Development of Peptide-Polymers for Drug and Gene Delivery to the Central Nervous System

Abstract

Diseases of the central nervous system are largely untreatable, with most current treatment strategies palliative. Current therapeutic strategies are limited by drugs of low potency, poor pharmacokinetics, and poor biodistribution following systemic administration. Diseases of the central nervous system are amongst the most debilitating and difficult to treat, significantly affecting the productivity and livelihood of those afflicted. In this work, polymeric display of bioactive peptides is used to rationally design novel therapeutics aimed at treating several central nervous system disorders. These materials address several limitations of peptides, such as poor proteolytic stability, rapid clearance, and low efficacy, via conjugation to polymeric backbones, improving pharmacokinetics and increasing peptide activity through multivalency and avidity. Three classes of materials were explored: cationic polymers for gene delivery; thrombin-inhibiting polymers for spinal cord injury and regeneration; and pro-apoptotic polymers for treating glioblastoma multiforme. Chapter 1 provides a short introduction towards using peptide-polymers as alternative therapeutics for many neurological disorders. Chapter 2 summarizes the use of living radical polymerization techniques for the development of synthetic gene delivery vectors. In Chapters 3-7, the inclusion of peptides into polymeric constructs were shown to (1) increase peptide bioactivity relative to free peptide, (2) tune peptide release and mediate enzyme-triggered polymer degradation, and (3) mediate cellular targeting via modulation of peptide ligand density. Chapter 8 concludes with recommendations for future work based on these findings.