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

Publication date: January 2018
Source:Biomaterials, Volume 151
Author(s): Weiwei Fan, Dengning Xia, Quanlei Zhu, Xiuying Li, Shufang He, Chunliu Zhu, Shiyan Guo, Lars Hovgaard, Mingshi Yang, Yong Gan
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.

Graphical abstract

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