Date of Award

Fall 12-2014

Degree Type


Degree Name

Doctor of Philosophy (PhD)


Polymers and High Performance Materials

Committee Chair

Charles L. McCormick

Committee Chair Department

Polymers and High Performance Materials

Committee Member 2

Daniel A. Savin

Committee Member 2 Department

Polymers and High Performance Materials

Committee Member 3

Derek L. Patton

Committee Member 3 Department

Polymers and High Performance Materials

Committee Member 4

Faqing Huang

Committee Member 4 Department

Chemistry and Biochemistry

Committee Member 5

Sergei I. Nazarenko

Committee Member 5 Department

Polymers and High Performance Materials


The advent of controlled radical polymerization (CRP) techniques, along with advancements in facile conjugation chemistry, now allow synthetic tailoring of precise, polymeric architectures necessary for drug/gene delivery. Reversible addition- fragmentation chain transfer (RAFT) polymerization and its aqueous counterpart (aRAFT) afford quantitative control over key synthetic parameters including block length, microstructure, and placement of structo-pendent and structo-terminal functionality for conjugation of active agents and targeting moieties. The relevance of water-soluble and amphiphilic (co)polymers synthesized by RAFT for in vitro delivery of therapeutics in biological fluids is an especially attractive feature. In many cases, polymerization, binding, conjugation, and stimulus-induced release can be accomplished directly in aqueous media. However, specific problems, barriers, and challenges regarding rational design of polymeric delivery systems for therapeutic siRNA still exist.

This dissertation focuses on RAFT synthesized (co)polymers as vectors and functional constructs to overcome delivery challenges. In section I, a modular copolymer consisting of HPMA and glutamic acid was synthesized to overcome hurdles of endosomal escape. Glutamic acid undergoes a coil-to-helix transition at endosomal pH- values, and these helices were stabilized with HPMA. As a proof-of-concept, the pH- responsive constructs demonstrated membrane disruption via red blood cell hemolysis and dye release from fluorescein-loaded POPC vesicles. In section II, hydrophilic-block-cationic copolymers were complexed with siRNA to ascertain the structure-property relationships governing siRNA release from block ionomer complexes (BICs). It was determined that the stability of the complexes, which increases with increasing cationic block length, delayed the time required to achieve gene suppression. These results indicated that decomplexation was facilitated via an ion exchange/substitution mechanism. In section III, AS1411, an anticancer biologic, was delivered utilizing hydrophilic-block-cationic copolymers. The prepared BICs were found to be monodisperse (PDIs < 0.1) and charge neutral (i.e., N:P = 1). The anti-proliferative ability of AS1411 was then assessed utilizing hydrophilic-block-cationic copolymers as delivery vehicles. After 72 h, AS1411 demonstrated successful cellular inhibition; however, negligible anti-proliferative activity was witnessed when AS1411 was delivered utilizing hydrophilic-block-cationic copolymers. This reduction in drug activity was attributed to reduction of available drug caused by increased BIC stability as was determined in Section II.