Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity

In this study, we developed oral pemetrexed (PMX) for metronomic dosing to enhance antitumor immunity. PMX was electrostatically complexed with positively charged lysine-linked deoxycholic acid (DL) as an intestinal permeation enhancer, forming PMX/DL, to enhance its intestinal permeability. PMX/DL...

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Autores principales:	Ruby Maharjan, Laxman Subedi, Rudra Pangeni, Saurav Kumar Jha, Seo Hee Kang, Kwan-Young Chang, Youngro Byun, Jeong Uk Choi, Jin Woo Park
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	pemetrexed colloidal dispersion oral metronomic chemotherapy immunogenic cell death antitumor immunity immunotherapy Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/ae87ec3ea3aa4f77beaa8a3f22a6c13f
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spelling	oai:doaj.org-article:ae87ec3ea3aa4f77beaa8a3f22a6c13f2021-11-04T15:00:41ZMetronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity1071-75441521-046410.1080/10717544.2021.1995077https://doaj.org/article/ae87ec3ea3aa4f77beaa8a3f22a6c13f2021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/10717544.2021.1995077https://doaj.org/toc/1071-7544https://doaj.org/toc/1521-0464In this study, we developed oral pemetrexed (PMX) for metronomic dosing to enhance antitumor immunity. PMX was electrostatically complexed with positively charged lysine-linked deoxycholic acid (DL) as an intestinal permeation enhancer, forming PMX/DL, to enhance its intestinal permeability. PMX/DL was also incorporated into a colloidal dispersion (CD) comprised of the block copolymer of poly(ethylene oxide) and poly(propylene oxide), and caprylocaproyl macrogol-8 glycerides (PMX/DL-CD). CD-containing PMX/DL complex in a 1:1 molar ratio [PMX/DL(1:1)-CD] showed 4.66- and 7.19-fold greater permeability than free PMX through the Caco-2 cell monolayer and rat intestine, respectively. This resulted in a 282% improvement in oral bioavailability in rats. In addition, low-dose metronomic PMX led to more immunogenic cell death in CT26.CL25 cells compared to high PMX concentrations at the maximum tolerated dose. In CT26.CL25 tumor-bearing mice, oral metronomic PMX/DL-CD elicited greater antitumor immunity not only by enhancing the number of tumor-infiltrating lymphocytes but also by suppressing T cell functions. Oral PMX/DL-CD substantially increased programmed cell death protein ligand-1 (PD-L1) expression on tumor cells compared to the control and PMX-IV groups. This increased antitumor efficacy in combination with anti-programmed cell death protein-1 (aPD-1) antibody in terms of tumor rejection and immunological memory compared to the combination of PMX-IV and aPD-1. These results suggest that oral metronomic scheduling of PMX/DL-CD in combination with immunotherapy has synergistic antitumor effects.Ruby MaharjanLaxman SubediRudra PangeniSaurav Kumar JhaSeo Hee KangKwan-Young ChangYoungro ByunJeong Uk ChoiJin Woo ParkTaylor & Francis Grouparticlepemetrexedcolloidal dispersionoral metronomic chemotherapyimmunogenic cell deathantitumor immunityimmunotherapyTherapeutics. PharmacologyRM1-950ENDrug Delivery, Vol 28, Iss 1, Pp 2313-2328 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pemetrexed colloidal dispersion oral metronomic chemotherapy immunogenic cell death antitumor immunity immunotherapy Therapeutics. Pharmacology RM1-950
spellingShingle	pemetrexed colloidal dispersion oral metronomic chemotherapy immunogenic cell death antitumor immunity immunotherapy Therapeutics. Pharmacology RM1-950 Ruby Maharjan Laxman Subedi Rudra Pangeni Saurav Kumar Jha Seo Hee Kang Kwan-Young Chang Youngro Byun Jeong Uk Choi Jin Woo Park Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity
description	In this study, we developed oral pemetrexed (PMX) for metronomic dosing to enhance antitumor immunity. PMX was electrostatically complexed with positively charged lysine-linked deoxycholic acid (DL) as an intestinal permeation enhancer, forming PMX/DL, to enhance its intestinal permeability. PMX/DL was also incorporated into a colloidal dispersion (CD) comprised of the block copolymer of poly(ethylene oxide) and poly(propylene oxide), and caprylocaproyl macrogol-8 glycerides (PMX/DL-CD). CD-containing PMX/DL complex in a 1:1 molar ratio [PMX/DL(1:1)-CD] showed 4.66- and 7.19-fold greater permeability than free PMX through the Caco-2 cell monolayer and rat intestine, respectively. This resulted in a 282% improvement in oral bioavailability in rats. In addition, low-dose metronomic PMX led to more immunogenic cell death in CT26.CL25 cells compared to high PMX concentrations at the maximum tolerated dose. In CT26.CL25 tumor-bearing mice, oral metronomic PMX/DL-CD elicited greater antitumor immunity not only by enhancing the number of tumor-infiltrating lymphocytes but also by suppressing T cell functions. Oral PMX/DL-CD substantially increased programmed cell death protein ligand-1 (PD-L1) expression on tumor cells compared to the control and PMX-IV groups. This increased antitumor efficacy in combination with anti-programmed cell death protein-1 (aPD-1) antibody in terms of tumor rejection and immunological memory compared to the combination of PMX-IV and aPD-1. These results suggest that oral metronomic scheduling of PMX/DL-CD in combination with immunotherapy has synergistic antitumor effects.
format	article
author	Ruby Maharjan Laxman Subedi Rudra Pangeni Saurav Kumar Jha Seo Hee Kang Kwan-Young Chang Youngro Byun Jeong Uk Choi Jin Woo Park
author_facet	Ruby Maharjan Laxman Subedi Rudra Pangeni Saurav Kumar Jha Seo Hee Kang Kwan-Young Chang Youngro Byun Jeong Uk Choi Jin Woo Park
author_sort	Ruby Maharjan
title	Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity
title_short	Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity
title_full	Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity
title_fullStr	Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity
title_full_unstemmed	Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity
title_sort	metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/ae87ec3ea3aa4f77beaa8a3f22a6c13f
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Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity

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