Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation

Rudra Pangeni,1,* Sang Won Choi,1,* Ok-Cheol Jeon,2 Youngro Byun,3 Jin Woo Park1 1Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, 2Pharosgen R&D Center, Asan Institute for Life Sciences, 3Department of Molecular Medic...

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Autores principales:	Pangeni R, Choi SW, Jeon O, Byun Y, Park JW
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2016
Materias:	oxaliplatin 5-fluorouracil deoxycholic acid derivative ion-pairing complex nanoemulsion oral delivery Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/b47615b9048f415ca9a3c0c26a0c0464
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spelling	oai:doaj.org-article:b47615b9048f415ca9a3c0c26a0c04642021-12-02T00:37:16ZMultiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation1178-2013https://doaj.org/article/b47615b9048f415ca9a3c0c26a0c04642016-11-01T00:00:00Zhttps://www.dovepress.com/multiple-nanoemulsion-system-for-an-oral-combinational-delivery-of-oxa-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Rudra Pangeni,1,* Sang Won Choi,1,* Ok-Cheol Jeon,2 Youngro Byun,3 Jin Woo Park1 1Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, 2Pharosgen R&D Center, Asan Institute for Life Sciences, 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: Oxaliplatin (OXA) is a third-generation cisplatin analog that has been approved as first-line chemotherapy in combination with 5-fluorouracil (5-FU) for the treatment of resectable and advanced colorectal cancer. However, the therapeutic efficacy of oral OXA and 5-FU is limited by their low bioavailability due to poor membrane permeability. The aim of the present study was to develop an oral delivery system for OXA and 5-FU. We constructed an ion-pairing complex of OXA with a deoxycholic acid derivative (Nα-deoxycholyl-L-lysyl-methylester, DCK) (OXA/DCK) as a permeation enhancer. Next, we prepared multiple water-in-oil-in-water nanoemulsions incorporating OXA/DCK and 5-FU to enhance their oral absorption. To evaluate their membrane permeability, we assessed in vitro permeabilities of OXA/DCK and 5-FU through an artificial intestinal membrane and Caco-2 cell monolayer. Finally, oral bioavailability in rats and tumor growth inhibition in the colorectal adenocarcinoma cell (CT26)-bearing mouse model were investigated after oral administration of nanoemulsion containing OXA/DCK and 5-FU. The droplet size of the optimized nanoemulsion was 20.3±0.22 nm with a zeta potential of -4.65±1.68 mV. In vitro permeabilities of OXA/DCK and 5-FU from the nanoemulsion through a Caco-2 cell monolayer were 4.80- and 4.30-fold greater than those of OXA and 5-FU, respectively. The oral absorption of OXA/DCK and 5-FU from the nanoemulsion also increased significantly, and the resulting oral bioavailability values of OXA/DCK and 5-FU in the nanoemulsive system were 9.19- and 1.39-fold higher than those of free OXA and 5-FU, respectively. Furthermore, tumor growth in CT26 tumor-bearing mice given the oral OXA/DCK- and 5-FU-loaded nanoemulsion was maximally inhibited by 73.9%, 48.5%, and 38.1%, compared with tumor volumes in the control group and the oral OXA and 5-FU groups, respectively. These findings demonstrate the therapeutic potential of a nanoemulsion incorporating OXA/DCK and 5-FU as an oral combination therapy for colorectal cancer. Keywords: oxaliplatin, 5-fluorouracil, deoxycholic acid derivative, ion-pairing complex, nanoemulsion, oral deliveryPangeni RChoi SWJeon OByun YPark JWDove Medical Pressarticleoxaliplatin5-fluorouracildeoxycholic acid derivativeion-pairing complexnanoemulsionoral deliveryMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 11, Pp 6379-6399 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	oxaliplatin 5-fluorouracil deoxycholic acid derivative ion-pairing complex nanoemulsion oral delivery Medicine (General) R5-920
spellingShingle	oxaliplatin 5-fluorouracil deoxycholic acid derivative ion-pairing complex nanoemulsion oral delivery Medicine (General) R5-920 Pangeni R Choi SW Jeon O Byun Y Park JW Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation
description	Rudra Pangeni,1,* Sang Won Choi,1,* Ok-Cheol Jeon,2 Youngro Byun,3 Jin Woo Park1 1Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, 2Pharosgen R&D Center, Asan Institute for Life Sciences, 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: Oxaliplatin (OXA) is a third-generation cisplatin analog that has been approved as first-line chemotherapy in combination with 5-fluorouracil (5-FU) for the treatment of resectable and advanced colorectal cancer. However, the therapeutic efficacy of oral OXA and 5-FU is limited by their low bioavailability due to poor membrane permeability. The aim of the present study was to develop an oral delivery system for OXA and 5-FU. We constructed an ion-pairing complex of OXA with a deoxycholic acid derivative (Nα-deoxycholyl-L-lysyl-methylester, DCK) (OXA/DCK) as a permeation enhancer. Next, we prepared multiple water-in-oil-in-water nanoemulsions incorporating OXA/DCK and 5-FU to enhance their oral absorption. To evaluate their membrane permeability, we assessed in vitro permeabilities of OXA/DCK and 5-FU through an artificial intestinal membrane and Caco-2 cell monolayer. Finally, oral bioavailability in rats and tumor growth inhibition in the colorectal adenocarcinoma cell (CT26)-bearing mouse model were investigated after oral administration of nanoemulsion containing OXA/DCK and 5-FU. The droplet size of the optimized nanoemulsion was 20.3±0.22 nm with a zeta potential of -4.65±1.68 mV. In vitro permeabilities of OXA/DCK and 5-FU from the nanoemulsion through a Caco-2 cell monolayer were 4.80- and 4.30-fold greater than those of OXA and 5-FU, respectively. The oral absorption of OXA/DCK and 5-FU from the nanoemulsion also increased significantly, and the resulting oral bioavailability values of OXA/DCK and 5-FU in the nanoemulsive system were 9.19- and 1.39-fold higher than those of free OXA and 5-FU, respectively. Furthermore, tumor growth in CT26 tumor-bearing mice given the oral OXA/DCK- and 5-FU-loaded nanoemulsion was maximally inhibited by 73.9%, 48.5%, and 38.1%, compared with tumor volumes in the control group and the oral OXA and 5-FU groups, respectively. These findings demonstrate the therapeutic potential of a nanoemulsion incorporating OXA/DCK and 5-FU as an oral combination therapy for colorectal cancer. Keywords: oxaliplatin, 5-fluorouracil, deoxycholic acid derivative, ion-pairing complex, nanoemulsion, oral delivery
format	article
author	Pangeni R Choi SW Jeon O Byun Y Park JW
author_facet	Pangeni R Choi SW Jeon O Byun Y Park JW
author_sort	Pangeni R
title	Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation
title_short	Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation
title_full	Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation
title_fullStr	Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation
title_full_unstemmed	Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation
title_sort	multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation
publisher	Dove Medical Press
publishDate	2016
url	https://doaj.org/article/b47615b9048f415ca9a3c0c26a0c0464
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Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation

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