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: | , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2020
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| Acceso en línea: | https://doaj.org/article/ea60572ea8364bc7920f19c22f70a688 |
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| Sumario: | 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 |
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