Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect

Enrui Chen,1,* Shangcong Han,1,* Bo Song,2 Lisa Xu,1 Haicheng Yuan,2 Mingtao Liang,3 Yong Sun1 1Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, People’s Republic of China; 2Department of Neurology, Qingdao Central Hospital, Qingdao, People’s Republic...

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Autores principales:	Chen E, Han S, Song B, Xu L, Yuan H, Liang M, Sun Y
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	hyaluronidase nanoparticles tumor penetration ecm Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/ea60572ea8364bc7920f19c22f70a688
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spelling	oai:doaj.org-article:ea60572ea8364bc7920f19c22f70a6882021-12-02T11:20:29ZMechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect1178-2013https://doaj.org/article/ea60572ea8364bc7920f19c22f70a6882020-08-01T00:00:00Zhttps://www.dovepress.com/mechanism-investigation-of-hyaluronidase-combined-multistage-nanoparti-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Enrui Chen,1,* Shangcong Han,1,* Bo Song,2 Lisa Xu,1 Haicheng Yuan,2 Mingtao Liang,3 Yong Sun1 1Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, People’s Republic of China; 2Department of Neurology, Qingdao Central Hospital, Qingdao, People’s Republic of China; 3Department of Pharmaceutics, School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia*These authors contributed equally to this workCorrespondence: Yong SunDepartment of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, People’s Republic of ChinaTel +86-532-82991203Email sunyong@qdu.edu.cnBackground: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors.Materials and Methods: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidase-combined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo.Results: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth.Conclusion: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.Keywords: hyaluronidase, nanoparticles, tumor penetration, ECMChen EHan SSong BXu LYuan HLiang MSun YDove Medical Pressarticlehyaluronidasenanoparticlestumor penetrationecmMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 6311-6324 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	hyaluronidase nanoparticles tumor penetration ecm Medicine (General) R5-920
spellingShingle	hyaluronidase nanoparticles tumor penetration ecm Medicine (General) R5-920 Chen E Han S Song B Xu L Yuan H Liang M Sun Y Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect
description	Enrui Chen,1,* Shangcong Han,1,* Bo Song,2 Lisa Xu,1 Haicheng Yuan,2 Mingtao Liang,3 Yong Sun1 1Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, People’s Republic of China; 2Department of Neurology, Qingdao Central Hospital, Qingdao, People’s Republic of China; 3Department of Pharmaceutics, School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia*These authors contributed equally to this workCorrespondence: Yong SunDepartment of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, People’s Republic of ChinaTel +86-532-82991203Email sunyong@qdu.edu.cnBackground: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors.Materials and Methods: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidase-combined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo.Results: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth.Conclusion: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.Keywords: hyaluronidase, nanoparticles, tumor penetration, ECM
format	article
author	Chen E Han S Song B Xu L Yuan H Liang M Sun Y
author_facet	Chen E Han S Song B Xu L Yuan H Liang M Sun Y
author_sort	Chen E
title	Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect
title_short	Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect
title_full	Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect
title_fullStr	Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect
title_full_unstemmed	Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect
title_sort	mechanism investigation of hyaluronidase-combined multistage nanoparticles for solid tumor penetration and antitumor effect
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/ea60572ea8364bc7920f19c22f70a688
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Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect

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