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

• Published in: Biomaterials Vol. 151; pp. 13 - 23
• Main Authors: Fan, Weiwei, Xia, Dengning, Zhu, Quanlei, Li, Xiuying, He, Shufang, Zhu, Chunliu, Guo, Shiyan, Hovgaard, Lars, Yang, Mingshi, Gan, Yong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.01.2018
• Subjects: Administration, Oral; Animals; Bile acid pathway; Bile Acids and Salts; Biological Availability; Caco-2 Cells; Cardiovascular System - metabolism; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Chitosan - chemistry; Deoxycholic Acid - chemistry; Deoxycholic Acid - metabolism; Diabetes Mellitus, Experimental - drug therapy; Drug Carriers - chemistry; Drug Liberation; Drug Trafficking; Endolysosomal escape; Functional nanoparticles; Humans; Insulin; Insulin - administration & dosage; Insulin - adverse effects; Insulin - pharmacokinetics; Insulin - pharmacology; Intestinal epithelium; Intestinal Mucosa - metabolism; Male; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Mucus - metabolism; Nanoparticles - chemistry; Oral delivery; Organic Anion Transporters, Sodium-Dependent - chemistry; Organic Anion Transporters, Sodium-Dependent - metabolism; Particle Size; Permeability; Rats, Sprague-Dawley; Surface Properties; Symporters - chemistry; Symporters - metabolism; Functional nanoparticles; Bile acid pathway; Intestinal epithelium; Insulin; Oral delivery; Endolysosomal escape
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2017.10.022

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. [Display omitted]