Inhaltszusammenfassung

Polyether lipids based on poly(ethylene glycol) (PEG) and polyglycerol (PG) have been synthesized and their application for the formation of lipid vesicles, so-called “liposomes”, and the characterization of their physical behavior are presented. During the last decades, PEG-modified lipids have attracted increased attention due to some exceptional characteristics, for instance their biocompatibility and their ability of self-assembly in various patterns. Especially in the field of biomedica...Polyether lipids based on poly(ethylene glycol) (PEG) and polyglycerol (PG) have been synthesized and their application for the formation of lipid vesicles, so-called “liposomes”, and the characterization of their physical behavior are presented. During the last decades, PEG-modified lipids have attracted increased attention due to some exceptional characteristics, for instance their biocompatibility and their ability of self-assembly in various patterns. Especially in the field of biomedical research, amphiphilic polymers, such as PEG-conjugated phospholipids, have been investigated and applied for the preparation of drug carrier systems. Thus, PEG-coated liposomes show improved stabilities during storage in cell culture as well as in in vivo experiments and are approved for the encapsulation of cytostatica in different cancer therapies. A review about the basic science concerning liposomes, the employed polymeric systems and the approved medical formulations is given in the introducing part of this thesis. The combination of linear and hyperbranched polymerization techniques for the ring-opening anionic polymerization of different epoxide monomers, such as ethylene oxide (EO), ethoxyethyl glycidyl ether (EEGE), isopropylidene glyceryl glycidyl ether (IGG) and glycidol using hydrophobic initiators allows the synthesis of multifunctional polyether lipids. Following this approach, a variety of amphiphilic stealth-type polymer lipids with systematically varied compositions (homopolymers, block copolymers and random copolymers) as well as structures (linear, branched and hyperbranched) have been obtained (Figure 1). Figure 1. Structural variation of amphiphilic polyethers obtained via oxyanionic ring-opening polymerization of different epoxide monomers. The resulting synthetic polyether lipids have been used for the preparation of functional liposomes and siRNA-loaded liposomes (cooperation Johannes Gutenberg-University Mainz, Prof. Langguth and Prof. Helm). The multiple functionality of the novel structures has been employed for the attachment of labeling moieties and specific targeting sites, exploiting the multivalent nature for active drug targeting. Furthermore, the characterization of the physical behavior of these synthetic polyether lipids, for instance the self-assembly on the water-air interface in Langmuir and Langmuir-Blodgett films, are presented (cooperation Martin-Luther-University Halle, Prof. Kressler). Additionally, the strong interactions of cholesterol-initiated liner-hyperbranched PEG-PG block copolymers with monolayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, which are crucial for the anchoring of the polyether lipids in liposomal membranes, have been investigated. Self-assembly in thermotropic phases has been long known for cholesterol-derived compounds. In fact, the first observation of liquid crystalline organization was made for cholesteryl benzoates and cholesteryl acetates. Unusual liquid crystalline polymers consisting of one single mesogenic cholesterol unit and linear polyglycerol (PG) as well as poly(ethylene glycol)- poly(glycerol) and poly(ethylene glycol)-poly(glyceryl glycidyl ether) block copolymer chains have been synthesized. The liquid crystalline behavior depends on the molecular weights and architecture of the polyether chains attached to the cholesterol moiety. Due to the strong ordering effect of cholesterol and the phase segregation between the apolar cholesterol and the highly polar polyether chains, LC phases are present over a broad temperature range and up to a high degree of polymerization (cooperation TU Darmstadt, Prof. Stühn). Cholesterol can thus be regarded as a valuable rod-type block for rod-coil block copolymers, exerting a strong ordering effect on the flexible, isotropic polyether chains. Several projects directed at novel, complex polyether lipids in this thesis have motivated intensified studies in a number of related directions. Due to the broad nature of these fields, several issues could not be resolved in the limited context of this thesis, but present intriguing scientific topics for subsequent works. In the field of liposome research further investigation of encapsulation efficiencies of PEG-PG- coated liposomes for siRNA as well as their stability during storage represents an ongoing project. Detailed studies regarding the cytotoxicity of these liposomal formulations and their transport properties are in progress. Furthermore, the specific targeting of the multifunctional liposomes using folate-mediated endocytosis is studied, exploiting the multivalent nature of the polyether lipids for active drug targeting. Intensified characterization of the liquid crystalline behavior of cholesterol-initiated PEG-PG and PEG-PGG block copolymers via small angle X-ray scattering is presently carried out and will be presented in the near future. In future projects, linear poly(glycerol) liquid crystals shall be functionalized with crosslinking moieties, such as methacrylates, in order to synthesize stable liquid crystalline hydrogels and networks.» weiterlesen» einklappen

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DDC Sachgruppe:
Chemie