title: Efficient Peroral Delivery of Insulin via Vitamin B12 Modified Trimethyl Chitosan Nanoparticles.
abstract: OBJECTIVE
  We investigated the effect of vitamin B12 (VB12) modification on the insulin absorption from trimethyl chitosan(TMC) nanoparticles (NPs) under the inﬂuence of mucus.
  
  
  METHODS
  TMC and TMC-VB12 were synthesized and insulin loaded TMC/TMC-VB12 nanoparticles were prepared and characterized. Modified and unmodified nanoparticles were studied with Caco-2/HT29-MTX cell model and ligated rat ileum loop.
  
  
  RESULTS
  Compared with unmodified NPs, VB12 modified NPs showed signiﬁcantly higher drug internalization in Caco-2/HT29-MTX cell model. The internalization mechanism via VB12 mediation included caveolae and clathrin-mediated endocytosis pathway. Meanwhile, an increased transportation of drugs was observed for VB12 modified NPs, possibly due to the ligand-receptor interaction via an intrinsic factor-dependent fashion. Although the uptake and transport of VB12 modiﬁed NPs could be partially inﬂuenced by mucus, they still showed higher drug permeation through Caco-2/HT29-MTX co-cultured cells than unmodified NPs in the presence or absence of mucus. Moreover, in situ study in ligated rat ileum loop demonstrated that VB12 modiﬁed nanoparticles could reduce the residual insulin in intestinal lumen (0.59 times) and increase their absorption in epithelial tissue (4.8 times) compared with the unmodified ones.
  
  
  CONCLUSIONS
  VB12 modiﬁed trimethyl chitosan nanoparticle is a promising carrier for peroral delivery of insulin.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery, Ministry of Education, Sichuan University, Chengdu, P.C. China.
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Ke
authors.forename: Han
authors.initials: H
authors.lastname: Guo
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.forename: Yun
authors.initials: Y
authors.lastname: Jin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002478:Cells, Cultured; D048271:Chitosan / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D019073:HT29 Cells; D006801:Humans; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000737:chemistry; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014805:Vitamin B 12 / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D007328:Insulin; C118071:N-trimethyl chitosan chloride; D048271:Chitosan; D014805:Vitamin B 12