Molecular Design Boosts Hydrolytic Stability of Diisopropanolamine Boronic Ester Hydrogel for Long-Term Drug Release

Boronic ester hydrogels are widely used in biomedicine for their stimulus responsiveness to multiple disease-related triggers. However, their applicability is limited by its low hydrolytic stability. Here, we created the highest hydrolytically stable boronic ester cross-linked network yet documented─novel diisopropanolamine boronic ester (DIPAB) hydrogel. The systematic study from a molecular level to a three-dimensional hydrogel network demonstrates that DIPAB has significantly greater hydrolytic stability and dynamic exchange activation energy than diethanolamine boronic ester (DEAB). Based on molecular structure and electron density analyses, the results clarify that the improved hydrolytic stability of DIPAB is attributable to the introduction of a methyl group, which enhances the conjugation effect of the molecule, the steric effect, and the covalent character of the boron nitrogen coordination bond (BNCB), and reduces the tension of the five-membered ring. The relative potential energy of the hydrolytic process of DIPAB is identified by applying density functional theory (DFT) calculations. Finally, tazarotene-loaded DIPAB hydrogels are created and prepared for sustained drug release, significantly promoting rat skin healing. We anticipate that this innovative DIPAB hydrogel will open up a new design strategy for responsive drug carriers, dynamic chemically bonded hydrogels, and recyclable cross-linked polymers. Furthermore, our findings may encourage other structural alterations of diethanolamine to improve the adaptability of the boronic ester bonds for different application conditions.