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

pH-Responsive nanoparticles composed of chitosan (G) and poly-gamma-glutamic acid (-y-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. Fr-IR and XRD results indicated that the spontaneous interaction between CS, insulin, gamma-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. (C) 2008 Elsevier B.V. All rights reserved.