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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Development and Evaluation of Lipodisks Intended for Use as Biomimetic Membranes and Drug Carriers

Morin Zetterberg, Malin January 2016 (has links)
Polyethylene glycol-stabilized lipodisks have emerged as a novel type of lipid-based nanoparticles with high potential as both drug carriers and biomimetic membranes. In this thesis we assess both of these applications, and show how the properties of the lipodisks can be further developed and optimized. Initially, we show that the antimicrobial peptides melittin, alamethicin and magainin 2, in spite of their very different physico-chemical properties and suggested modes of action on membranes, all have high affinity to lipodisks. Using melittin as a model peptide, we confirm a maintained antimicrobial effect of disk-formulated peptides. We also show that melittin dissociates slowly from the disks, resulting in extended drug release and prolonged antibacterial effect. Additionally, we present evidence that the peptide is protected against enzymatic degradation when formulated in the disks. Further, we develop a stable HPLC-MS system with immobilized lipodisks as model membranes. The stability of the system is confirmed by drug partitioning analysis using 15 different drug compounds. We also show how the lipodisk column can be supplemented with cyclooxygenase by in situ incorporation of the protein in the lipodisks. The specific binding of the protein to the disks is confirmed using QCM-D. Finally, by changing the polymer length and applying a new preparation protocol, we have optimized the lipodisks for use as drug carriers and biomimetic membranes. Previous lipodisk studies have been conducted on systems containing PEG-lipids with polymer molecular weights of 2000 or 5000 Da. Also, conventional protocols for the preparation of lipodisks typically require a PEG-lipid concentration of 15 mol% or more. Here we show that stable lipodisks can also be produced using PEG-lipids with a 1000 Da molecular weight polymer and that the use of shorter PEG-lipids dramatically improve the amount of lipodisks that can be immobilized on silica surfaces. Moreover, through the development of a method in which lipid mixtures are sonicated at low temperatures, we produce lipodisks containing as little as 2 mol% PEG-lipid. We present data verifying that these disks are superior to disks with higher PEG-lipid content in terms of their ability to incorporate externally added PEG-lipids functionalized with targeting agents.
2

Sterically stabilised liposomes and related lipid aggregates : Fundamental studies on aggragate structure and stability

Johnsson, Markus January 2001 (has links)
<p>Various aspects of and approaches towards the steric stabilisation of liposomes have been investigated, mainly by use of fluorescence techniques and cryo-transmission electron microscopy (cryo-TEM). It is shown that PEG(2000)-lipids can be incorporated in the liposome membrane up to a critical concentration of 8-10 mol% without any observable structural perturbations. Above 10 mol%, a breakdown of the liposome structure into flat lamellar discs was observed. The sterically stabilised liposomes displayed similar, or even reduced, membrane permeability as compared with conventional liposomes. The presence of PEG-lipids in the EPC membrane was shown to affect the liposome-to-micelle transition in mixtures containing OG. Little or no effects of the PEG-lipids were found on the transition in mixtures containing C<sub>12</sub>E<sub>8</sub>.</p><p>The interactions between a number of PEO-PPO-PEO triblock copolymers and PC or PC/Chol liposomes have been investigated. It is shown that these polymers adsorb rapidly onto the liposome surface and induce a substantial increase in membrane permeability as well as structural perturbations. No evidence of an effective steric stabilisation due to the presence of the polymers at the membrane surface was found. This was shown, by the use of a QCM-technique, to be a consequence of the weak interaction between the polymers and the lipid membrane. </p><p>Dispersions of reversed lipid phases in mixtures of DOPE and PEG-lipids were characterised using cryo-TEM. Dispersions displaying reasonable colloidal stability were obtained and particles exhibiting a periodic dense inner structure were observed.</p><p>PEG-lipid micelles were characterised mainly using light scattering techniques. Micelle aggregation numbers and hydrodynamic radii were determined as a function of temperature. It is shown that the inter-micellar interactions are dominated by the steric repulsion.</p><p>PEG-lipid stabilised liposomes loaded with boronated drugs intended for BNCT have been characterised. The drugs were efficiently encapsulated into the liposomes, resulting in a drug precipitation in the water core of the liposomes.</p>
3

