title: Enhanced transport of nanocage stabilized pure nanodrug across intestinal epithelial barrier mimicking Listeria monocytogenes.
abstract: Ligand grafted nanoparticles have been shown to enhance drug transport across epithelium barrier and are expected to improve drug delivery. However, grafting of these ligands to the surface of pure nanodrug, i.e., nanocrystals (NCs), is a critical challenge due to the shedding of ligands along with the stabilizer upon high dilution or dissolving of the drug. Herein, a non-sheddable nanocage-like stabilizer was designed by covalent cross-linking of poly(acrylic acid)-b-poly(methyl acrylate) on drug nanocrystal surface, and a ligand, wheat germ agglutinin (WGA), was successfully anchored to the surface of itraconazole (ITZ) NCs by covalent conjugation to the nanocage (WGA-cage-NCs). The cellular study showed that large amount of WGA-cage-NCs were adhered to Caco-2 cell membrane, and invaded into cells, resulting in a higher drug uptake than that of ordinary NCs (ONCs). After oral administration to rats, WGA-cage-NC were largely accumulated on the apical side of epithelium cells, facilitating drug diffusing across epithelium barrier. Interestingly, WGA-cage-NCs were capable of invading rat intestinal villi and reaching to lamina propria by transcytosis across goblet cells, which behaved like a foodborne pathogen, Listeria monocytogenes. The WGA-cage-NCs showed an improved oral bioavailability, which was 17.5- and 2.41-folds higher than that of coarse crystals and ONCs, respectively. To our best knowledge, this may represent the first report that a functional ligand was successfully anchored to the surface of pure nanodrug by using a cage-like stabilizer, showing unique biological functions in gastrointestinal tract and having an important significance in oral drug delivery.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Dengning
authors.initials: D
authors.lastname: Xia
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; Department of Pharmacy, Medical College of Nanchang University, 461 Bayi Road, Nanchang 330066, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Tao
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; Department of Pharmaceutics, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Quanlei
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Miaorong
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Fude
authors.initials: F
authors.lastname: Cui
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China. Electronic address: simm2122@vip.sina.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gan
mesh_terms: D065567:Absorption, Physiological / Q000187:drug effects; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D004705:Endocytosis / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017964:Itraconazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008089:Listeria monocytogenes / Q000502:physiology*; D008297:Male; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D017207:Rats, Sprague-Dawley; D055672:Static Electricity; D014909:Wheat Germ Agglutinins / Q000737:chemistry
chemical_list: D014909:Wheat Germ Agglutinins; D017964:Itraconazole
keywords: Epithelial barrier; Goblet cells; Nanocage; Nanocrystals; Wheat germ agglutinin