Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery
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Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery. / Fan, Weiwei; Xia, Dengning; Zhu, Quanlei; Li, Xiuying; He, Shufang; Zhu, Chunliu; Guo, Shiyan; Hovgaard, Lars; Yang, Mingshi; Gan, Yong.
In: Biomaterials, Vol. 151, 01.2018, p. 13-23.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery
AU - Fan, Weiwei
AU - Xia, Dengning
AU - Zhu, Quanlei
AU - Li, Xiuying
AU - He, Shufang
AU - Zhu, Chunliu
AU - Guo, Shiyan
AU - Hovgaard, Lars
AU - Yang, Mingshi
AU - Gan, Yong
N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.
PY - 2018/1
Y1 - 2018/1
N2 - Oral absorption of protein/peptide-loaded nanoparticles is often limited by multiple barriers of the intestinal epithelium. In addition to mucus translocation and apical endocytosis, highly efficient transepithelial absorption of nanoparticles requires successful intracellular trafficking, especially to avoid lysosomal degradation, and basolateral release. Here, the functional material, deoxycholic acid-conjugated chitosan, is synthesized and loaded with the model protein drug insulin into deoxycholic acid-modified nanoparticles (DNPs). The DNPs designed in this study are demonstrated to overcome multiple barriers of the intestinal epithelium by exploiting the bile acid pathway. In Caco-2 cell monolayers, DNPs are internalized via apical sodium-dependent bile acid transporter (ASBT)-mediated endocytosis. Interestingly, insulin degradation in the epithelium is significantly prevented due to endolysosomal escape of DNPs. Additionally, DNPs can interact with a cytosolic ileal bile acid-binding protein that facilitates the intracellular trafficking and basolateral release of insulin. In rats, intravital two-photon microscopy also reveals that the transport of DNPs into the intestinal villi is mediated by ASBT. Further pharmacokinetic studies disclose an oral bioavailability of 15.9% in type I diabetic rats after loading freeze-dried DNPs into enteric-coated capsules. Thus, deoxycholic acid-modified chitosan nanoparticles can overcome multiple barriers of the intestinal epithelium for oral delivery of insulin.
AB - Oral absorption of protein/peptide-loaded nanoparticles is often limited by multiple barriers of the intestinal epithelium. In addition to mucus translocation and apical endocytosis, highly efficient transepithelial absorption of nanoparticles requires successful intracellular trafficking, especially to avoid lysosomal degradation, and basolateral release. Here, the functional material, deoxycholic acid-conjugated chitosan, is synthesized and loaded with the model protein drug insulin into deoxycholic acid-modified nanoparticles (DNPs). The DNPs designed in this study are demonstrated to overcome multiple barriers of the intestinal epithelium by exploiting the bile acid pathway. In Caco-2 cell monolayers, DNPs are internalized via apical sodium-dependent bile acid transporter (ASBT)-mediated endocytosis. Interestingly, insulin degradation in the epithelium is significantly prevented due to endolysosomal escape of DNPs. Additionally, DNPs can interact with a cytosolic ileal bile acid-binding protein that facilitates the intracellular trafficking and basolateral release of insulin. In rats, intravital two-photon microscopy also reveals that the transport of DNPs into the intestinal villi is mediated by ASBT. Further pharmacokinetic studies disclose an oral bioavailability of 15.9% in type I diabetic rats after loading freeze-dried DNPs into enteric-coated capsules. Thus, deoxycholic acid-modified chitosan nanoparticles can overcome multiple barriers of the intestinal epithelium for oral delivery of insulin.
KW - Journal Article
U2 - 10.1016/j.biomaterials.2017.10.022
DO - 10.1016/j.biomaterials.2017.10.022
M3 - Journal article
C2 - 29055774
VL - 151
SP - 13
EP - 23
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
ER -
ID: 185402866