Biocompatible zwitterionic polymer chemistries and hydrogels for gene therapy, drug delivery, and regenerative medicine

Abstract

Zwitterionic polymers have recently gained significant attention as a unique class of biomaterials, with their superhydrophilicity and unrivaled biocompatibility setting them apart from non-ionic and single-charged polymers. In particular, polycarboxybetaine (PCB) is easy to functionalize, highly resistant to nonspecific cell and protein interactions, and able to evade immunological responses in the body. The work described in this dissertation uses several strategies to add new functionality to PCB-based materials; specifically, it strives for simple and elegant approaches to engineer the chemical and material properties of PCB-based polymers and hydrogels toward clinical applications. First, PCB-ester side chain chemistries were tailored to engineer a nontoxic gene delivery platform, based on optimized pH buffering during gene trafficking and cationic-to-zwitterionic charge switching through hydrolytic and photolabile groups. Next, step-growth polymerization strategies were investigated to design a new class of heterodifunctional "linear" PCB architectures featuring zwitterionic groups positioned directly along the polymer backbone; these polymers are promising candidates to reduce immunogenicity and extend the circulation time of biologics. Then, new physical and chemical crosslink- ing strategies were explored to expand the capabilities of PCB hydrogels. In one approach, bioorthogonal thiol chemistries were combined with star-shaped PCB architectures to facilitate cytocompatible stem cell encapsulation and robust ex vivo expansion. Finally, a versatile strategy was developed to give PCB hydrogels dynamic viscoelasticity. These "zwitterionic injectable pellet" (ZIP) hydrogels exhibit tunable shear-thinning and self-healing attributes, are simple to make and use at any scale, and can be sterilized, lyophilized, and reconstituted into custom injectable drug formulations and cell-protective materials.