Glucose-Responsive Nanoparticles for Rapid and Extended Self-Regulated Insulin Delivery

Abstract

To mimic native insulin activity, materials have been developed that encapsulate insulin, glucose oxidase, and catalase for glucose-responsive insulin delivery. A major challenge, however, has been achieving the desired kinetics of both rapid and extended release. Here, we tune insulin release profiles from polymeric nanoparticles by altering the degree of modification of acid-degradable, acetalated-dextran polymers. Nanoparticles synthesized from dextran with a high acyclic acetal content (94% of residues) show rapid release kinetics, while nanoparticles from dextran with a high cyclic acetal content (71% of residues) release insulin more slowly. Thus, coformulation of these two materials affords both rapid and extended glucose-responsive insulin delivery. In vivo analyses using both streptozotocin-induced type 1 diabetic and healthy mouse models indicate that this delivery system has the ability to respond to glucose on a therapeutically relevant time scale. Importantly, the concentration of human insulin in mouse serum is enhanced more than 3-fold with elevated glucose levels, providing direct evidence of glucose-responsiveness in animals. We further show that a single subcutaneous injection provides 16 h of glycemic control in diabetic mice. We believe the nanoparticle formulations developed here may provide a generalized strategy for the development of glucose-responsive insulin delivery systems.

Engineering precision nanoparticles for drug delivery

“…This enables delivery of various payloads including hydrophobic and hydrophilic compounds, as well as cargos with different molecular weights such as small molecules, biological macromolecules, proteins and vaccines [30][31][32][33][34][35] , making polymeric NPs ideal for co-delivery applications 36 . By modulating properties such as composition, stability, responsivity and surface charge, the loading efficacies and release kinetics of these therapeutics can be precisely controlled 37,38 .…”

Smart Nanomaterials for Biomedical Applications—A Review

“…The response to the pH change is a volume transition of the polymer, and in this manner, the body's glucose level is driven by conformational polymer changes [115]. Some authors synthesized acetalated dextran nanoparticles or acryloyl cross-linked dextran dialdehyde (ACDD) nanocarriers containing enzymes and insulin to facilitate glucose-sensitive release [103,116]. Boronic acid-derived hydrogels were used to obtain glucosesensitive platforms for drug delivery [104,117].…”

Bioresponsive drug delivery systems for the treatment of inflammatory diseases

“…Fréchet et al also reported facile synthesis of acid-responsive materials by acetalation of dextran using 2-methoxypropene or other functional molecules [ [163] , [164] , [165] ]. Thus obtained acetalated dextran polymers have been examined for encapsulation and pH-triggerable release of small molecules, nucleotides, and proteins in the forms of nanoparticles or microparticles [ 164 , [166] , [167] , [168] , [169] ]. Our group demonstrated that kinetically controlled acetalation can be carried out for cyclic oligosaccharides, such as α-CD, β-CD, and their polymers, thereby affording a series of acid-labile biocompatible materials [ 170 , 171 ].…”