Oral delivery of peptide drugs using nanoparticles self-assembled by poly(γ-glutamic acid) and a chitosan derivative functionalized by trimethylation

Fwu Long Mi, Yong Yi Wu, Yu Hsin Lin, Kiran Sonaje, Yi Cheng Ho, Chiung Tong Chen, Jyuhn Huarng Juang, Hsing Wen Sung

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

In the study, chitosan (CS) was conjugated with trimethyl groups for the synthesis of N-trimethyl chitosan (TMC) polymers with different degrees of quaternization. Nanoparticles (NPs) self-assembled by the synthesized TMC and poly(γ-glutamic acid) (γ-PGA, TMC/γ-PGA NPs) were prepared for oral delivery of insulin. The loading efficiency and loading content of insulin in TMC/γ-PGA NPs were 73.8 ± 2.9% and 23.5 ± 2.1%, respectively. TMC/γ-PGA NPs had superior stability in a broader pH range to CS/γ-PGA NPs; the in vitro release profiles of insulin from both test NPs were significantly affected by their stability at distinct pH environments. At pH 7.0, CS/γ-PGA NPs became disintegrated, resulting in a rapid release of insulin, which failed to provide an adequate retention of loaded insulin, while the cumulative amount of insulin released from TMC/γ-PGA NPs was significantly reduced. At pH 7.4, TMC/γ-PGA NPs were significantly swelled and a sustained release profile of insulin was observed. Confocal microscopy confirmed that TMC40/γ-PGA NPs opened the tight junctions of Caco-2 cells to allow the transport of insulin along the paracellular pathway. Transepithelial-electrical-resistance measurements and transport studies implied that CS/γ-PGA NPs can be effective as an insulin carrier only in a limited area of the intestinal lumen where the pH values are close to the pKa of CS. In contrast, TMC40/γ-PGA NPs may be a suitable carrier for transmucosal delivery of insulin within the entire intestinal tract.

Original languageEnglish
Pages (from-to)1248-1255
Number of pages8
JournalBioconjugate Chemistry
Volume19
Issue number6
DOIs
Publication statusPublished - Jun 2008
Externally publishedYes

Fingerprint

Prostaglandins A
Chitosan
Nanoparticles
Insulin
Peptides
Glutamic Acid
Derivatives
Acids
Pharmaceutical Preparations
Acoustic impedance
Caco-2 Cells
Confocal microscopy
Tight Junctions
Electric Impedance
Confocal Microscopy
Polymers

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Oral delivery of peptide drugs using nanoparticles self-assembled by poly(γ-glutamic acid) and a chitosan derivative functionalized by trimethylation. / Mi, Fwu Long; Wu, Yong Yi; Lin, Yu Hsin; Sonaje, Kiran; Ho, Yi Cheng; Chen, Chiung Tong; Juang, Jyuhn Huarng; Sung, Hsing Wen.

In: Bioconjugate Chemistry, Vol. 19, No. 6, 06.2008, p. 1248-1255.

Research output: Contribution to journalArticle

Mi, Fwu Long ; Wu, Yong Yi ; Lin, Yu Hsin ; Sonaje, Kiran ; Ho, Yi Cheng ; Chen, Chiung Tong ; Juang, Jyuhn Huarng ; Sung, Hsing Wen. / Oral delivery of peptide drugs using nanoparticles self-assembled by poly(γ-glutamic acid) and a chitosan derivative functionalized by trimethylation. In: Bioconjugate Chemistry. 2008 ; Vol. 19, No. 6. pp. 1248-1255.
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abstract = "In the study, chitosan (CS) was conjugated with trimethyl groups for the synthesis of N-trimethyl chitosan (TMC) polymers with different degrees of quaternization. Nanoparticles (NPs) self-assembled by the synthesized TMC and poly(γ-glutamic acid) (γ-PGA, TMC/γ-PGA NPs) were prepared for oral delivery of insulin. The loading efficiency and loading content of insulin in TMC/γ-PGA NPs were 73.8 ± 2.9{\%} and 23.5 ± 2.1{\%}, respectively. TMC/γ-PGA NPs had superior stability in a broader pH range to CS/γ-PGA NPs; the in vitro release profiles of insulin from both test NPs were significantly affected by their stability at distinct pH environments. At pH 7.0, CS/γ-PGA NPs became disintegrated, resulting in a rapid release of insulin, which failed to provide an adequate retention of loaded insulin, while the cumulative amount of insulin released from TMC/γ-PGA NPs was significantly reduced. At pH 7.4, TMC/γ-PGA NPs were significantly swelled and a sustained release profile of insulin was observed. Confocal microscopy confirmed that TMC40/γ-PGA NPs opened the tight junctions of Caco-2 cells to allow the transport of insulin along the paracellular pathway. Transepithelial-electrical-resistance measurements and transport studies implied that CS/γ-PGA NPs can be effective as an insulin carrier only in a limited area of the intestinal lumen where the pH values are close to the pKa of CS. In contrast, TMC40/γ-PGA NPs may be a suitable carrier for transmucosal delivery of insulin within the entire intestinal tract.",
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AU - Mi, Fwu Long

AU - Wu, Yong Yi

AU - Lin, Yu Hsin

AU - Sonaje, Kiran

AU - Ho, Yi Cheng

AU - Chen, Chiung Tong

AU - Juang, Jyuhn Huarng

AU - Sung, Hsing Wen

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AB - In the study, chitosan (CS) was conjugated with trimethyl groups for the synthesis of N-trimethyl chitosan (TMC) polymers with different degrees of quaternization. Nanoparticles (NPs) self-assembled by the synthesized TMC and poly(γ-glutamic acid) (γ-PGA, TMC/γ-PGA NPs) were prepared for oral delivery of insulin. The loading efficiency and loading content of insulin in TMC/γ-PGA NPs were 73.8 ± 2.9% and 23.5 ± 2.1%, respectively. TMC/γ-PGA NPs had superior stability in a broader pH range to CS/γ-PGA NPs; the in vitro release profiles of insulin from both test NPs were significantly affected by their stability at distinct pH environments. At pH 7.0, CS/γ-PGA NPs became disintegrated, resulting in a rapid release of insulin, which failed to provide an adequate retention of loaded insulin, while the cumulative amount of insulin released from TMC/γ-PGA NPs was significantly reduced. At pH 7.4, TMC/γ-PGA NPs were significantly swelled and a sustained release profile of insulin was observed. Confocal microscopy confirmed that TMC40/γ-PGA NPs opened the tight junctions of Caco-2 cells to allow the transport of insulin along the paracellular pathway. Transepithelial-electrical-resistance measurements and transport studies implied that CS/γ-PGA NPs can be effective as an insulin carrier only in a limited area of the intestinal lumen where the pH values are close to the pKa of CS. In contrast, TMC40/γ-PGA NPs may be a suitable carrier for transmucosal delivery of insulin within the entire intestinal tract.

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