Effect of drug physicochemical properties on the release from liposomal systems in vitro and in vivo

Liposomes were discovered about 40 years ago by A. Bangham and since then they became very versatile tools in biology, biochemistry and medicine. Liposomes are the smallest artificial vesicles of spherical shape that can be produced from natural untoxic phospholipids and cholesterol. Liposome vesicles can be used as drug carriers and become loaded with a great variety of molecules, such as small drug molecules, proteins, nucleotides and even plasmids. Due to the variability of liposomal compositions they can be used for a large number of applications. In this thesis the β-adrenoceptor antagonists propranolol, metoprolol, atenolol and pindolol, glucose, 18F-Fluorodeoxyglucose (FDG) and Er-DTPA were used for encapsulation in liposomes, characterization and in vitro release studies. Multilamellar vesicles (MLV), large unilamellar vesicles (LUV) and smaller unilamellar vesicles (SUV) were prepared using one of the following lipids: 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC), 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC), Phospholipone 90H (Ph90H) or a mixture of DSPC and DMPC (1:1). The freeze thawing method was used for preparation of liposomes because it has three advantages (1) avoiding the use of chloroform, which is used in other methods and causes toxicity (2) it is a simple method and (3) it gives high entrapping efficiency. The percentage of entrapping efficiencies (EE) was different depending on the type and phase transition temperature (Tc) of the lipid used. The average particle size and particle size distribution of the prepared liposomes were determined using both dynamic light scattering (DLS) and laser diffraction analyzer (LDA). The average particle size of the prepared liposomes differs according to both liposomal type and lipid type. Dispersion and dialysis techniques were used for the study of the in vitro release of β-adrenoceptor antagonists. The in vitro release rate of β-adrenoceptor antagonists was increased from MLV to LUV to SUV. Regarding the lipid type, β-adrenoceptor antagonists exhibited different in vitro release pattern from one lipid to another. Two different concentrations (50 and 100mg/ml) of Ph90H were used for studying the effect of lipid concentration on the in vitro release of β-adrenoceptor antagonists. It was found that liposomes made from 50 mg/ml Ph90H exhibited higher release rates than liposomes made at 100 mg/ml Ph90H. Also glucose was encapsulated in MLV, LUV and SUV using 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC), 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC), Phospholipone 90H (Ph90H), soybean lipid (Syb) or a mixture of DSPC and DMPC (1:1). The average particle size and size distribution were determined using laser diffraction analysis. It was found that both EE and average particle size differ depending on both lipid and liposomal types. The in vitro release of glucose from different types of liposomes was performed using a dispersion method. It was found that the in vitro release of glucose from different liposomes is dependent on the lipid type. 18F-FDG was encapsulated in MLV 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC), 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC), Phospholipone 90H (Ph90H), soybean lipid (Syb) or a mixture of DSPC and DMPC (1:1). FDG-containing LUV and SUV were prepared using Ph90H lipid. The in vitro release of FDG from the different types of lipids was accomplished using a dispersion method. Results similar to that of glucose release were obtained. In vivo imaging of FDG in both uncapsulated FDG and FDG-containing MLV was performed in the brain and the whole body of rats using PET scanner. It was found that the release of FDG from FDG-containing MLV was sustained. In vitro-In vivo correlation was studied using the in vitro release data of FDG from liposomes and in vivo absorption data of FDG from injected liposomes using microPET. Erbium, which is a lanthanide metal, was used as a chelate with DTPA for encapsulation in SUV liposomes for the indirect radiation therapy of cancer. The liposomes were prepared using three different concentrations of soybean lipid (30, 50 and 70 mg/ml). The stability of Er-DTPA SUV liposomes was carried out by storage of the prepared liposomes at three different temperatures (4, 25 and 37 °C). It was found that the release of Er-DTPA complex is temperature dependent, the higher the temperature, the higher the release. There was an inverse relationship between the release of the Er-DTPA complex and the concentration of lipid.

