Targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol

Aisha Rafique,1 Anders Etzerodt,2 Jonas H Graversen,3 Søren K Moestrup,3 Frederik Dagnæs-Hansen,2 Holger Jon Møller1 1Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; 2Institute of Biomedicine, Aarhus University, Aarhus, Denmark; 3Dep...

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Autores principales:	Rafique A, Etzerodt A, Graversen JH, Moestrup SK, Dagnæs-Hansen F, Møller HJ
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	Macrophages targeted drug delivery calcitriol TNF-α HLA-DR CD80 IL-6 NF-kB MCP-1 CD163 mRNA gene expression ELISA flow cytometry confocal microscopy lipid nanoparticles low-grade inflammation immunomodulation in vivo imaging Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/019bb5149d1b4c3f9c3ecc584bed5be1
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spelling	oai:doaj.org-article:019bb5149d1b4c3f9c3ecc584bed5be12021-12-02T01:55:26ZTargeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol1178-2013https://doaj.org/article/019bb5149d1b4c3f9c3ecc584bed5be12019-04-01T00:00:00Zhttps://www.dovepress.com/targeted-lipid-nanoparticle-delivery-of-calcitriol-to-human-monocyte-d-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Aisha Rafique,1 Anders Etzerodt,2 Jonas H Graversen,3 Søren K Moestrup,3 Frederik Dagnæs-Hansen,2 Holger Jon Møller1 1Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; 2Institute of Biomedicine, Aarhus University, Aarhus, Denmark; 3Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark Background: Vitamin D3 possesses anti-inflammatory and modulatory properties in addition to its role in calcium and phosphate homeostasis. Upon activation, macrophages (M) can initiate and sustain pro-inflammatory cytokine production in inflammatory disorders and play a pathogenic role in certain cancers. Purpose: The main purpose of this study was to encapsulate and specifically target calcitriol to macrophages and investigate the anti-inflammatory properties of calcitriol in vitro and in vivo.Methods: In this study we have designed and developed near-infrared calcitriol PEGylated nanoparticles (PEG-LNP(Cal)) using a microfluidic mixing technique and modified lipid nanoparticles (LNPs) to target the M specific endocytic receptor CD163. We have investigated LNP cellular uptake and anti-inflammatory effect in LPS-induced M in vitro by flow cytometry, confocal microscopy and gene expression analyses. LNP pharmacodynamics, bio-distribution and organ specific LNP accumulation was also investigated in mice in vivo. Results: In vitro, we observed the specific uptake of PEG-LNP(Cal)-hCD163 in human M, which was significantly higher than the non-specific uptake of control PEG-LNP(Cal)-IgG(h) in M. Pre-treatment with encapsulated calcitriol was able to attenuate intracellular TNF- expression, and M surface marker HLA-DR expression more efficiently than free calcitriol in LPS-induced M in vitro. Encapsulated calcitriol diminished mRNA gene levels of TNF-, NF-B, MCP-1 and IL-6, while upregulating IL-10. TNF- and IL-6 protein secretion also decreased. In mice, an in vivo pharmacodynamic study of PEG-LNP(Cal) showed a rapid clearance of IgG and CD163 modified LNPs compared to PEG-LNP(Cal). Antibody modified PEG-LNP(Cal) accumulated in the liver, spleen and kidney, whereas unmodified PEG-LNP(Cal) accumulation was only observed in the liver.Conclusion: Our results show that calcitriol can be effectively targeted to M. Our data confirms the anti-inflammatory properties of calcitriol and this may be a potential way to deliver high dose bioactive calcitriol to M during inflammation in vivo. Keywords: macrophages, 1.25(OH)2D3, calcitriol, lipid nanoparticles, pro-inflammatory cytokines, CD163 targeted drug delivery, gene expression analyses, in vivo pharmacodynamicsRafique AEtzerodt AGraversen JHMoestrup SKDagnæs-Hansen FMøller HJDove Medical PressarticleMacrophagestargeted drug deliverycalcitriolTNF-αHLA-DRCD80IL-6NF-kBMCP-1CD163mRNA gene expressionELISAflow cytometryconfocal microscopylipid nanoparticleslow-grade inflammationimmunomodulationin vivo imagingMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 2829-2846 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Macrophages targeted drug delivery calcitriol TNF-α HLA-DR CD80 IL-6 NF-kB MCP-1 CD163 mRNA gene expression ELISA flow cytometry confocal microscopy lipid nanoparticles low-grade inflammation immunomodulation in vivo imaging Medicine (General) R5-920
