Abstract

Calcium (Ca2+) has a crucial role in maintaining the intestinal protease activity and in forming the apical junction 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. 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 chelating 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 hypoglycemic effect in diabetic rats. The above results confirm that this γPGA-EGTA conjugate is a promising candidate for oral insulin delivery.
Original languageEnglish
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Publication statusPublished - 2016

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Egtazic Acid
Drug delivery
Nanoparticles
Proteins
Glutamic Acid
Acids
Insulin
Pharmaceutical Preparations
Ethylene glycol
Chitosan
Chelating Agents
Atoms
Chelation
Rats
Peptide Hydrolases
Calcium
Single photon emission computed tomography
Oxygen
Enzyme inhibition
Kidney Pelvis

Cite this

Multifunctional nanoparticles for oral protein drug delivery. / Chuang, Er-Yuan; Lin, Kun Ju; Su, Fang Yi; Mi, Fwu-Long; Chen, Chiung Tong; Juang, Jyuhn Huarng; Sung, Hsing Wen.

In: Nanomedicine: Nanotechnology, Biology, and Medicine, 2016.

Research output: Contribution to journalArticle

Chuang, Er-Yuan ; Lin, Kun Ju ; Su, Fang Yi ; Mi, Fwu-Long ; Chen, Chiung Tong ; Juang, Jyuhn Huarng ; Sung, Hsing Wen. / Multifunctional nanoparticles for oral protein drug delivery. In: Nanomedicine: Nanotechnology, Biology, and Medicine. 2016.
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abstract = "Calcium (Ca2+) has a crucial role in maintaining the intestinal protease activity and in forming the apical junction 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. 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 chelating 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 hypoglycemic effect in diabetic rats. The above results confirm that this γPGA-EGTA conjugate is a promising candidate for oral insulin delivery.",
author = "Er-Yuan Chuang and Lin, {Kun Ju} and Su, {Fang Yi} and Fwu-Long Mi and Chen, {Chiung Tong} and Juang, {Jyuhn Huarng} and Sung, {Hsing Wen}",
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AU - Chuang, Er-Yuan

AU - Lin, Kun Ju

AU - Su, Fang Yi

AU - Mi, Fwu-Long

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AU - Juang, Jyuhn Huarng

AU - Sung, Hsing Wen

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