期刊
INTERNATIONAL JOURNAL OF NANOMEDICINE
卷 16, 期 -, 页码 7861-7873出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/IJN.S323381
关键词
nanoparticle delivery system; insulin bioavailability; hypoglycemic effect; tight junctions
资金
- National Natural Science Foundation of China [81673360]
- Major Science and Technology Innovation Projects of Shandong Province [2018CXGC1408]
- Science and Technology Projects for people's livelihood of Qingdao [18-6-1-93-nsh]
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.
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 INS@LDH-DCA-HA. 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 mu g/mL. Flow cytometry analysis revealed that Caco-2 cells absorbed INS@LDH-DCA-HA more readily than insulin. Measurement of transepithelial electrical resistance indicated that INS@LDH-DCA-HA 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 INS@LDH-DCA-HA 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 INS@LDH-DCA-HA 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 INS@LDH-DCA-HA. 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.
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