spellingShingle	Macrophages targeted drug delivery calcitriol TNF-α HLA-DR CD80 IL-6 NF-kB MCP-1 CD163 mRNA gene expression ELISA flow cytometry confocal microscopy lipid nanoparticles low-grade inflammation immunomodulation in vivo imaging Medicine (General) R5-920 Rafique A Etzerodt A Graversen JH Moestrup SK Dagnæs-Hansen F Møller HJ Targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol
description	Aisha Rafique,1 Anders Etzerodt,2 Jonas H Graversen,3 Søren K Moestrup,3 Frederik Dagnæs-Hansen,2 Holger Jon Møller1 1Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; 2Institute of Biomedicine, Aarhus University, Aarhus, Denmark; 3Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark Background: Vitamin D3 possesses anti-inflammatory and modulatory properties in addition to its role in calcium and phosphate homeostasis. Upon activation, macrophages (M) can initiate and sustain pro-inflammatory cytokine production in inflammatory disorders and play a pathogenic role in certain cancers. Purpose: The main purpose of this study was to encapsulate and specifically target calcitriol to macrophages and investigate the anti-inflammatory properties of calcitriol in vitro and in vivo.Methods: In this study we have designed and developed near-infrared calcitriol PEGylated nanoparticles (PEG-LNP(Cal)) using a microfluidic mixing technique and modified lipid nanoparticles (LNPs) to target the M specific endocytic receptor CD163. We have investigated LNP cellular uptake and anti-inflammatory effect in LPS-induced M in vitro by flow cytometry, confocal microscopy and gene expression analyses. LNP pharmacodynamics, bio-distribution and organ specific LNP accumulation was also investigated in mice in vivo. Results: In vitro, we observed the specific uptake of PEG-LNP(Cal)-hCD163 in human M, which was significantly higher than the non-specific uptake of control PEG-LNP(Cal)-IgG(h) in M. Pre-treatment with encapsulated calcitriol was able to attenuate intracellular TNF- expression, and M surface marker HLA-DR expression more efficiently than free calcitriol in LPS-induced M in vitro. Encapsulated calcitriol diminished mRNA gene levels of TNF-, NF-B, MCP-1 and IL-6, while upregulating IL-10. TNF- and IL-6 protein secretion also decreased. In mice, an in vivo pharmacodynamic study of PEG-LNP(Cal) showed a rapid clearance of IgG and CD163 modified LNPs compared to PEG-LNP(Cal). Antibody modified PEG-LNP(Cal) accumulated in the liver, spleen and kidney, whereas unmodified PEG-LNP(Cal) accumulation was only observed in the liver.Conclusion: Our results show that calcitriol can be effectively targeted to M. Our data confirms the anti-inflammatory properties of calcitriol and this may be a potential way to deliver high dose bioactive calcitriol to M during inflammation in vivo. Keywords: macrophages, 1.25(OH)2D3, calcitriol, lipid nanoparticles, pro-inflammatory cytokines, CD163 targeted drug delivery, gene expression analyses, in vivo pharmacodynamics
format	article
author	Rafique A Etzerodt A Graversen JH Moestrup SK Dagnæs-Hansen F Møller HJ
author_facet	Rafique A Etzerodt A Graversen JH Moestrup SK Dagnæs-Hansen F Møller HJ
author_sort	Rafique A
title	Targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol
title_short	Targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol
title_full	Targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol
title_fullStr	Targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol
title_full_unstemmed	Targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol
title_sort	targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/019bb5149d1b4c3f9c3ecc584bed5be1
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Targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol

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