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Liver-Targeting and pH-Sensitive Sulfated Hyaluronic Acid Mixed Micelles for Hepatoma Therapy

Authors Li Z, Tian G, Jiang H, Pan R, Lian B, Wang M, Gao Z, Zhang B, Wu J

Received 5 May 2019

Accepted for publication 8 November 2019

Published 2 December 2019 Volume 2019:14 Pages 9437—9452

DOI https://doi.org/10.2147/IJN.S214528

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Melinda Thomas

Peer reviewer comments 2

Editor who approved publication: Dr Mian Wang


Zhi-peng Li,1,* Gui-xiang Tian,1,* Hong Jiang,1,* Rui-yan Pan,2 Bo Lian,1 Min Wang,1 Zhi-qin Gao,1 Bo Zhang,2 Jing-liang Wu1

1School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 2School of Pharmacy, Weifang Medical University, Weifang, Shandong, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Bo Zhang
School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of China
Email bozh315@163.com
Jing-liang Wu
School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of China
Tel +86 536 846 2541
Email jlwu2008@163.com

Background: The tumor-targeting ability and pH-sensitive properties of intelligent drug delivery systems are crucial for effective drug delivery and anti-tumor therapy.
Methods: In this study, sHA-DOX/HA-GA mixed micelles were designed with the following properties: sulfated hyaluronic acid (sHA) was synthesized to block cell migration by inhibiting HAase; sHA-DOX conjugates were synthesized via pH-sensitive hydrazone bond to realize DOX-sensitive release. The introduction of HA-GA conjugate could improve active-targeting ability and cellular uptake.
Results: The results showed that the mixed micelles possessed a nearly spherical shape, nanoscale particle size (217.70±0.89 nm), narrow size distribution (PDI=0.07±0.04), negative zeta potential (−31.87±0.61 mV) and pH-dependent DOX release. In addition, the sHA-DOX/HA-GA micelles exhibited concentration-dependent cytotoxicities against liver carcinoma cells (HepG2) and HeLa cells, and were shown to be effectively taken up by HepG2 cells by confocal microscopy analysis. Furthermore, the in vivo anti-tumor study showed that mixed micelles had a superior anti-tumor effect compared to that of free DOX. Further evidence obtained from the hematoxylin–eosin staining and immunohistochemistry analysis also demonstrated that sHA-DOX/HA-GA exhibited stronger tumor inhibition and lower systemic toxicity than free DOX.
Conclusion: The sHA-DOX/HA-GA mixed micelles could be a potential drug delivery system for anti-hepatoma therapy.

Keywords: hyaluronic acid, glycyrrhetinic acid, hepatoma-targeting, pH-sensitive, micelles, anti-tumor therapy

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