From anionic polymerization in continuous flow to macromolecular architectures and stimuli-responsive surfaces

The thesis can be divided in four parts and summarized as follows:(i) The investigation and development of a continuous flow synthesis procedure affording end-functional polymers by anionic polymerization and subsequent termination in one reaction step and on a multigram scale was carried out. Furthermore, the implementation of not only a single hydroxyl but multiple orthogonal functionalities at the chain terminus was achieved by utilizing individually designed, functional epoxide-based end-capping reagents.(ii) In an additional step, the respective polymers were used as macroinitiators to prepare in-chain functionalized block copolymers and star polymers bearing intriguing novel structural and material properties. Thus, the second part of this thesis presents the utilization of end-functional polymers as precursors for the synthesis of amphiphilic complex and in some cases unprecedented macromolecular architectures, such as miktoarm star polymers based on poly(vinyl pyridine), poly(vinyl ferrocene) and PEO.(iii) Based on these structures, the third part of this thesis represents a detailed investigation of the preparation of stimuli-responsive ultrathin polymer films, using amphiphilic junction point-reactive block copolymers. The single functionality at the block interface can be employed as anchor group for the covalent attachment on surfaces. Furthermore, the change of surface properties was studied by applying different external stimuli.(iv) An additional topic related to the oxyanionic polymerizations carried out in the context of this thesis was the investigation of viscoelastic properties of different hyperbranched polyethers, inspired by the recent and intense research activities in the field of biomedical applications of multi-functional hyperbranched materials.

Stratospheric aerosol extinction retrieved from SCIAMACHY measurements in limb geometry

Stratosphärische Partikel sind typischerweise mit dem bloßen Auge nicht wahrnehmbar. Dennoch haben sie einen signifikanten Einfluss auf die Strahlungsbilanz der Erde und die heteorogene Chemie in der Stratosphäre. Kontinuierliche, vertikal aufgelöste, globale Datensätze sind daher essenziell für das Verständnis physikalischer und chemischer Prozesse in diesem Teil der Atmosphäre. Beginnend mit den Messungen des zweiten Stratospheric Aerosol Measurement (SAM II) Instruments im Jahre 1978 existiert eine kontinuierliche Zeitreihe für stratosphärische Aerosol-Extinktionsprofile, welche von Messinstrumenten wie dem zweiten Stratospheric Aerosol and Gas Experiment (SAGE II), dem SCIAMACHY, dem OSIRIS und dem OMPS bis heute fortgeführt wird. rnrnIn dieser Arbeit wird ein neu entwickelter Algorithmus vorgestellt, der das sogenannte ,,Zwiebel-Schäl Prinzip'' verwendet, um Extinktionsprofile zwischen 12 und 33 km zu berechnen. Dafür wird der Algorithmus auf Radianzprofile einzelner Wellenlängen angewandt, die von SCIAMACHY in der Limb-Geometrie gemessen wurden. SCIAMACHY's einzigartige Methode abwechselnder Limb- und Nadir-Messungen bietet den Vorteil, hochaufgelöste vertikale und horizontale Messungen mit zeitlicher und räumlicher Koinzidenz durchführen zu können. Die dadurch erlangten Zusatzinformationen können verwendet werden, um die Effekte von horizontalen Gradienten entlang der Sichtlinie des Messinstruments zu korrigieren, welche vor allem kurz nach Vulkanausbrüchen und für polare Stratosphärenwolken beobachtet werden. Wenn diese Gradienten für die Berechnung von Extinktionsprofilen nicht beachtet werden, so kann dies dazu führen, dass sowohl die optischen Dicke als auch die Höhe von Vulkanfahnen oder polarer Stratosphärenwolken unterschätzt werden. In dieser Arbeit wird ein Verfahren vorgestellt, welches mit Hilfe von dreidimensionalen Strahlungstransportsimulationen und horizontal aufgelösten Datensätzen die berechneten Extinktionsprofile korrigiert.rnrnVergleichsstudien mit den Ergebnissen von Satelliten- (SAGE II) und Ballonmessungen zeigen, dass Extinktionsprofile von stratosphärischen Partikeln mit Hilfe des neu entwickelten Algorithmus berechnet werden können und gut mit bestehenden Datensätzen übereinstimmen. Untersuchungen des Nabro Vulkanausbruchs 2011 und des Auftretens von polaren Stratosphärenwolken in der südlichen Hemisphäre zeigen, dass das Korrekturverfahren für horizontale Gradienten die berechneten Extinktionsprofile deutlich verbessert.