Author: Matthew Skinner

Publisher:

Published: 2018

Total Pages:

ISBN-13:

This dissertation describes the synthesis, characterization, and investigation of novel zwitterionic polymers containing phosphorylcholine (PC), sulfobetaine (SB), and functional choline phosphate (CP) zwitterions for use as surfactants, self-assembled nanomaterials, and therapeutics. Facile, reproducible, and modular chemistries were utilized for incorporating zwitterions into a range of polymer backbones, and strategies were developed for overcoming difficult challenges encountered in zwitterionic polymer synthesis, especially related to the varying solubility of zwitterions, hydrophobic polymers, and functional comonomers. Synthetic strategies utilized in this work give access to well-defined materials with narrow molecular weight distributions, tunable compositions and architectures, and versatile chemical functionality. Chapter 2 describes the synthesis of water-soluble PC- and SB-functionalized siloxane polymers. PC- and SB-siloxane homopolymers and block copolymers were synthesized using thiol-ene 'click' chemistry, and their assembly in water and at oil-water interfaces was investigated. Chapter 3 describes the preparation of zwitterionic block copolymer analogues of commercial Pluronic® surfactants. PC-containing triblock copolymers were prepared with tunable zwitterion content (5-47 mole percent) and relatively narrow molecular weight distributions. These block copolymer amphiphiles readily formed nanoparticles in water and served as novel surfactants. Through the copolymerization of PC- and CP-methacrylate monomers, functional mimics of conventional Pluronic structures became amenable to crosslinking and the successful synthesis of nanomaterials and robust gels. Chapter 4 presents the in vivo evaluation of poly(2-methacryloyloxyethyl phosphorylcholine)-doxorubicin (polyMPC-Dox) prodrugs for treating human ovarian tumors (SKOV-3). In human ovarian tumor-bearing mice, polyMPC-Dox prodrugs with an approximate Dox loading of 19 weight percent accumulated in tumor tissue at twice the level of free Dox, and animals treated with polyMPC-Dox exhibited enhanced survival and retarded tumor growth compared to conventional Dox treatment. Finally, Chapter 5 augments the polyMPC prodrug concept with the development of polymer-temozolomide (TMZ) conjugates intended for glioblastoma treatment. PolyMPC-TMZ prodrugs were prepared by the controlled free radical copolymerization of MPC and novel TMZ-methacrylate monomers, affording copolymers with random and block architectures. Polymer conjugation significantly improved the solution stability of TMZ, and the antitumor activity of polyMPC-TMZ prodrugs was demonstrated in TMZ-sensitive (U87MG) and TMZ-resistant (T98G) glioblastoma cell lines. The impact of drug loading, polymer architecture, and adjuvant co-delivery on the cytotoxicity of polyMPC-TMZ conjugates was investigated.