Modulating Boronic Ester Stability in Block Copolymer Micelles via the Neighbor Effect of Copolymerized Tertiary Amines for Controlled Release of Polyphenolic Drugs

Abstract

The traceless and pH-sensitive properties of boronic esters are attractive for the synthesis of polymer-drug conjugates, but current platforms suffer from both low stability under physiologically relevant conditions and synthetically demanding optimization to tune drug release profiles. We hypothesized that the high catechol affinity and stability of Wulff-type boronic acids could be mimicked by copolymerization of phenyl boronic acid with a tertiary amine and subsequent micellization. This strategy yielded a versatile platform for the preparation of reversible polymer–drug conjugates, which more than doubled the oxidative stability of encapsulated polyphenolic drug cargo at physiologically relevant pH and enabled simple and incremental tuning of drug release kinetics. Moreover, we validated, with 19F NMR, that these copolymers exhibit uniquely high catechol affinity that could not be replicated by combinations of similarly functionalized small molecules. Overall, this report demonstrates that copolymerization of boronic acid and tertiary amine monomers is a powerful and modular approach to improving boronic ester chemistry for drug delivery applications.