Effects of pH on molecular mechanisms of chitosan-integrin interactions and resulting tight-junction disruptions

Li Wen Hsu, Yi Cheng Ho, Er-Tuan Chuang, Chiung Tong Chen, Jyuhn Huarng Juang, Fang Yi Su, Shiaw Min Hwang, Hsing Wen Sung

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Chitosan (CS) is a potential paracellular permeation enhancer for trans-epithelial drug delivery; however, its ability to enhance epithelial permeability in a pH-dependent manner remains unclear. This study was designed to explore the underlying molecular mechanisms with regard to the effect of CS on tight junction (TJ) disruption at different pH environments in Caco-2 cell monolayers. The experimental results revealed that the direct interaction between CS and integrin αVβ3 on cell surfaces has a crucial role in CS-induced TJ opening, an indication of receptor activation. The mechanism of action appeared to be the electrostatic interaction between the positively-charged CS and the negatively-charged integrin αVβ3. This electrostatic interaction led to the conformation change of integrin αVβ3 and its clustering along the cell border, F-actin reorganization, and CLDN4 down-regulation, eventually resulting in the disruption of TJs and an increase in paracellular permeability. The above observations were all in a pH-dependent manner. As pH increased, CS became less positively charged, thereby losing its capability to interact with integrin αVβ3 and failing to induce the TJ opening. These consequences might help to better understand the molecular mechanism of TJ opening mediated by CS, thereby facilitating the use of CS for trans-epithelial drug delivery.

Original languageEnglish
Pages (from-to)784-793
Number of pages10
JournalBiomaterials
Volume34
Issue number3
DOIs
Publication statusPublished - Jan 2013
Externally publishedYes

Keywords

  • Chitosan
  • Integrin receptor
  • Oral drug delivery
  • Paracellular permeability
  • Tight junction

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

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