Sterically stabilised liposomes and related lipid aggregates : Fundamental studies on aggragate structure and stability

Johnsson, Markus January 2001 (has links)
Various aspects of and approaches towards the steric stabilisation of liposomes have been investigated, mainly by use of fluorescence techniques and cryo-transmission electron microscopy (cryo-TEM). It is shown that PEG(2000)-lipids can be incorporated in the liposome membrane up to a critical concentration of 8-10 mol% without any observable structural perturbations. Above 10 mol%, a breakdown of the liposome structure into flat lamellar discs was observed. The sterically stabilised liposomes displayed similar, or even reduced, membrane permeability as compared with conventional liposomes. The presence of PEG-lipids in the EPC membrane was shown to affect the liposome-to-micelle transition in mixtures containing OG. Little or no effects of the PEG-lipids were found on the transition in mixtures containing C12E8. The interactions between a number of PEO-PPO-PEO triblock copolymers and PC or PC/Chol liposomes have been investigated. It is shown that these polymers adsorb rapidly onto the liposome surface and induce a substantial increase in membrane permeability as well as structural perturbations. No evidence of an effective steric stabilisation due to the presence of the polymers at the membrane surface was found. This was shown, by the use of a QCM-technique, to be a consequence of the weak interaction between the polymers and the lipid membrane. Dispersions of reversed lipid phases in mixtures of DOPE and PEG-lipids were characterised using cryo-TEM. Dispersions displaying reasonable colloidal stability were obtained and particles exhibiting a periodic dense inner structure were observed. PEG-lipid micelles were characterised mainly using light scattering techniques. Micelle aggregation numbers and hydrodynamic radii were determined as a function of temperature. It is shown that the inter-micellar interactions are dominated by the steric repulsion. PEG-lipid stabilised liposomes loaded with boronated drugs intended for BNCT have been characterised. The drugs were efficiently encapsulated into the liposomes, resulting in a drug precipitation in the water core of the liposomes.
4

Bilayer Discs - Fundamental Investigations and Applications of Nanosized Membrane Models

Johansson, Emma January 2007 (has links)
The bilayer disc is a flat, lipid aggregate structure in the nanometre regime. It is composed of a bilayer of amphiphilic molecules with micelle-forming amphiphilic molecules supporting the rim, which prevent disc fusion and self-closure. Stable discs have been found in lipid mixtures containing polyethylene glycol (PEG)-lipids as a rim-stabilizing component. One of the aims of the work described in this thesis was to increase the fundamental knowledge and understanding of the systems in which these discs are formed. Other micelle-forming surfactants apart from PEG-lipids were also explored to see if they could be used to stabilize the disc aggregate structure. Due to the similarities of these lipid discs with natural membranes it was hypothesized that they could be used as models for biological membranes. It was demonstrated that discs are formed in PEG-lipid/lipid systems when the lipid mixture contains components that reduce the spontaneous curvature and increase the monolayer bending rigidity. Discoidal structures are furthermore preferred when the lipids are in the gel phase, probably due to a combination of high bending rigidity and reduced PEG-lipid/lipid miscibility. The disc size could be varied by changing the PEG-lipid concentration. The size and size homogeneity of the discs could also be varied by changing the preparation path. Generally, the preferences of certain lipid systems to form discs remained when the PEG-lipid was replaced by more conventional surfactants. However, discs prepared in PEG-lipid/lipid systems are more useful as model membranes because of their relatively large size and good temperature, dilution and long-term stability. Data obtained with isothermal titration calorimetry and drug partition chromatography indicate that these bilayer discs may serve as an attractive and sometimes superior alternative to liposomes in studies of drug-membrane interactions.
5

Structural investigations using small angle scattering techniques and contrast variation

