Stimuli-responsive boronic acid copolymers prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization

Interest in stimuli-responsive polymers has persisted over many decades, and a great deal of work has been dedicated to developing environmentally sensitive macromolecules that can be crafted into new smart materials. One of the most common forms of stimuli-responsive polymers are those with an AB diblock architecture in which one block (A) is hydrophilic and the other (B) can be hydrophilic or hydrophobic depending on the conditions of the surrounding environment. When an appropriate stimulus is applied, the transition of the B block from hydrophilic to hydrophobic can lead to self-assembly into a variety of multimolecular morphologies. The goal of this research was to prepare block copolymers that respond to changes in the concentration of small organic molecules, specifically 1,2-diols (e.g., sugars). By capitalizing on this unique response, we aimed to prepare nanomaterials with potential controlled release ability such that therapeutics (e.g., insulin) can be automatically delivered when high glucose concentrations are detected.;Controlled radical polymerization (CRP) allows for the synthesis of well-defined, controlled-structure polymers. Reversible addition-fragmentation chain transfer (RAFT) polymerization, one type of CRP, is useful for the polymerization of highly functional monomers. We demonstrated two synthetic routes for the synthesis of well-defined boronic acid block copolymers. One approach involved the polymerization of boronic ester containing vinyl monomers followed by postpolymerization deprotection. Utilizing this method, 4-pinacolatoborylstyrene (pBSt) was polymerized via RAFT to yield polymeric boronic acid precursors with well-controlled molecular weights in the range of M n = 17,000--32,000 g/mol. The resulting poly(4-pinacolatoborylstyrene) homopolymers were employed as macro-chain transfer agents (macro-CTA) for block copolymerization with N,N-dimethylacrylamide (DMA) to yield amphiphilic block copolymers that formed micelles in aqueous media. The pinacol ester derivatized (co)polymers were easily deprotected by a mild and convenient strategy to yield free boronic acid polymers.;The second route to well-defined organoboron polymers relied on the direct polymerization of boronic acid monomers. Polymerization of 3-acrylamidophenylboronic acid (APBA) via RAFT resulted in well-defined homopolymers with narrow molecular weight distributions and molecular weights between 16,000--38,000 g/mol. Block copolymerization with DMA led to copolymers capable of self-assembly at pH values below the pKa of the boronic acid residues. Increasing solution pH or glucose concentration led to complete water solubility of the block copolymers and subsequent aggregate dissociation. While there are numerous examples in the literature of responsive polymers, these block copolymers were unique in that they demonstrated both pH- and sugar-responsiveness, as a result of the robust chemistry of their boronic acid moieties. Chain extension of the poly(3-acrylamidophenylboronic acid) (PAPBA) macro-CTA with N-isopropylacrylamide (NIPAM) resulted in triply-responsive polymers that self-assembled in response to changes in pH, sugar, and temperature.;PAPBA (co)polymers could also be prepared by the polymerization of pinacol protected boronic ester monomers. Using the polymerization and postpolymerization deprotection procedures developed for pBSt, RAFT polymerization of the of 3-acrylamidophenylboronic acid pinacol ester (APBAE) resulted in polymers with molecular weights between 12,000--37,000 g/mol. The resulting homopolymers were employed as macro-CTAs during the polymerization of DMA. These polymers were also investigated for their pH- and sugar-responsive solution behavior. Aggregate size, dissociation kinetics, and the effect of various sugars were considered. The resulting aggregates were able to solubilize and release model hydrophobic compounds, as demonstrated by fluorescent studies.;To investigate whether it was possible to tune the critical sugar concentration needed for aggregate dissociation, the boronic acid-containing segment of the poly(N,N-dimethylacrylamide) (PDMA)-b-PAPBA block copolymers was replaced with a statistical copolymer of APBA and the hydrophilic monomer DMA. Depending on the DMA content in the responsive segment of the resulting PDMA-b-poly(APBA-stat -DMA) block copolymers, aggregate dissociation at significantly reduced glucose concentrations was possible. This method should allow boronic acid block copolymers to be tuned to respond at physiologically relevant glucose concentrations.