Fabrication and evaluation of reduction-sensitive supramolecular hydrogel based on cyclodextrin/polymer inclusion for injectable drug-carrier application

Supramolecular hydrogels based on cyclodextrin/polymer inclusion are an emerging injectable biomaterial for drug controlled-release and cell capsulation. Although the pH- and temperature-sensitivity has been focused on contributing to intelligence, the system sensitive to physiological reduction condition caused by glutathione tripepetide (GSH) has not been reported so far. In this work, novel reduction-sensitive supramolecular hydrogels were, for the first time, fabricated by the inclusion of [poly(ethylene glycol) monomethyl ether]-graft-[disulfide-linked poly(amido amine)] (mPEG-g-SS-PAA) with alpha-cyclodextrin (alpha-CD) in aqueous solution. The reduction-sensitivity was ascribed to the disulfide linker in the SS-PAA main chain while various physical conjugations contributed to a reversible gel-sol transition under shearing as a key of injectable function. The drug release from such a supramolecular hydrogel showed a prominent sustained release profile, and the release rate could further be regulated depending upon the reduction condition. It is worth noting that incorporating a low loading-level of reducing agent did not inhibit the formation of hydrogel. As a result, it became possible to use the reduction-sensitivity to regulate the drug release profile in extracellular milieus and normal tissue. Combined with acceptable cytotoxicity, this kind of reduction-sensitive supramolecular hydrogel based on cyclodextrin/polymer inclusion showed a great potential as an injectable smart biomaterial for the application of drug controlled-release.