Multi-ion-crosslinked nanoparticles with pH-responsive characteristics for oral delivery of protein drugs

Yu Hsin Lin, Kiran Sonaje, Kurt M. Lin, Jyuhn Huarng Juang, Fwu Long Mi, Han Wen Yang, Hsing Wen Sung

Research output: Contribution to journalArticlepeer-review

167 Citations (Scopus)


pH-Responsive nanoparticles composed of chitosan (CS) and poly-γ-glutamic acid (γ-PGA) blended with tripolyphosphate (TPP) and MgSO4 (multi-ion-crosslinked NPs) were prepared and characterized to determine their effectiveness in the oral delivery of insulin. Their counterparts without TPP and MgSO4 (NPs) were used as a control. FT-IR and XRD results indicated that the spontaneous interaction between CS, insulin, γ-PGA, MgSO4 and TPP can form an ionically crosslinked network-structure, leading to the formation of nanoparticles. Multi-ion-crosslinked NPs were more compact than NPs, while their zeta potential values were comparable. During storage, multi-ion-crosslinked NPs suspended in deionized water were stable for at least 10 weeks. Multi-ion-crosslinked NPs had a superior stability over a broader pH range than NPs. In the in vitro release study, NPs failed to provide an adequate retention of loaded insulin in dissolution media compared to multi-ion-crosslinked NPs. Transepithelial-electrical-resistance and transport experiments demonstrated that multi-ion-crosslinked NPs significantly more effectively transported insulin than NPs; confocal visualization further validated the enhanced permeation of insulin via the paracellular pathway. The aforementioned results suggest that multi-ion-crosslinked NPs are a promising carrier for improved transmucosal delivery of insulin in the small intestine.

Original languageEnglish
Pages (from-to)141-149
Number of pages9
JournalJournal of Controlled Release
Issue number2
Publication statusPublished - Dec 8 2008
Externally publishedYes


  • Insulin
  • Nanoparticles
  • Oral delivery
  • Paracellular transport
  • Tight junction

ASJC Scopus subject areas

  • Pharmaceutical Science


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