Preventive Effects of Thermosensitive Biopolymer‐Conjugated C‐Peptide against High Glucose‐Induced Endothelial Cell Dysfunction

: C-peptide has emerged as a potential drug for treating diabetic complications. However, clinical application of C-peptide is limited by its short half-life during circulation and costly synthesis methods. To overcome these limitations, a biocompatible and thermosensitive biopolymer-C-peptide conjugate composed of human C-peptide genetically conjugated at the C-terminus of nine repeats of lysine-containing elastin-like polypeptide (K9-C-peptide) is generated. K9-C-peptide exhibits reversible thermal phase behavior with a transition temperature dependent on polypeptide concentration. Degradation of K9-C-peptide hydrogel depends on the concentration of four cleavage enzymes as well as the reaction time and frequency of treatments with elastase-2. The preventive effect of K9-C-peptide against high glucose-induced human aortic endothelial cell dysfunction is further investigated. K9-C-peptide inhibits high glucose-induced intracellular reactive oxygen species generation, transglutaminase 2 activation, and apoptosis, similar to the inhibitory effects of human C-peptide. Thus, K9-C-peptide is a potential drug depot for the sustained delivery of C-peptide to treat diabetic complications.