Amphiphilic glycopolymers and glycopeptides. properties and applications

Abstract

In this thesis, the properties and potential application fields of saccharide-based block copolymers are explored. The anionic polysaccharide heparin was coupled to hydrophobic blocks – poly(dimethyl siloxane) (PDMS) and poly (ethyl ethylene) (PEE) – using different synthetic methods, and investigated in terms of self-assembly behavior and insertion into polymeric membranes. We studied whether heparin’s intrinsic anticoagulant activity is persistent upon chemical transformation and insertion into polymer membranes. We observed that coupling does not influence the anticoagulant activity, whereas methods involving degradation of heparin led to an almost complete loss of activity. We also coupled heparin to the hydrophilic polymer poly(ehtylene glycol) (PEG), which produced a bis-hydrophilic block copolymer. Self-assembly of this anionic material in association with gadolinium cations was investigated by transmission electron microscopy. Electron paramagnetic resonance (EPR) spectroscopy provided more details about the polymer – metal interactions. The choice of gadolinium was justified by the fact that it has good contrast properties for medical imaging. In combination with the polymer, toxicity of gadolinium could be decreased. In addition, its relaxivity was enhanced. This way we obtained a new type of contrast agent. MRI experiments proved that the relaxivity of the polymer-bound gadolinium was significantly higher than of unbound gadolinium and of commercially available gadolinium-based contrast agents. To further lower toxicity of gadolinium, we added phosphate to form small insoluble GdPO4 particles, which were in fact stabilized in solution by polymer aggregates. Their contrast properties only slightly decreased compared to polymer-bound gadolinium ions. Apart from synthetic blocks, we also combined sugar units with peptides. Firstly, we established new synthetic routes towards such biohybrids, using monosaccharides and a short peptide (named TRUNK). The coupling of D-glucuronic acid to the TRUNK was successfully achieved on solid phase. The resulting glycopeptide was investigated in terms of its self-assembly behavior. This thesis is structured in eight parts. The first chapter is an introduction, focusing on amphiphiles and copolymers based on biological blocks. Chapter two includes the motivation and the concept of this work. In the third chapter, the results are described and discussed in detail. This chapter is divided into four main sections, dealing with heparin-based copolymers with amphiphilic as well as bis-hydrophilic properties. The latter was explored as a matrix for MRI contrast agents. Additionally, the synthesis and self-assembly behavior of materials combining carbohydrate and peptide blocks are discussed. In chapters four and five we draw the conclusions and present the outlook for prospective experiments. The experimental conditions are given in chapter six, as well as descriptions of methods and equipment. The thesis finalizes with the references in chapter seven and an appendix including a historical outline of heparin in chapter eight.