Zwitterionic Polymer-based Platforms for Biotherapeutics and Implants

Abstract

Novel biotherapeutics and advanced implantable devices have greatly improved the quality of life for many patients. Biotherapeutics offer great advantages of high specificity towards difficult diseases, yet biotherapeutics are often physiochemical unstable and immunogenic; implantable devices with multiple functionalities create effective solutions to medical situations, yet they often suffer from reduced longevity due to the foreign body reaction triggered. Many biomaterials have been developed to tackle these issues. However, few biomaterials have been transferred from benchtop to clinical treatments, and biocompatibility issues of biomaterials have started to draw concerns. Thus, the development of new biomaterials is essential for the realization of contemporary medical treatments. In this dissertation, we discuss the development of zwitterionic polymer-based platforms for peptide therapeutics, non-invasive drug delivery, and implants. We first investigate how zwitterionic polymers would enhance the performance of peptides therapeutics. The native glucagon-like peptide-1 (GLP-1) no longer suffers from rapid renal clearance and degradation after the conjugation of a zwitterionic polymer and provides glycemic control in mice for up to 6 days, demonstrating its potential as a diabetes treatment. We next develop a non-invasive pulmonary systemic delivery platform for large protein drugs. The zwitterionic polymers significantly improved the bioavailability of organophosphate hydrolase (OPH) and the prevention of organophosphate poisoning through the non-invasive delivery of the conjugated OPH shows significant potential for protecting our warfighters in threat of nerve agents. In addition, we also design high-strength, pure zwitterionic-elastomeric-networked (ZEN) hydrogels through the mechanisms of swellability and the locking effect. The ZEN hydrogels can be considered highly biocompatible as no fibrotic capsule was formed after one year of implantation, which showed great potential for implantable devices. In these studies, we explore and expand the capacity of using zwitterionic polymers for protein/peptide drug delivery and long-term implantation. The new findings could provide new solutions and advance the field of biotherapeutics development, non-invasive drug delivery system, and implantable devices.