Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy

Mengyuan Zhang, Jianhua He, Cuiping Jiang, Wenli Zhang, Yun Yang, Zhiyu Wang, Jianping LiuDepartment of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of ChinaAbstract: Increasing evidence has highlighted the pivotal role that intimal macrophage (iMΦ) pl...

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Autores principales:	Zhang M, He J, Jiang C, Zhang W, Yang Y, Wang Z, Liu J
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	covalent HA coating rHDL HAase-response multistage-targeting for intimal macrophage cholesterol efflux antiatherogenic efficacies Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/fbe71605c3c4466da1ae61e59f4b3b73
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spelling	oai:doaj.org-article:fbe71605c3c4466da1ae61e59f4b3b732021-12-02T07:22:53ZPlaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy1178-2013https://doaj.org/article/fbe71605c3c4466da1ae61e59f4b3b732017-01-01T00:00:00Zhttps://www.dovepress.com/plaque-hyaluronidase-responsive-high-density-lipoprotein-mimetic-nanop-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Mengyuan Zhang, Jianhua He, Cuiping Jiang, Wenli Zhang, Yun Yang, Zhiyu Wang, Jianping LiuDepartment of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of ChinaAbstract: Increasing evidence has highlighted the pivotal role that intimal macrophage (iMΦ) plays in the pathophysiology of atherosclerotic plaques, which represents an attractive target for atherosclerosis treatment. In this work, to address the insufficient specificity of conventional reconstituted high-density lipoprotein (rHDL) for iMΦ and its limited cholesterol efflux ability, we designed a hyaluronan (HA)-anchored core–shell rHDL. This nanoparticle achieved efficient iMΦ-targeted drug delivery via a multistage-targeting approach, and excellent cellular cholesterol removal. It contained a biodegradable poly (lactic-co-glycolic acid) (PLGA) core within a lipid bilayer, and apolipoprotein A-I (apoA-I) absorbing on the lipid bilayer was covalently decorated with HA. The covalent HA coating with superior stability and greater shielding was favorable for not only minimizing the liver uptake but also facilitating the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors in atherosclerotic plaques. The ultimate iMΦ homing was achieved via apoA-I after HA coating degraded by hyaluronidase (HAase) (abundant in atherosclerotic plaque). The multistage-targeting mechanism was revealed on the established injured endothelium–macrophage co-culture dynamic system. Upon treatment with HAase in vitro, the nanoparticle HA-(C)-PLGA-rHDL exhibited a greater cholesterol efflux capacity compared with conventional rHDL (2.43-fold). Better targeting efficiency toward iMΦ and attenuated liver accumulation were further proved by results from ex vivo imaging and iMΦ-specific fluorescence localization. Ultimately, HA-(C)-PLGA-rHDL loaded with simvastatin realized the most potent anti-atherogenic efficacies in model animals over other preparations. Thus, the HAase-responsive HDL-mimetic nanoparticle was shown in this study to be a promising nanocarrier for anti-atherogenic therapy, in the light of efficient iMΦ-targeted drug delivery and excellent function of mediating cellular cholesterol efflux.Keywords: covalent HA coating, rHDL, HAase response, multistage targeting for intimal macrophage, cholesterol efflux, anti-atherogenic efficaciesZhang MHe JJiang CZhang WYang YWang ZLiu JDove Medical Pressarticlecovalent HA coatingrHDLHAase-responsemultistage-targeting for intimal macrophagecholesterol effluxantiatherogenic efficaciesMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 533-558 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	covalent HA coating rHDL HAase-response multistage-targeting for intimal macrophage cholesterol efflux antiatherogenic efficacies Medicine (General) R5-920
spellingShingle	covalent HA coating rHDL HAase-response multistage-targeting for intimal macrophage cholesterol efflux antiatherogenic efficacies Medicine (General) R5-920 Zhang M He J Jiang C Zhang W Yang Y Wang Z Liu J Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy
description	Mengyuan Zhang, Jianhua He, Cuiping Jiang, Wenli Zhang, Yun Yang, Zhiyu Wang, Jianping LiuDepartment of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of ChinaAbstract: Increasing evidence has highlighted the pivotal role that intimal macrophage (iMΦ) plays in the pathophysiology of atherosclerotic plaques, which represents an attractive target for atherosclerosis treatment. In this work, to address the insufficient specificity of conventional reconstituted high-density lipoprotein (rHDL) for iMΦ and its limited cholesterol efflux ability, we designed a hyaluronan (HA)-anchored core–shell rHDL. This nanoparticle achieved efficient iMΦ-targeted drug delivery via a multistage-targeting approach, and excellent cellular cholesterol removal. It contained a biodegradable poly (lactic-co-glycolic acid) (PLGA) core within a lipid bilayer, and apolipoprotein A-I (apoA-I) absorbing on the lipid bilayer was covalently decorated with HA. The covalent HA coating with superior stability and greater shielding was favorable for not only minimizing the liver uptake but also facilitating the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors in atherosclerotic plaques. The ultimate iMΦ homing was achieved via apoA-I after HA coating degraded by hyaluronidase (HAase) (abundant in atherosclerotic plaque). The multistage-targeting mechanism was revealed on the established injured endothelium–macrophage co-culture dynamic system. Upon treatment with HAase in vitro, the nanoparticle HA-(C)-PLGA-rHDL exhibited a greater cholesterol efflux capacity compared with conventional rHDL (2.43-fold). Better targeting efficiency toward iMΦ and attenuated liver accumulation were further proved by results from ex vivo imaging and iMΦ-specific fluorescence localization. Ultimately, HA-(C)-PLGA-rHDL loaded with simvastatin realized the most potent anti-atherogenic efficacies in model animals over other preparations. Thus, the HAase-responsive HDL-mimetic nanoparticle was shown in this study to be a promising nanocarrier for anti-atherogenic therapy, in the light of efficient iMΦ-targeted drug delivery and excellent function of mediating cellular cholesterol efflux.Keywords: covalent HA coating, rHDL, HAase response, multistage targeting for intimal macrophage, cholesterol efflux, anti-atherogenic efficacies
format	article
author	Zhang M He J Jiang C Zhang W Yang Y Wang Z Liu J
author_facet	Zhang M He J Jiang C Zhang W Yang Y Wang Z Liu J
author_sort	Zhang M
title	Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy
title_short	Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy
title_full	Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy
title_fullStr	Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy
title_full_unstemmed	Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy
title_sort	plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/fbe71605c3c4466da1ae61e59f4b3b73
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Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy

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