Design and Synthesis of Stimuli-Responsive Polymers with Programmable Cleavability

Abstract

Polymers comprise a large portion of modern-day materials, from everyday plastics that we can hold and use, to nanomaterials imperceptible to the naked eye. Applying synthetic chemistry to impart structural changes to established polymers offers a promising path to introduce novel functionalities for applications ranging from biology to sustainability. In particular, this thesis explores the synthesis, characterization and evaluation of polymeric platforms containing rational incorporation of moieties that can undergo chemical cleavage, effecting enhancements in their design and performance. In the first half, we explore advancements to linker design and controlled release of payloads from molecular bottlebrush polymers. The first chapter introduces bottlebrush polymers as nanocarriers for therapeutics, and provides a detailed literature analysis of the synthetic and architectural developments that have been reported for these constructs, as well as outlooks for the future. The second chapter reports the first synthesis of peptide-containing bivalent bottlebrush (co)polymers (BBPs), featuring caspase-3-cleavable peptides linked to fluorogenic probes that provide a “turnon” signal upon enzymatic cleavage. The impacts of different architectural features of these polymers on enzyme access reveal insights into the interactions of enzymes with BBPs, and provide design criteria for future therapeutic systems leveraging this approach. The third chapter investigates a synergistic approach to treating pancreatic ductal adenocarcinoma (PDAC) with drug-loaded BBPs by leveraging multiple facets of structural modularity, including linker and drug identities and concentration ratios. This mechanism-guided approach to combination therapy is validated with the translation of in vitro studies that identify synergy across axes of both drug release timing and mechanism of action to in vivo validation of enhanced therapeutic efficacy of the combination BBP system. The remaining two chapters are a departure from BBPs, instead introducing a novel approach to cleavable comonomers for improving plastic end-of-life sustainability. The fourth chapter thus provides detailed background on the current plastic waste outlook, vinyl polymers and their synthesis, radical ring-opening polymerization, and current approaches to cleavable comonomers and the end-of-life options they offer commodity polymers. The fifth and final chapter reports the first “mixed” cleavable comonomer approach to degradable polymers towards a polyacrylic acid system optimized for biodegradability. A computational model offers parameters for controlling degradation fragment molecular weight and dispersity that are validated experimentally, and the material performance properties of the homopolymer are retained for its cleavable analog. Overall, this thesis leverages structure-activity relationships of cleavable functionalities in stimuli-responsive polymers, and expands the scope under which they can be utilized during their productive lifetime or processed thereafter.