Rabe, Christian 30 March 2015 (has links)
Die Analyse der Röntgen- und Neutronenkleinwinkelstreuung stellt ein ideales Werkzeug für Untersuchungen der Struktur submikroskopischer Teilchen und deren Wechselwirkungen dar. Hierbei eröffnet die Variation des Streukontrastes ein zusätzliches Spektrum an Informationen. Wie in der vorliegenden Arbeit gezeigt wird, kann durch die Verwendung komplementäre Verfahren ein detailliertes Bild der untersuchten Systeme erarbeitet werden. Im Fokus der Diskussion stehen Polyethylennanopartikel und Strukturen basierend auf hyperverzweigtem Polyglycerol. Die durchgeführten Untersuchungen liefern beispielsweise Rückschlüsse auf den Mechanismus, der zu einer nahezu idealen Anordnung unverzweigter Polymerketten, während der Bildung der Polyethylennanopartikel, führt. Im amorphen Anteil dieser plättchenförmigen Partikel findet demnach ausschließlich eine Richtungsänderung beim Wiedereintritt der Polymerketten in die kristalline Phase statt, wodurch eine ungehinderte Kettendiffusion möglich ist. Der Einfluss von Defekten entlang der Polymerkette auf die Partikelstruktur konnte durch Untersuchungen eines präzise verzweigten Polyethylens ermittelt werden. Bei weiteren Untersuchungen von wässrigen Dispersionen eines hyperverzweigten Polyglycerols konnte die übergeordnete Struktur als Fraktal beschrieben werden. Der signifikante Beitrag der Mikrostrukturierung des Moleküls zu dessen Kleinwinkelstreuung wurde in den Analysen berücksichtigt. Die Strukturuntersuchungen von Molekülen mit dem polaren hyperverzweigten Kern und einer nahezu vollständigen Funktionalisierung durch bipolare Ketten profitierte von diesen Ergebnissen. Hierbei wurde die Struktur dieser Moleküle in polaren und unpolaren Medien ermittelt. In einer polaren Umgebung wurde die Bildung von Assoziaten beschrieben. Dies liefert wertvolle Hinweise auf die Wirkungsweise als Wirkstofftransportsystem liefert. / The analysis of the small angel X-Ray and neutron scattering is an ideal tool for the discussion of the structure and interactions of submicroscopic particles. Herein, the variation of the scattering contrast enlarges the spectrum of information, additionally. As shown in the presented work, complementary probes give a detailed picture of the investigated systems. The focal point of the discussion is set on polyethylene nanoparticles and structures based on hyperbranched polyglycerol. The analyses provide, for instance, information on the mechanism that leads to an ideal arrangement of the non-branched polymer chains during the formation of the platelet-like polyethylene nanoparticles. The amorphous phase exclusively hosts the redirection of the polymer chains into the crystalline domain. This allows the unimpeded chain diffusion. The effect of defects along the polymer chain on the particle structure was studied by the analyses of polyethylene with precisely placed methyl groups. Analyses of aqueous dispersions of hyperbranched polyglycerol reveal the fractal-like character of the global molecule structure. Additionally, the significant contribution of the molecule’s microstructure to the corresponding small angle scattering was considered. The analyses of molecules composed of the hyperbranched core and a complete functionalisation with bipolar chains profited from these results. Hereby, the molecule structure in polar and non-polar media was identified. In polar surrounding the formation of well-defined aggregates was described. This provides essential information for a further discussion of this type of molecules as drug delivery platform.
6

Physico-Chemical Investigations of Bilayer Discs and Related Lipid Structures Formed in Liposomal Systems Intended for Triggered Release

