Synthesis of Well-Defined Fatty Acid Polymers as Potential Membrane Destabilizing Agents

Abstract

The aim of this thesis is to synthesize well-defined, fatty acid polymers via reversible addition fragmentation chain transfer (RAFT) polymerization, as potential membrane destabilizing agents which can be used for intracellular drug delivery applications. A new methacrylate monomer, derived from an unsaturated fatty acid, 11-[2-(2-methyl-acryloyloxy)-ethylsulfanyl] undecanoic acid (UDAMA), was synthesized using 10-undecenoic acid as a starting compound. Monomer synthesis was composed of two steps: In the first step, thiol-ene thermal addition of 2-mercaptoethanol to 10-undecenoic acid was performed. The yield of the reaction was 85 %. In the second step, the addition product was reacted with methacryoyl chloride to yield a new monomer, UDAMA. The yield of the second synthetic step was 92%, calculated from 1H NMR spectroscopy. UDAMA was polymerized via both conventional free radical and RAFT polymerization techniques. Polymers were characterized using 1H-NMR spectroscopy and gel permeation chromatography (GPC). Linear increase in ln [M]0/[M] with polymerization time, and Mn with monomer conversion indicated the RAFT-controlled polymerization of UDAMA monomer under the conditions tested. The new monomer, UDAMA was also copolymerized with methacrylic acid (MAA) via RAFT polymerization to obtain water-soluble, pH-responsive polymers. Random copolymers of MAA and UDAMA were synthesized using two different polymerization feed composition having 20 mol% or 50 mol% UDAMA content. Copolymerizations were also found to be controlled by RAFT mechanism, as evidenced by measurements via 1H-NMR spectroscopy and GPC. The pH-responsive behavior of copolymers was demonstrated via UV−visible spectroscopy and dynamic light scattering measurements. Hemolysis assays revealed that the copolymers with 20 mol% UDAMA content demonstrated pH-dependent hemolytic activity.