Potential Use of Gamma-cyclodextrin Polypseudorotaxane Hydrogels As an Injectable Sustained Release System for Insulin

The development of injectable hydrogels for protein delivery is a major challenge. In this study, insulin/alpha-cyclodextrin (alpha-CyD) and gamma-CyD polypseudorotaxane (PPRX) hydrogels were prepared through inclusion complexation between high molecular weight poly(ethylene glycol) (PEG) and CyDs. The alpha-CyD and gamma-CyD PPRX hydrogels were formed by inserting one PEG chain in the alpha-CyD cavity and two PEG chains in the gamma-CyD cavity. Insulin/CyD PPRX hydrogel formation was based on physical crosslinking induced by self-assembling without chemical crosslinking reagent. The supramolecular structures of insulin/CyD PPRX hydrogels were confirmed with (1)H nuclear magnetic resonance ((1)H NMR), X-ray diffraction, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release study showed that the release rate of insulin from the CyDs PPRX hydrogels decreased in the order of gamma-CyD PPRX hydrogel>alpha-CyD PPRX hydrogel. This decrease was controlled by the addition of CyDs to the medium. The serum insulin level after subcutaneous administration of gamma-CyD PPRX hydrogel to rats was significantly prolonged, accompanying with an increase in the area under serum concentration-time curve, which was clearly reflected in the prolonged hypoglycemic effect. In conclusion, these results suggest the potential use of gamma-CyD PPRX hydrogel as an injectable sustained release system for insulin.