End-Group Modified Bottlebrush Polymers to Deliver Active Pharmaceutical Ingredients

Abstract

Bottlebrush polymers have great potential as vehicles to noncovalently sequester, stabilize, and deliver active pharmaceutical ingredients. To this end, this dissertation will span fundamental investigations to define the mechanism of noncovalent sequestration to applications in oral drug delivery and the complexation of nucleic acid-based cargos. Chapter 3 outlines a fundamental understanding of how hydrophobic end-groups and hydrophilic comonomers effect the thermoresponsive properties of poly(N-isopropylacrylamide)-containing multiblock copolymer in solution. That work lead investigation into using post-polymerization end-group modification to modulate the thermoresponsiveness of poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) bottlebrush copolymer architectures. These bottlebrush copolymers were used to noncovalently sequester and solubilize a model therapeutic, and the solubility enhancement increased significantly with the hydrophilicity of the end group moiety. which will be discussed in detail in Chapter 4. The carboxylated bottlebrush copolymer solubilized the model compound at higher drug loadings in amorphous solid dispersions than equivalent linear copolymer analogues that formed micelles in solution. The importance of the type of drug-polymer nanostructure in solution on the solubilization efficacy of these bottlebrush architectures was tested in Chapter 5 with an orally administered breast cancer therapeutic. Bottlebrush copolymers were found to solubilize small molecule actives as unimolecular drug loaded nanoparticles and were more stable to changing solution environments compared to linear copolymer and commercial controls. This technology is further adapted to new copolymer compositions for oral drug delivery and to cationic bottlebrush polymers for the delivery of nucleic acid-based payloads in Chapter 6. Bottlebrush copolymers are a powerful and tailorable tool with many synthetic handles to optimize for applications in medicine and in vitro to in vivo translational technologies.