Establishment of controlled insulin delivery system using glucose-responsive nanogel

Abstract

Glucose-responsive insulin delivery systems have been recently proposed as a promising alternative to conventional intravascular administration methods, which causes much inconvenience and has been related to low patient compliance due to its controlled release characteristics. However, protein-based glucose-responsive systems using glucose oxidase and lectin poses many hurdles in passing through clinical trials because of their low biostability and potential cytotoxicity. In order to overcome such issues, the phenylboronic acid (PBA)-derivatives acting as a glucose-responsive functional group by a change from hydrophobic to hydrophilic moiety have played a key role in controlled insulin release systems due to their better biostability and high biocompatibility. In order to endow a glucose-responsive characteristic to insulin delivery carriers using PBA derivatives, glycol chitosan (GC)/sodium alginate (SA)-poly (L-glutmate-co-N-3-L-glutamylphenylboronic acid) (PGGA) graft polymer double-layered nanogel were synthesized by N-carboxyanhydride polymerization and carbodiimide coupling reactions. GC/SA-PGGA double-layered nanogel controllably releases insulin at diabetic glucose levels in vitro, and has high biocompatibility, as determined by cell viability and hemolysis assay. Moreover, controlled insulin release at high glucose levels were accomplished using GC/SA-PGGA double-layered nanogel in mouse studies. Therefore, GC/SA-PGGA double-layered nanogel characterized by effective glucose-sensitivity and superior biocom-patibility may act as a potential platform for the enhancement of conventional insulin delivery systems.