Synthesis of Bioapplicable Polymers Using Atom Transfer Radical Polymerization and Ring Opening Metathesis Polymerization

Abstract

Biomaterials are used to make devices which can be replace a part or function of the body in a safe, reliable and physiologically acceptable manner. A variety of devices and materials are used in the treatment of disease or injury. Biomaterials are classified into metal, ceramic, polymer and composite materials according to type of materials. Whereas metal and ceramic are used mainly for mechanical properties, organic-based materials are applied mainly to biological and pharmacology. The range of application is diverse such as artificial hearts, blood vessels, bones, kidneys and ears etc. Biomaterials are required proper physical properties and excellent biocompatibility because they directly contact with living tissue. They must have tissue compatibility and hemocompatibility that must not cause tissue necrosis and blood coagulation in contact with human body. They have non-allergic or non-immune response as well as non-toxic. Also, they must perform function of replaced body parts and at the same time they are no degradation of the physical properties.<br/> Among them, polymeric materials have a wide variety applications for implantation. They have less resistance to the human body than the metal and ceramic materials. So, they have applied in biomedical fields such as medical device, tissue engineering and drug delivery etc. Especially, synthetic polymers can be used as various biological materials because they can control the chemical and physical properties of monomers and introduce various functions during synthesis and processing. However, when they are used as biomaterials, nonspecific protein adsorption and blood coagulation can be caused on the surface. These symptoms get worse, they lose the natural functions and cause inflammatory and immune response. <br/> Natural polymeric materials, which have good biocompatibility, such as collagen, cellulose and chitin are used in biomedical field. However, they are difficult to apply for tissues which must bear a lot of the weight such as bone or cartilage due to their weak hardness.<br/> First, I focused to synthesizing biocompatible polymers using atom transfer radical polymerization. I suggested synthesis of biomembrane-mimic polymers. Like 2-methacryloyloxyethyl phosphorylcholine (MPC), monomers were synthesized as custom methacrylate with phospholipid head groups on the side chain for atom transfer radical polymerization (ATRP). I synthesized three different phospholipid-mimic polymers with phosphatidic acid (PA), phosphatidylethanolamine (PE), and phosphatidylserine (PS) head groups. I developed a new synthetic method to prepare monomers and ATRP was used to control the polymerization of the phospholipid-mimic polymers. Considering phospholipid compositions in cell membranes vary between organs, tissues, cells, and even cellular organelles, the biomembrane-mimic polymers based on diverse phospholipid head groups can be a potential platform for the preparation of cell- or tissue-specific surfaces with both biocompatibility and bioactivity, which are difficult to be obtained by only PC-based polymers for biomedical applications.<br/> Recently, smart materials which have external signal-sensitive degradation of chemical bonds have been developed. These have degradable moieties responding to biologically tolerable signals such as light, enzyme, pH and glutathione. Among these biosignals, pH is commonly applied to selectively trigger degradation because pH in different tissues and cellular compartments exist in human body. Different tissues have individual pH conditions and pH values decrease gradually in the endocytic process. In addition, tumor cells extracellular matrix pH is lower than in healthy cells. Therefore, a degradable bond at a specific pH value can be used for the release of conjugated drugs based on specific conditions and target sites. <br/> So, for biodegradable polymers, I proposed synthesis of pH-responsive polymers having cis-α,β-unsaturated anhydrides. I synthesized polymers with pH-sensitive molecule, maleic acid anhydride-mimic, as a monomer unit using ring opening metathesis polymerization (ROMP). In order to control pH-sensitivity, I synthesized various bicyclic α,β-unsaturated anhydride derivative monomers which were changed the substituents group of the cis-α,β-double bonds. I synthesized monomers which are pH-sensitive moiety and ring strain for ROMP using Diels-Alder reaction. Monomers were tailored to control the rate of degradability at acidic condition. They were polymerized by ROMP using 2nd generation Grubbs catalyst. In addition, maleic acid amide bond was introduced by amidation between polymer and n-propylamine. And rate of degradability was confirmed at various pH condition by detecting released amine. Furthermore, I studied in vitro bioactivity of alendronate-grafted polymers using breast cancer cell at pH 5.8, 6.5 and 7.4. The ROMP polymers with α,β-unsaturated anhydrides can be controlled pH-sensitivity to environmental signals upon substituents group of the cis-α,β- double bonds and theirs tunable pH-responsiveness is very useful property as the targeting and release of therapeutic agents.