Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion

Saed Abbasi,* Kazuaki Kajimoto,* Hideyoshi Harashima Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan *These authors contributed equally to this work Abstract: 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has a dual action of stimulating anti-inf...

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Autores principales:	Abbasi S, Kajimoto K, Harashima H
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2016
Materias:	drug release surface localization anti-proliferative effect cellular uptake Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/fc5036ff0d42407aa90e7e2bc9ed4a71
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spelling	oai:doaj.org-article:fc5036ff0d42407aa90e7e2bc9ed4a712021-12-02T07:22:53ZElimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion1178-2013https://doaj.org/article/fc5036ff0d42407aa90e7e2bc9ed4a712016-06-01T00:00:00Zhttps://www.dovepress.com/elimination-of-the-biphasic-pharmacodynamics-of-15d-pgj2-by-controllin-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Saed Abbasi,* Kazuaki Kajimoto,* Hideyoshi Harashima Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan *These authors contributed equally to this work Abstract: 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has a dual action of stimulating anti-inflammation and anti-proliferation when exogenously administered at high doses. However, at lower doses, it can be toxic inducing opposite actions, ie, stimulation of both inflammation and cell proliferation. This biphasic phenomenon of 15d-PGJ2 is believed to be due to its multitarget behavior. In this study, we provide a strategy for controlling such biphasic pharmacodynamics by separating its dual actions while retaining the beneficial one by using a nanoemulsion (NE). The 15d-PGJ2 was encapsulated in the NE composed of triolein/distearoyl phosphatidylcholine/Tween 80 at a high encapsulation ratio (>83%). Furthermore, NE enhanced drug retention by slowing down its release rate, which was, unconventionally, inversely dependent on the total surface area of the NE system. Next, focusing on the biphasic effect on cell proliferation, we found that the 15d-PGJ2-loaded slow-release NE showed only a dose-dependent inhibition of the viability of a mouse macrophage cell line, RAW264.7, although a fast-release NE as well as free 15d-PGJ2 exerted a biphasic effect. The observed slow-release kinetics are believed to be responsible for elimination of the biphasic pharmacodynamics of 15d-PGJ2 mainly for two reasons: 1) a high proportion of 15d-PGJ2 that is retained in the NE was delivered to the cytosol, where proapoptotic targets are located and 2) 15d-PGJ2 was able to bypass cell membrane-associated targets that lead to the induction of cellular proliferation. Collectively, our strategy of eliminating the 15d-PGJ2-induced biphasic pharmacodynamics was based on the delivery of 15d-PGJ2 to its desired site of action, excluding undesired sites, on a subcellular level. Keywords: drug release, surface localization, anti-proliferative effect, cellular uptake, subcellular deliveryAbbasi SKajimoto KHarashima HDove Medical Pressarticledrug releasesurface localizationanti-proliferative effectcellular uptakeMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2016, Iss default, Pp 2685-2694 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	drug release surface localization anti-proliferative effect cellular uptake Medicine (General) R5-920
spellingShingle	drug release surface localization anti-proliferative effect cellular uptake Medicine (General) R5-920 Abbasi S Kajimoto K Harashima H Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion
description	Saed Abbasi,* Kazuaki Kajimoto,* Hideyoshi Harashima Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan *These authors contributed equally to this work Abstract: 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has a dual action of stimulating anti-inflammation and anti-proliferation when exogenously administered at high doses. However, at lower doses, it can be toxic inducing opposite actions, ie, stimulation of both inflammation and cell proliferation. This biphasic phenomenon of 15d-PGJ2 is believed to be due to its multitarget behavior. In this study, we provide a strategy for controlling such biphasic pharmacodynamics by separating its dual actions while retaining the beneficial one by using a nanoemulsion (NE). The 15d-PGJ2 was encapsulated in the NE composed of triolein/distearoyl phosphatidylcholine/Tween 80 at a high encapsulation ratio (>83%). Furthermore, NE enhanced drug retention by slowing down its release rate, which was, unconventionally, inversely dependent on the total surface area of the NE system. Next, focusing on the biphasic effect on cell proliferation, we found that the 15d-PGJ2-loaded slow-release NE showed only a dose-dependent inhibition of the viability of a mouse macrophage cell line, RAW264.7, although a fast-release NE as well as free 15d-PGJ2 exerted a biphasic effect. The observed slow-release kinetics are believed to be responsible for elimination of the biphasic pharmacodynamics of 15d-PGJ2 mainly for two reasons: 1) a high proportion of 15d-PGJ2 that is retained in the NE was delivered to the cytosol, where proapoptotic targets are located and 2) 15d-PGJ2 was able to bypass cell membrane-associated targets that lead to the induction of cellular proliferation. Collectively, our strategy of eliminating the 15d-PGJ2-induced biphasic pharmacodynamics was based on the delivery of 15d-PGJ2 to its desired site of action, excluding undesired sites, on a subcellular level. Keywords: drug release, surface localization, anti-proliferative effect, cellular uptake, subcellular delivery
format	article
author	Abbasi S Kajimoto K Harashima H
author_facet	Abbasi S Kajimoto K Harashima H
author_sort	Abbasi S
title	Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion
title_short	Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion
title_full	Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion
title_fullStr	Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion
title_full_unstemmed	Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion
title_sort	elimination of the biphasic pharmacodynamics of 15d-pgj2 by controlling its release from a nanoemulsion
publisher	Dove Medical Press
publishDate	2016
url	https://doaj.org/article/fc5036ff0d42407aa90e7e2bc9ed4a71
work_keys_str_mv	AT abbasis eliminationofthebiphasicpharmacodynamicsof15dpgj2bycontrollingitsreleasefromananoemulsion AT kajimotok eliminationofthebiphasicpharmacodynamicsof15dpgj2bycontrollingitsreleasefromananoemulsion AT harashimah eliminationofthebiphasicpharmacodynamicsof15dpgj2bycontrollingitsreleasefromananoemulsion
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Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion

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