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Layered Double Hydroxide Modified with Deoxycholic and Hyaluronic Acids for Efficient Oral Insulin Absorption

Authors Huang X, Han S, Chen Z, Zhao L , Wang C, Guo Q, Li Y, Sun Y 

Received 17 June 2021

Accepted for publication 10 November 2021

Published 1 December 2021 Volume 2021:16 Pages 7861—7873

DOI https://doi.org/10.2147/IJN.S323381

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Farooq A. Shiekh

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Xia Huang, 1,* Shangcong Han, 1,* Zuxian Chen, 1 Lei Zhao, 2 Changduo Wang, 1 Qingyang Guo, 3 Yanfeng Li, 1 Yong Sun 1

1Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, People’s Republic of China; 2Lunan Better Pharmaceutical Co., Ltd, Linyi, People’s Republic of China; 3College of Fisheries, Henan Normal University, Xinxiang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yong Sun Email [email protected]

Introduction: This study aimed to construct a layered double hydroxide (LDH) nanoparticle delivery system that was modified by deoxycholic acid (DCA) and hyaluronic acid (HA) to increase the bioavailability of oral insulin.
Methods: LDH-DCA-HA was synthesized by the hybridization of DCA and HA with LDH. Subsequently, insulin was loaded onto LDH-DCA-HA, resulting in the formation of [email protected] The in vivo and in vitro mechanisms of insulin release, as well as the efficiency of insulin absorption, were analyzed before and after DCA-HA modification.
Results: MTT assay showed that there was satisfactory biocompatibility between LDH-DCA-HA and Caco-2 cells at a concentration below 1000 μg/mL. Flow cytometry analysis revealed that Caco-2 cells absorbed [email protected] more readily than insulin. Measurement of transepithelial electrical resistance indicated that [email protected] induced the reversible opening of tight cell junctions, thereby facilitating its absorption. This was confirmed via laser confocal microscopy analysis, revealing that a large amount of zonula occludens-1 tight junction (TJ) protein was utilized for the paracellular pathway of nanoparticles. We also measured the blood glucose levels of type I diabetic mice and found that oral [email protected] exerted a steady hypoglycemic effect lasting 12 h, with a small range of postprandial blood glucose fluctuation. Immunofluorescence analysis showed that the strong penetration ability of [email protected] allowed insulin to enter epithelial cells more readily than free insulin. Finally, immunohistochemical analysis of anti-SLC10A1 protein confirmed that the cholic acid transporter receptor protein played a key role in the functioning of [email protected]
Conclusion: LDH nanoparticles modified by DCA and HA improved the absorption efficiency of insulin by opening the TJs of cells and interacting with the cholic acid transporter receptor protein.

Keywords: nanoparticle delivery system, insulin bioavailability, hypoglycemic effect, tight junctions

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