Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery

doi:10.1016/j.biomaterials.2017.10.022

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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 1,5; Xia, Dengning 1; Zhu, Quanlei 1; Li, Xiuying 4; He, Shufang 1,5; Zhu, Chunliu1 ; Guo, Shiyan 1; Hovgaard, Lars 3; Yang, Mingshi 2; Gan, Yong1,5
刊名	BIOMATERIALS
	2018-01
卷号	151 页码:13-23
关键词	Oral delivery Insulin Functional nanoparticles Bile acid pathway Intestinal epithelium Endolysosomal escape
ISSN号	0142-9612
DOI	10.1016/j.biomaterials.2017.10.022
文献子类	Article
英文摘要	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 trans epithelial 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 mono layers, 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 ASST. 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. (C) 2017 Elsevier Ltd. All rights reserved.
资助项目	National Natural Science Foundation of China[81373356] ; National Natural Science Foundation of China[81573378] ; "Science and technology innovation action plan for basic research" of Shanghai, Chinese Academy of Sciences Key Technology Talent[14JC1493200] ; Novo Nordisk-Chinese Academy of Sciences Research Foundation[NNCAS-2012-4] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120153020]
WOS关键词	DRUG-DELIVERY ; POLYMERIC NANOPARTICLES ; DEOXYCHOLIC-ACID ; BIODEGRADABLE NANOPARTICLES ; MEDIATED ENDOCYTOSIS ; CELLULAR UPTAKE ; SIRNA DELIVERY ; IN-VITRO ; TRANSPORT ; ABSORPTION
WOS研究方向	Engineering ; Materials Science
语种	英语
出版者	ELSEVIER SCI LTD
WOS记录号	WOS:000416190500002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272349]
专题	药物制剂研究中心
通讯作者	Gan, Yong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen, Denmark 3.Novo Nordisk AS, Oral Formulat Dev, DK-2760 Malov, Denmark; 4.Univ Texas Dallas, Dept Mech Engn, Richardson, TX 75080 USA; 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
推荐引用方式 GB/T 7714	Fan, Weiwei,Xia, Dengning,Zhu, Quanlei,et al. Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery[J]. BIOMATERIALS,2018,151:13-23.
APA	Fan, Weiwei.,Xia, Dengning.,Zhu, Quanlei.,Li, Xiuying.,He, Shufang.,...&Gan, Yong.(2018).Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery.BIOMATERIALS,151,13-23.
MLA	Fan, Weiwei,et al."Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery".BIOMATERIALS 151(2018):13-23.