Calcium depletion-mediated protease inhibition and apical-junctional- complex disassembly via an EGTA-conjugated carrier for oral insulin delivery

Er Yuan Chuang, Kun Ju Lin, Fang Yi Su, Hsin Lung Chen, Barnali Maiti, Yi Cheng Ho, Tzu Chen Yen, Nilendu Panda, Hsing Wen Sung*

*此作品的通信作者

研究成果: 期刊稿件文章同行評審

67 引文 斯高帕斯(Scopus)

摘要

Calcium (Ca2+) has a crucial role in maintaining the intestinal protease activity and in forming the apical junctional complex (AJC) that preserves epithelial barrier function. Ethylene glycol tetraacetic acid (EGTA) is a Ca2+-specific chelating agent. To maintain the concentration of this chelator in areas where enzyme inhibition and paracellular permeation enhancement are needed, this study synthesized a poly(γ-glutamic acid)-EGTA conjugate (γPGA-EGTA) to form nanoparticles (NPs) with chitosan (CS) for oral insulin delivery. The results of our molecular dynamic (MD) simulations indicate that Ca2+ ions could be specifically chelated to the nitrogen atoms, ether oxygen atoms, and carboxylate oxygen atoms in [Ca(EGTA)]2- anions. By che-lating Ca2+, γPGA-EGTA conferred a significant insulin protection effect against proteases in intestinal tracts isolated from rats. Additionally, calcium depletion by γPGA-EGTA could stimulate the endocytosis of AJC components in Caco-2 cell monolayers, which led to a reversible opening of AJCs and thus increased their paracellular permeability. Single-photon emission computed tomography images performed in the biodistribution study clearly show the 123I-insulin orally delivered by CS/γPGA-EGTA NPs in the heart, aorta, renal cortex, renal pelvis and liver, which ultimately produced a significant and prolonged hypoglyce-mic effect in diabetic rats. The above results confirm that this γPGA-EGTA conjugate is a promising candidate for oral insulin delivery.

原文英語
頁(從 - 到)296-305
頁數10
期刊Journal of Controlled Release
169
發行號3
DOIs
出版狀態已出版 - 2013

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