Development of pH-responsive, glycopolymer micelles for DNA delivery

Abstract

DNA-based vaccines offer significant therapeutic potential but safe, efficacious delivery systems are still needed to enable clinical applications. Well-defined nonviral vectors, including those produced via reversible addition-fragmentation chain transfer (RAFT) polymerization, represent one approach for overcoming barriers to DNA delivery. Block copolymer micelles are an example of a complex architecture achievable by the RAFT process, adopting a core-shell morphology under physiological conditions. These polymeric nanoparticles consist of discrete segments capable of specific physicochemical and biological activities determined by their chemical composition. This thesis describes synthetic approaches focused on engineering the intra- and extracellular activity of this class of nanomaterials, with the goal of developing an in vivo DNA delivery platform. Chapter 1 focuses on how polymerization and carbohydrate chemistry techniques can be utilized to develop DNA-based cancer vaccines. Chapter 2 introduces a pH-responsive, diblock copolymer micelle platform with a tunable mode of endosomal disruption to facilitate intracellular delivery of DNA. Chapter 3 describes the synthesis of glycopolymers with carbohydrate-specific lectin-binding activity in vivo and in vitro. Chapter 4 incorporates these glycopolymer segments into a micellar architecture and evaluates the bioactivity of these materials. Chapter 5 describes analytical techniques that assess how the chemical composition of the micellar corona affects the stability and physicochemical properties of the resultant particles. Chapter 6 integrates the findings of these previous chapters into the development of glycopolymer micelles and determines their efficacy for in vivo DNA delivery.