Synthesis, structural characterization and applications of hyperbranched polymers based on L-lysine
L-lysine is an essential a-amino acid and a necessary building block for all proteins in the body. As an essential amino acid, L-lysine is not synthesized by humans or animals. Industrially produced L-lysine has therefore a big market as food additive, e.g. in pig food. In the body, L-lysine plays a major role in calcium absorption, building muscle proteins, recovering from surgery or sports injuries, and the body's production of hormones, enzymes, and antibodies.1 From a chemical point of view, L-lysine is an AB2 building block that contains two amino groups and one carboxylic acid group, which makes it an interesting monomer for the synthesis of dendrimers and hyperbranched polymers. L-lysine indeed has been extensively used to synthesize dendrimers2-4 or conjugates of dendrimers and linear polymers.5,6 These dendrimers and linear-dendritic hybrid architectures have attracted interest for various medical applications, including gene delivery,3,6-8 as drug carriers,9 for the development of multiple antigen peptide systems,10,11 and as magnetic resonance imaging agents.12 The drawback of these dendrimers and linear-dendritic hybrid architectures is their time consuming synthesis and their expensive large scale production. This thesis evaluates the feasibility of L-lysine as a monomer to synthesize hyperbranched polymers and investigates the potential of these materials as encapsulation agents and for various biomedical applications. As the hyperbranched polylysines are prepared in a single step and can be produced conveniently at a large scale, they may offer an interesting alternative to their widely used dendritic analogues. Including this introduction, this thesis consists of 8 chapters, which are briefly described below. Chapter 2 gives a general overview of dendritic and hyperbranched polymers build up of amide bonds. Their synthesis and applications in medicine and catalysis as well as their self-assembling and encapsulation properties will be discussed. Chapter 3 reports on the synthesis of hyperbranched polylysines via the thermal polymerization of L-lysine hydrochloride.13 Different catalysts were investigated to improve the reaction kinetics. The structure of the polymers was determined by 1H-NMR spectroscopy, and the degree of branching and the average number of branches were calculated. Chapter 4 will discuss the feasibility of different approaches to control polymer architecture during the thermal hyperbranched polymerization of L-lysine hydrochloride.14 The reactivity of the more reactive ε-NH2 group was modulated by introducing temporary protective groups. The distribution of structural units was analyzed by 1H-NMR spectroscopy and the degree of branching and the average number of branches were calculated. Chapter 5 will describe the dilute solution and solid state structure of hyperbranched polylysines and polyelectrolyte complexes generated from hyperbranched polylysine and various anionic, sodium alkyl sulfate surfactants.15 Structural models for the obtained liquid crystalline phases will be proposed. Chapter 6 will show some preliminary results of the end group modification of hyperbranched polylysine with different hydrophilic and hydrophobic agents. The feasibility of these hydrophobically modified hyperbranched polylysines to encapsulate hydrophilic dyes and transfer them from aqueous to organic media has been investigated. Chapter 7 provides a first insight into the biological properties of hyperbranched polylysine. In this chapter the results from preliminary cytotoxicity and cellular uptake experiments will be discussed. Chapter 8 will give a short summary of the work done in this thesis and an outlook. References Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6. Denkewalter, R. G.; Kolc, J. F.; Lukasavage, W. J. In U.S. Pat. 4289872; Allied Corporation, 1981; Chem. Abstr. 1981, 102, 79324. Ohsaki, M.; Okuda, T.; Wada, A.; Hirayama, T.; Niidome, T.; Aoyagi, H. Bioconjugate Chem. 2002, 13, 510-517. Driffield, M.; Goodall, D. M.; Smith, D. K. Org. Biomol. Chem. 2003, 1, 2612-2620. Lübbert, A.; Nguyen, T. Q.; Sun, F.; Sheiko, S. S.; Klok, H.-A. Macromolecules 2005, 38, 2064-2071. Choi, J. S.; Joo, D. K.; Kim, C. H.; Kim, K.; Park, J. S. J. Am. Chem. Soc. 2000, 122, 474-480. Vlasov, G. P.; Korol'kov, V. I.; Pankova, G. A.; Tarasenko, I. I.; Baranov, A. N.; Glazkov, P. B.; Kiselev, A. V.; Ostapenko, O. V.; Lesina, E. A.; Baranov, V. S. Russ. J. Bioorg. Chem. 2004, 30, 12-20. Choi, J. S.; Lee, E. J.; Choi, Y. H.; Jeong, Y. J.; Park, J. S. Bioconjugate Chem. 1999, 10, 62-65. Sakthivel, T.; Toth, I.; Florence, A. T. Pharm. Res. 1998, 15, 776-782. Tam, J. P. Proc. Natl. Acad. Sci. U. S. A. 1988, 85, 5409-5413. Pessi, A.; Bianchi, E.; Bonelli, F.; Chiappinelli, L. J. Chem. Soc., Chem. Commun. 1990, 8-9. Nicolle, G. M.; Tóth, E.; Schmitt-Willich, H.; Radüchel, B.; Merbach, A. E. Chem. Eur. J. 2002, 8, 1040-1048. Scholl, M.; Nguyen T. Q.; Bruchmann, B.; Klok, H.-A. J. Polym. Sci. Part A Polym. Chem. 2007, 45, 5494-5508. Scholl, M.; Nguyen T. Q.; Bruchmann, B.; Klok, H.-A. Macromolecules 2007, 40, 5726-5734. Canilho, N.; Scholl, M.; Mezzenga, R.; Klok, H.-A. Macromolecules 2007, 40, 8374-8383.
Keywords: Hyperbranched polymers ; polypeptides ; polylysine ; thermal polymerization ; L-lysine ; degree of branching ; reaction kinetics ; imines ; [alpha]-amino-[epsilon]-caprolactam ; liquid crystalline polymers ; polyelectrolyte complexes ; surfactants ; encapsulation ; nanocarriers ; cytotoxicity ; cellular uptakeThèse École polytechnique fédérale de Lausanne EPFL, n° 3965 (2007)
Programme doctoral Sciences et Génie des matériaux
Faculté des sciences et techniques de l'ingénieur
Institut des matériaux
Laboratoire des polymères
Record created on 2007-09-26, modified on 2016-08-08