A
Bergère M
Pottier A
Levy L
Vibert E
Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel
description Marion Paolini,1,2 Laurence Poul,1 Céline Berjaud,1 Matthieu Germain,1 Audrey Darmon,1 Maxime Bergère,1 Agnès Pottier,1 Laurent Levy,1 Eric Vibert2 1Nanobiotix, Paris, 2UMR-S 1193 INSERM/Paris-Sud University, Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France Abstract: Most drugs are metabolized by hepatic cytochrome P450 3A4 (CYP3A4), resulting in their reduced bioavailability. In this study, we present the design and evaluation of biocompatible nanocarriers trapping a natural CYP3A4-inhibiting compound. Our aim in using nanocarriers was to target the natural CYP3A4-inhibiting agent to hepatic CYP3A4 and leave drug-metabolizing enzymes in other organs undisturbed. In the design of such nanocarriers, we took advantage of the nonspecific accumulation of small nanoparticles in the liver. Specific targeting functionalization was added to direct nanocarriers toward hepatocytes. Nanocarriers were evaluated in vitro for their CYP3A4 inhibition capacity and in vivo for their biodistribution, and finally injected 24 hours prior to the drug docetaxel, for their ability to improve the efficiency of the drug docetaxel. Nanoparticles of poly(lactic-co-glycolic) acid (PLGA) with a hydrodynamic diameter of 63 nm, functionalized with galactosamine, showed efficient in vitro CYP3A4 inhibition and the highest accumulation in hepatocytes. When compared to docetaxel alone, in nude mice bearing the human breast cancer, MDA-MB-231 model, they significantly improved the delay in tumor growth (treated group versus docetaxel alone, percent treated versus control ratio [%T/C] of 32%) and demonstrated a major improvement in overall survival (survival rate of 67% versus 0% at day 55). Keywords: hepatic metabolism, CYP3A4, PLGA nanoparticles, hepatocyte targeting, galactosamine
format article
author Paolini M
Poul L
Berjaud C
Germain M
Darmon A
Bergère M
Pottier A
Levy L
Vibert E
author_facet Paolini M
Poul L
Berjaud C
Germain M
Darmon A
Bergère M
Pottier A
Levy L
Vibert E
author_sort Paolini M
title Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel
title_short Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel
title_full Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel
title_fullStr Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel
title_full_unstemmed Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel
title_sort nano-sized cytochrome p450 3a4 inhibitors to block hepatic metabolism of docetaxel
publisher Dove Medical Press
publishDate 2017
url https://doaj.org/article/d495815586474c7caa4136da95f20901
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