Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative

Rudra Pangeni,1,* Saurav Kumar Jha,1,* Ruby Maharjan,2 Jeong Uk Choi,2 Kwan-Young Chang,3 Young Kweon Choi,3 Youngro Byun,4 Jin Woo Park11Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; 2Research Instit...

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Autores principales:	Pangeni R, Jha SK, Maharjan R, Choi JU, Chang KY, Choi YK, Byun Y, Park JW
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	pemetrexed bile acid derivative oral powder formulation intestinal membrane permeability oral delivery oral metronomic chemotherapy Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/febfa9bba52d4cb0a578dc018a3c4370
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spelling	oai:doaj.org-article:febfa9bba52d4cb0a578dc018a3c43702021-12-02T08:04:49ZIntestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative1178-2013https://doaj.org/article/febfa9bba52d4cb0a578dc018a3c43702019-08-01T00:00:00Zhttps://www.dovepress.com/intestinal-transport-mechanism-and-in-vivo-anticancer-efficacy-of-a-so-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Rudra Pangeni,1,* Saurav Kumar Jha,1,* Ruby Maharjan,2 Jeong Uk Choi,2 Kwan-Young Chang,3 Young Kweon Choi,3 Youngro Byun,4 Jin Woo Park11Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; 2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; 3Global R&D Center, Icure BNP, Seoul 06170, Republic of Korea; 4Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea*These authors contributed equally to this workObjective: The rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy.Methods: PMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP).Results: The apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively.Conclusion: These findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.Keywords: pemetrexed, bile acid derivative, oral powder formulation, intestinal membrane permeability, oral delivery, oral metronomic chemotherapy  Pangeni RJha SKMaharjan RChoi JUChang KYChoi YKByun YPark JWDove Medical Pressarticlepemetrexedbile acid derivativeoral powder formulationintestinal membrane permeabilityoral deliveryoral metronomic chemotherapyMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 6339-6356 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	pemetrexed bile acid derivative oral powder formulation intestinal membrane permeability oral delivery oral metronomic chemotherapy Medicine (General) R5-920
spellingShingle	pemetrexed bile acid derivative oral powder formulation intestinal membrane permeability oral delivery oral metronomic chemotherapy Medicine (General) R5-920 Pangeni R Jha SK Maharjan R Choi JU Chang KY Choi YK Byun Y Park JW Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative
description	Rudra Pangeni,1,* Saurav Kumar Jha,1,* Ruby Maharjan,2 Jeong Uk Choi,2 Kwan-Young Chang,3 Young Kweon Choi,3 Youngro Byun,4 Jin Woo Park11Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; 2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; 3Global R&D Center, Icure BNP, Seoul 06170, Republic of Korea; 4Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea*These authors contributed equally to this workObjective: The rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy.Methods: PMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP).Results: The apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively.Conclusion: These findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.Keywords: pemetrexed, bile acid derivative, oral powder formulation, intestinal membrane permeability, oral delivery, oral metronomic chemotherapy
format	article
author	Pangeni R Jha SK Maharjan R Choi JU Chang KY Choi YK Byun Y Park JW
author_facet	Pangeni R Jha SK Maharjan R Choi JU Chang KY Choi YK Byun Y Park JW
author_sort	Pangeni R
title	Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative
title_short	Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative
title_full	Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative
title_fullStr	Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative
title_full_unstemmed	Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative
title_sort	intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/febfa9bba52d4cb0a578dc018a3c4370
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Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative

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