Preparation of Carboxylic Acid Functionalized Glycopolymers Through RAFT and Post-Polymerization Modification For Biomedical Application

Husnu Alp Aliededeoglu


The primary theme of this dissertation involves the synthesis of well-defined primary amine functionalized polymers, subsequent modification of the polymers to produce novel carboxylic acid functionalized glycopolymers and surface polymerization of these systems utilizing controlled polymerization techniques. Additionally, the synthesis of new water-based allylic copolymer latexes is described. Reversible addition-fragmentation chain transfer polymerization (RAFT) is arguably the most versatile living radical polymerization technique in terms of the reaction conditions and monomer selection. Since the introduction of RAFT in 1998, researchers have employed the RAFT process to synthesize a wide range of water soluble (co)polymers with predetermined molecular weights, low polydispersities, and advanced architectures. However the RAFT polymerization of primary amine containing monomers such as 2-(aminoethyl metharylate) (AEMA) and N -(3-aminopropyl methacrylamide) (APMA) directly in water has yet to be reported. The overall goal of this research is to prepare well-defined synthetic anionic glycosaminoglycan polymers by combining well-defined primary amine functionalized polymers with carboxylic acid functionalized sugars through a one-step reductive amination reaction. To achieve these goals, first, primary amine functionalized polymers were prepared through aqueous RAFT polymerization of AEMA and APMA. Second, D-glucuronic acid sodium salt was attached to reactive polymer precursors via reductive amination reactions in alkaline medium. Finally, the surface modification capabilities of primary amine functionalized polymers were investigated using "click" chemistry to create reactive surfaces allowing post-polymerization reactions. In this thesis, the first chapter concerns the first successful RAFT polymerization of unprotected AEMA directly in water and its successful block copolymerization with N -2-hydroxypropylmethacrylamide (HPMA). The controlled "living" polymerization of AEMA was carried out directly in aqueous buffer using 4-cyanopentanoic acid dithiobenzoate (CTP) as the chain transfer agent (CTA), and 2,2'-Azobis(2-imidazolinylpropane) dihydrochloride (VA-044) as the initiator at 50°C. The living character of the polymerization was verified with pseudo first order kinetic plots, a linear increase of the molecular weight with conversion, and low polydispersities (PDIs) (<1.2). In addition, well-defined copolymers of poly(2-aminoethyl methacrylate- b-N -2-hydroxypropylmethacrylamide) (PAEMA-b -PHPMA) have been prepared through chain extension of poly(2-aminoethyl methacrylate) (PAEMA) macroCTA with HPMA in water. It is shown that the macroCTA can be extended in a controlled fashion resulting in near monodisperse block copolymers. The second chapter demonstrates the synthesis of novel carboxylic acid functionalized glycopolymers prepared via one step post-polymerization modification of poly(N -[3-aminopropyl] methacrylamide) (PAPMA), a water soluble primary amine methacrylamide, in aqueous medium. PAPMA was first polymerized via aqueous RAFT polymerization using CTP as CTA, and 4,4'-Azobis(4-cyanovaleric acid) (V-501) as the initiator at 70°C. The resulting well-defined PAPMA was then conjugated with D-glucuronic acid sodium salt through reductive amination in alkaline medium (pH 8.5) at 45°C. The successful bioconjugation was proven through proton ( 1 H) and carbon ( 13 C) Nuclear Magnetic Resonance (NMR) spectroscopy and Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) mass spectroscopy analysis, which indicated allylic acetate comonomer into the polymer chain. Copolymer thermal properties are reported. (Abstract shortened by UMI.)