Injectable insulin-lysozyme-loaded nanogels with enzymatically-controlled degradation and release for basal insulin treatment: In vitro characterization and in vivo observation

Abstract

Diabetes is a common global disease that causes immense suffering for individuals and huge costs for the health care system. To minimize complications such as organ degeneration, diabetic patients are required to undergo treatments to maintain the blood glucose level in the normal range, ideally mimicking normal insulin secretion. The normal physiological insulin secretion pattern in healthy individuals consists of a base (basal) level through the day and increased secretion after meals (bolus insulin). Thus effective treatments may combine long acting, low-level insulin therapy with boosts of short acting insulin and/or oral agents. To achieve long term management of basal insulin level, an injectable insulin-loaded gel composed of self-assembled nanoparticles from carboxymethyl-hexanoyl chitosan (CHC) and integrated lysozyme for controlled biodegradation and insulin release was developed. In vitro characterizations and evaluations confirmed that lysozyme was active on CHC and that the amount of lysozyme in a CHC hydrogel determined the degradation and insulin release rate. The degradation products were found to be highly cytocompatible using a cell assay. In vivo evaluation of the system in a diabetic mouse model revealed that the fasted blood glucose level could be maintained in the normal range for 10 days with a single injection of insulin-loaded CHC-lysozyme gel. The insulin-loaded CHC-lysozyme gels clearly show promise for use as a novel injectable long-acting insulin delivery system, with potential to manage the basal insulin level for many days with a single injection. (C) 2015 Elsevier B.V. All rights reserved.