Biodistribution, activation, and retention of proinsulin-transferrin fusion protein in the liver: Mechanism of liver-targeting as an insulin prodrug

Journal of Controlled Release : Official Journal of the Controlled Release Society
Yuqian LiuWei-Chiang Shen

Abstract

A recombinant proinsulin-transferrin fusion protein (ProINS-Tf) has been previously reported to be a novel long-lasting INS analog, acting specifically on the inhibition of hepatic glucose output. In this study, we investigated the biodistribution, activation and tissue retention of ProINS-Tf to elucidate its liver targeted anti-diabetic mechanism. The biodistribution study revealed that ProINS-Tf exhibited liver specific accumulation after a single intravenous injection, whereas transferrin (Tf) or insulin (INS) showed relatively even distribution among different organs. The conversion of inactive ProINS-Tf into an active immune-reactive INS-Tf form (irINS-Tf) via a Tf receptor (TfR) mediated process only occurred in the liver, but not in other organs. In addition, ProINS-Tf demonstrated a prolonged retention in the liver after an intravenous injection, suggesting the enhanced association of the bifunctional active form, irINS-Tf, within liver cells. Taken together, our results indicate that ProINS-Tf is a highly liver-targeted INS prodrug with a combination of 3 specific actions in liver cells: (1) TfR-mediated binding and uptake of the prodrug on the cell surface, (2) liver-specific, TfR-mediated conversion of the prodrug in...Continue Reading

Related Concepts

Related Feeds

Autoimmune Diabetes & Tolerance

Patients with type I diabetes lack insulin-producing beta cells due to the loss of immunological tolerance and autoimmune disease. Discover the latest research on targeting tolerance to prevent diabetes.