Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo

Lan Feng1, Huali Wu2, Ping Ma1, Russell J Mumper1,3, S Rahima Benhabbour11Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, 2Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, 3UNC Lineberger Com...

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Autores principales:	Feng L, Wu H, Ma P, Mumper RJ, Benhabbour SR
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2011
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/b3809ac44be248b0a96a437d73425ee5
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spelling	oai:doaj.org-article:b3809ac44be248b0a96a437d73425ee52021-12-02T01:32:21ZDevelopment and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo1176-91141178-2013https://doaj.org/article/b3809ac44be248b0a96a437d73425ee52011-10-01T00:00:00Zhttp://www.dovepress.com/development-and-optimization-of-oil-filled-lipid-nanoparticles-contain-a8528https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Lan Feng1, Huali Wu2, Ping Ma1, Russell J Mumper1,3, S Rahima Benhabbour11Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, 2Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, 3UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USAAbstract: Three docetaxel (DX) lipid conjugates: 2&rsquo;-lauroyl-docetaxel (C12-DX), 2&rsquo;-stearoyl-docetaxel (C18-DX), and 2&rsquo;-behenoyl-docetaxel (C22-DX) were synthesized to enhance drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The three conjugates showed ten-fold higher solubility in the liquid oil phase Miglyol 808 than DX. To further increase the drug entrapment efficiency in NPs, orthogonal design was performed. The optimized formulation was composed of Miglyol 808, Brij 78, and Vitamin E tocopheryl polyethylene glycol succinate (TPGS). The conjugates were successfully entrapped in the reduced-surfactant NPs with entrapment efficiencies of about 50%&ndash;60% as measured by gel permeation chromatography (GPC) at a final concentration of 0.5 mg/mL. All three conjugates showed 45% initial burst release in 100% mouse plasma. Whereas C12-DX showed another 40% release over the next 8 hours, C18-DX and C22-DX in NPs showed no additional release after the initial burst of drug. All conjugates showed significantly lower cytotoxicity than DX in human DU-145 prostate cancer cells. The half maximal inhibitory concentration values (IC50) of free conjugates and conjugate NPs were comparable except for C22-DX, which was nontoxic in the tested concentration range and showed only vehicle toxicity when entrapped in NPs. In vivo, the total area under the curve (AUC0-&infin;) values of all DX conjugate NPs were significantly greater than that of Taxotere, demonstrating prolonged retention of drug in the blood. The AUC0-&infin; value of DX in Taxotere was 8.3-fold, 358.0-fold, and 454.5-fold lower than that of NP-formulated C12-DX, C18-DX, and C22-DX, respectively. The results of these studies strongly support the idea that the physical/chemical properties of DX conjugates may be fine-tuned to influence the affinity and retention of DX in oil-filled lipid NPs, which leads to very different pharmacokinetic profiles and blood exposure of an otherwise potent chemotherapeutic agent. These studies and methodologies may allow for improved and more potent nanoparticle-based formulations.Keywords: docetaxel, nanoparticles, ester prodrug, sustained releaseFeng LWu HMa PMumper RJBenhabbour SRDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2011, Iss default, Pp 2545-2556 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Feng L Wu H Ma P Mumper RJ Benhabbour SR Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo
description	Lan Feng1, Huali Wu2, Ping Ma1, Russell J Mumper1,3, S Rahima Benhabbour11Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, 2Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, 3UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USAAbstract: Three docetaxel (DX) lipid conjugates: 2&rsquo;-lauroyl-docetaxel (C12-DX), 2&rsquo;-stearoyl-docetaxel (C18-DX), and 2&rsquo;-behenoyl-docetaxel (C22-DX) were synthesized to enhance drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The three conjugates showed ten-fold higher solubility in the liquid oil phase Miglyol 808 than DX. To further increase the drug entrapment efficiency in NPs, orthogonal design was performed. The optimized formulation was composed of Miglyol 808, Brij 78, and Vitamin E tocopheryl polyethylene glycol succinate (TPGS). The conjugates were successfully entrapped in the reduced-surfactant NPs with entrapment efficiencies of about 50%&ndash;60% as measured by gel permeation chromatography (GPC) at a final concentration of 0.5 mg/mL. All three conjugates showed 45% initial burst release in 100% mouse plasma. Whereas C12-DX showed another 40% release over the next 8 hours, C18-DX and C22-DX in NPs showed no additional release after the initial burst of drug. All conjugates showed significantly lower cytotoxicity than DX in human DU-145 prostate cancer cells. The half maximal inhibitory concentration values (IC50) of free conjugates and conjugate NPs were comparable except for C22-DX, which was nontoxic in the tested concentration range and showed only vehicle toxicity when entrapped in NPs. In vivo, the total area under the curve (AUC0-&infin;) values of all DX conjugate NPs were significantly greater than that of Taxotere, demonstrating prolonged retention of drug in the blood. The AUC0-&infin; value of DX in Taxotere was 8.3-fold, 358.0-fold, and 454.5-fold lower than that of NP-formulated C12-DX, C18-DX, and C22-DX, respectively. The results of these studies strongly support the idea that the physical/chemical properties of DX conjugates may be fine-tuned to influence the affinity and retention of DX in oil-filled lipid NPs, which leads to very different pharmacokinetic profiles and blood exposure of an otherwise potent chemotherapeutic agent. These studies and methodologies may allow for improved and more potent nanoparticle-based formulations.Keywords: docetaxel, nanoparticles, ester prodrug, sustained release
format	article
author	Feng L Wu H Ma P Mumper RJ Benhabbour SR
author_facet	Feng L Wu H Ma P Mumper RJ Benhabbour SR
author_sort	Feng L
title	Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo
title_short	Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo
title_full	Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo
title_fullStr	Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo
title_full_unstemmed	Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo
title_sort	development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo
publisher	Dove Medical Press
publishDate	2011
url	https://doaj.org/article/b3809ac44be248b0a96a437d73425ee5
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Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo

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