Injectable dynamic covalent hydrogels of boronic acid polymers cross-linked by bioactive plant-derived polyphenols

Abstract

Plant polyphenols are a family of naturally derived compounds that contain a high concentration of phenolic hydroxyl groups. These molecules are linked to diverse biological functions and are highly celebrated for their complex bioactivities and antioxidant behavior. A high dietary intake of polyphenols has been linked to a reduced incidence of a number of diseases, including cancer, diabetes, osteoporosis as well as cardiovascular and neurodegenerative diseases, and several polyphenols have been investigated as therapeutics. However, despite their impressive therapeutic effects, polyphenols suffer from a number of drawbacks which limit their clinical translation, including poor bioavailability, rapid metabolism, and poor membrane permeability. Therefore, development of an efficient delivery method for these beneficial therapeutic molecules would be a milestone in translation into the clinic. The high hydroxyl content and rich bioactivity spectrum of polyphenols presents a unique opportunity to form therapeutically active dynamic covalent hydrogels with boronic acid polymers. Herein we exploit the pH dependence and dynamic nature of complexes between boronic acid functionalized PEG and polyphenols as bioactive injectable hydrogels (Figure 1). In this concept, the polyphenol functions both as crosslinker and therapeutic, forming a hydrogel by injection of a precursor solution of polymer and polyphenol that solidifies through formation of boronate ester cross-links upon neutralization to physiologic pH. The dynamic nature of the boronate ester bond provides a mechanism for latent hydrogel disassembly and release of therapeutic polyphenols into the surrounding environment.