In Situ-Forming Protein-Polymer Hydrogel for Glucose-Responsive Insulin Release

Abstract

Phenylboronic acid (PBA)-containing hydrogels (HGs), capable of glucose-responsive insulin release, have shown promise in diabetes management in preclinical studies. However, sustainable material usage and attaining an optimum insulin release profile pose a significant challenge in such HG design. Herein, we present the development of a straightforward fabrication strategy for glucose-responsive protein-polymer hybrid HGs (PPHGs). We prepare PPHGs by crosslinking polyvinyl alcohol (PVA) with various nature-abundant proteins, such as bovine serum albumin (BSA), egg albumin, casein, whey protein, and so forth, using formylphenylboronic acid (FPBA)-based crosslinkers. We showcase PPHGs with diverse bulk rheological properties that are appropriately modulated by the positions of aldehyde, boronic acid, and fluorine substitutions in the FPBA-crosslinker. The orthogonal imine and boronate ester bonds formed by FPBAs are susceptible to the acidic pH environment and glucose concentrations, leading to the glucose-responsive dissolution of the PPHGs. We further demonstrate that by an appropriate selection of FPBAs, glucose-responsive insulin release profiles of the PPHGs can be precisely engineered at the molecular level. Importantly, PPHGs are injectable, incur no cytotoxicity, and, therefore, hold great potential as smart insulin for in vivo applications in the near future.

Controlled Interfacial Polymer Self‐Assembly Coordinates Ultrahigh Drug Loading and Zero‐Order Release in Particles Prepared under Continuous Flow

“…Recently, Ali et al developed a straightforward strategy to fabricate glucose-responsive protein-polymer hybrid hydrogels by cross-linking poly(vinyl alcohol) with various proteins using formylphenylboronic-acid-based crosslinkers. [38] The glucose-responsive insulin release from the hydrogels was precisely engineered based on the molecular structure of formylphenylboronic acid ligands. The proteinpolymer hybrid hydrogels may be a potential smart insulin delivery system for in vivo applications.…”

Glucose-Responsive Chitosan Nanoparticle/Poly(vinyl alcohol) Hydrogels for Sustained Insulin Release In Vivo

“…The examinations were performed at lower and higher magnifications of 5000× and 100 000× at an acceleration voltage of 3 kV. The freeze-dried HGs or nanoparticle dispersions were prepared and mounted on circular aluminum stubs with double-sided adhesive tape and coated with gold before the observation …”

“…Equivolume insulin/PVA solution, 25 mg/mL chitosan solution, and 50 mM of each cross-linker solution were mixed and thoroughly measured with pipettes to form each gel. Human insulin was attached to ATTO 495 NHS ester and purified using G25 microspin G25 columns (GE Healthcare) before the incorporation …”

“…Therefore, these materials are amenable to external use, such as catheters and microneedles. Using biopolymers, such as carbohydrates and proteins, is one of the avenues to solve this issue. − Due to natural abundance and high biocompatibility and degradability, carbohydrates are emerging as a viable alternative to synthetic polymers.…”

“…We are inspired by several HG systems that employ imine and boronate esterbased cross-links in their network. 32,50,51 These FPBA crosslinks show significant binding affinity to saccharides under various pH conditions, leading to glucose-responsive characteristics. 18 To highlight the versatility and modularity of our approach, we used six FPBA derivatives with aldehyde and boronic acid/ester functionalities (Figure 1b).…”