Oral Delivery of Peptide Drugs Using Nanoparticles Self-Assembled by Poly(γ-glutamic acid) and a Chitosan Derivative Functionalized by Trimethylation
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- 作者：Fwu-Long Mi ; Yong-Yi Wu ; Yu-Hsin Lin ; Kiran Sonaje ; Yi-Cheng Ho ; Chiung-Tong Chen ; Jyuhn-Huarng Juang ; Hsing-Wen Sung
- 刊名：Bioconjugate Chemistry
- 出版年：2008
- 出版时间：June 2008
- 年：2008
- 卷：19
- 期：6
- 页码：1248 - 1255
- 全文大小：2391K
- 年卷期：v.19,no.6(June 2008)
- ISSN：1520-4812
文摘
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.
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.