Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel
| Autor: | Audrey Darmon, Eric Vibert, Laurence Poul, Laurent Levy, Maxime Bergère, Agnès Pottier, Céline Berjaud, Marion Paolini, Matthieu Germain |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
CYP3A4
Pharmaceutical Science 02 engineering and technology Docetaxel Pharmacology chemistry.chemical_compound 0302 clinical medicine Polylactic Acid-Polyglycolic Acid Copolymer International Journal of Nanomedicine Furocoumarins Drug Discovery Cytochrome P-450 CYP3A Tissue Distribution Original Research Drug Carriers Chemistry General Medicine 021001 nanoscience & nanotechnology PLGA Liver 030220 oncology & carcinogenesis Inactivation Metabolic Female Taxoids 0210 nano-technology medicine.drug Biodistribution Biophysics galactosamine Mice Nude Bioengineering Antineoplastic Agents Biomaterials 03 medical and health sciences In vivo medicine hepatocyte targeting Animals Humans Lactic Acid hepatic metabolism Organic Chemistry Bioavailability PLGA nanoparticles Hepatocytes Cytochrome P-450 CYP3A Inhibitors Nanoparticles Nanocarriers Drug metabolism Polyglycolic Acid |
| Zdroj: | International Journal of Nanomedicine |
| ISSN: | 1178-2013 1176-9114 |
| Popis: | 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 24hours 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 63nm, functionalized with galactosamine, showed efficient invitro 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 |
| Databáze: | OpenAIRE |
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