Globally, there are over 420 million people living with diabetes, who suffer from impaired regulation of hepatic glucose production, which eventually leads to β-cell failure. Current insulin treatments are highly burdensome, resulting in poor patient compliance, and can sometimes cause dangerous hypoglycemic events. In contrast, treatment strategies based on glucagon-like peptide-1 (GLP-1), an incretin hormone secreted from the intestinal L-cells, reduce the risk of hypoglycemia by stimulating insulin and decreasing glucagon secretion in a glucose-dependent manner. Unfortunately, current GLP-1 receptor agonists (GLP-1 RAs) must be administered either daily (Liraglutide) or weekly (Semaglutide), which results in significant patient burden and reduced patient compliance. For this purpose, we have developed a novel injectable hydrogel technology that forms through dynamic, supramolecular interactions between biodegradable nanoparticles and modified hydroxypropyl methylcellulose (HPMC) polymers. Our work aims to use this injectable depot technology as the foundation of a long-acting GLP-1 RA drug product providing 4-months of therapy per administration. Here, we exploit fatty acid moieties on Semaglutide to non-covalently embed the molecules within the hydrogel network during fabrication. We demonstrate the ability of hydrogel-based depot delivery to prolong the pharmacokinetics of Semaglutide in rat models and compare efficacy against repeated bolus dosing. We also evaluate the effect of network density, hydrophobicity of modifications to HPMC, and hydrophobic surface area of nanoparticles on cargo diffusivity and release kinetics, showing that they are highly tunable to accommodate the properties of the payload and the desired timing of its release. Overall, we anticipate this work will catalyze the development of a GLP-1 RA depot drug product for the management of diabetes by dramatically reducing the frequency of therapeutic interventions, significantly increasing patient quality of life and affording thus far unrealized therapeutic impact.

Polymer-nanoparticle hydrogels for prolonged release of GLP-1 biopharmaceuticals to improve diabetes treatment

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.