Cyclodextrin-based sustained and controllable release system of insulin utilizing the combination system of self-assembly PEGylation and polypseudorotaxane formation

•Combination system of cyclodextrin-based supramolecular drug delivery technologies.•Sustained and controllable release system for insulin.•Evaluation of cyclodextrin-based supramolecular drug carriers in vitro and in vivo. Sustained and controllable release of insulin is strongly required to achieve the ideal treatment of diabetes. We previously developed “self-assembly PEGylation retaining activity (SPRA) technology” via a host–guest interaction between PEGylated β-cyclodextrin and adamantane-appended insulin, and resulting PEGylated insulin was termed SPRA-insulin. So far, we also demonstrated that covalently PEGylated insulin forms polypseudorotaxanes (PPRXs) with cyclodextrins (PPRX technology). In the present study, we designed and evaluated the combination system of SPRA technology and PPRX technology to achieve a sustained and controllable release system of insulin. SPRA-insulin formed PPRXs with α-cyclodextrin and γ-cyclodextrin. In addition, SPRA-insulin/cyclodextrin PPRXs provided sustained and controllable release of insulin beyond the each single technology both in vitro and in vivo. These results suggest that the combination system of SPRA technology and PPRX technology is useful for design of a sustained and controllable release system of insulin.