title: Intestinal mucosa permeability following oral insulin delivery using core shell corona nanolipoparticles.
abstract: Chitosan nanoparticles (NC) have excellent capacity for protein entrapment, favorable epithelial permeability, and are regarded as promising nanocarriers for oral protein delivery. Herein, we designed and evaluated a class of core shell corona nanolipoparticles (CSC) to further improve the absorption through enhanced intestinal mucus penetration. CSC contains chitosan nanoparticles as a core component and pluronic F127-lipid vesicles as a shell with hydrophilic chain and polyethylene oxide PEO as a corona. These particles were developed by hydration of a dry pluronic F127-lipid film with NC suspensions followed by extrusion. Insulin nested inside CSC was well protected from enzymatic degradation. Compared with NC, CSC exhibited significantly higher efficiency of mucosal penetration and, consequently, higher cellular internalization of insulin in mucus secreting E12 cells. The cellular level of insulin after CSC treatment was 36-fold higher compared to treatment with free insulin, and 10-fold higher compared to NC. CSC significantly facilitated the permeation of insulin across the ileum epithelia, as demonstrated in an ex vivo study and an in vivo absorption study. CSC pharmacological studies in diabetic rats showed that the hypoglycemic effects of orally administrated CSC were 2.5-fold higher compared to NC. In conclusion, CSC is a promising oral protein delivery system to enhance the stability, intestinal mucosal permeability, and oral absorption of insulin.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Li
authors.forename: Shiyan
authors.initials: S
authors.lastname: Guo
authors.forename: Chunliu
authors.initials: C
authors.lastname: Zhu
authors.forename: Quanlei
authors.initials: Q
authors.lastname: Zhu
authors.forename: Yong
authors.initials: Y
authors.lastname: Gan
authors.forename: Jukka
authors.initials: J
authors.lastname: Rantanen
authors.forename: Ulrik Lytt
authors.initials: UL
authors.lastname: Rahbek
authors.forename: Lars
authors.initials: L
authors.lastname: Hovgaard
authors.forename: Mingshi
authors.initials: M
authors.lastname: Yang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D048271:Chitosan / Q000737:chemistry*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D016503:Drug Delivery Systems; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D010539:Permeability; D020442:Poloxamer / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D020442:Poloxamer; D011092:Polyethylene Glycols; D048271:Chitosan
keywords: Cellular uptake; Core shell corona; Insulin; Mucus penetrating particles; Oral protein delivery