Sandström, Maria January 2007 (has links)
<p>This thesis describes results from fundamental studies of liposomes intended for drug delivery and pH or temperature triggered release. In addition, the effect of lipid composition on bilayer disc formation and a potential application of the bilayer discs were investigated.</p><p>The lower pH encountered by endocytosed liposomes can be utilized to trigger drug release. The mechanisms behind cytosolic drug delivery were investigated using two different kinds of pH-sensitive liposomes. The results indicate that incorporation of non-lamellar forming lipids into the endosome membrane may allow for drug escape into the cytosol.</p><p>Temperature-sensitive liposomes containing lysolipid (LTSL) release their content almost instantly when heated to temperatures close to the gel to liquid crystalline phase transition temperature (T<i>C</i>). Morphological changes of the liposomes in response to temperature cycling were studied. Temperature cycling induced liposome openings and disintegration of the liposomes into bilayer discs. Incubation of LTSL in the presence of multilamellar liposomes (MLVs) resulted in relocalisation of lysolipid into the MLVs, which affected the rapid release from LTSL. We propose that the presence of micelle-forming components, such as lysolipids and PEG-lipids, facilitates the formation of defects and membrane openings during the initial phase of membrane melting, resulting in the observed rapid release. Similar to added lysolipids, also hydrolysis generated lysolipids induce disc-formation upon heating through T<i>C</i> of the lipid mixture.</p><p>Two fundamentally different micelles may form in PEG-lipid/lipid mixtures. We found that discoidal structures are preferred over cylindrical micelles when the mixture contains components that reduce the spontaneous curvature, increase the monolayer bending modulus, or reduce PEG-lipid/lipid miscibility. The large discoidal micelles found at low PEG-lipid content are better described as bilayer discs. We evaluated such discs as model membranes in drug partitioning studies, and suggest that they, in some cases, produce more accurate data than liposomes.</p>
7

Investigation of Polymer Systems in Solutions with Electron Microscopy and Scattering Methods / Untersuchung von Polymersystemen in Lösung mittels Transmissionselektronenmikroskopie und Streumethoden

Schellkopf, Leonard 21 May 2015 (has links) (PDF)
This work is focused on the visualization and thus in the aid in finding explanations for the behavior of polymer structures as they exist in solution. For this aim, preparation and imaging techniques based on cryo-TEM protocols were developed for a large variety of polymeric specimens using new commercially available devices and the results were compared with the findings of other means of structural investigations. The systems used in this work were chosen, as their investigations can be adapted to other polymer systems by slight adaptation of the preparation procedures.
8

Physico-Chemical Investigations of Bilayer Discs and Related Lipid Structures Formed in Liposomal Systems Intended for Triggered Release

Sandström, Maria January 2007 (has links)
This thesis describes results from fundamental studies of liposomes intended for drug delivery and pH or temperature triggered release. In addition, the effect of lipid composition on bilayer disc formation and a potential application of the bilayer discs were investigated. The lower pH encountered by endocytosed liposomes can be utilized to trigger drug release. The mechanisms behind cytosolic drug delivery were investigated using two different kinds of pH-sensitive liposomes. The results indicate that incorporation of non-lamellar forming lipids into the endosome membrane may allow for drug escape into the cytosol. Temperature-sensitive liposomes containing lysolipid (LTSL) release their content almost instantly when heated to temperatures close to the gel to liquid crystalline phase transition temperature (TC). Morphological changes of the liposomes in response to temperature cycling were studied. Temperature cycling induced liposome openings and disintegration of the liposomes into bilayer discs. Incubation of LTSL in the presence of multilamellar liposomes (MLVs) resulted in relocalisation of lysolipid into the MLVs, which affected the rapid release from LTSL. We propose that the presence of micelle-forming components, such as lysolipids and PEG-lipids, facilitates the formation of defects and membrane openings during the initial phase of membrane melting, resulting in the observed rapid release. Similar to added lysolipids, also hydrolysis generated lysolipids induce disc-formation upon heating through TC of the lipid mixture. Two fundamentally different micelles may form in PEG-lipid/lipid mixtures. We found that discoidal structures are preferred over cylindrical micelles when the mixture contains components that reduce the spontaneous curvature, increase the monolayer bending modulus, or reduce PEG-lipid/lipid miscibility. The large discoidal micelles found at low PEG-lipid content are better described as bilayer discs. We evaluated such discs as model membranes in drug partitioning studies, and suggest that they, in some cases, produce more accurate data than liposomes.
9

Investigation of the micelle-to-vesicle transition in mixtures of an anionic and a cationic surfactant: the effect of adding salt

Leifsdotter, Josefine January 2012 (has links)
Catanoinic systems spontaneously form micelles and vesicles, which are self-assembled spherical structures made up by surfactants. In the core of the micelle a drug, or other organic substance, can be kept to stabilize it when placed in an aqueous environment. The micelle-to-vesicle transition corresponds to the moment when the drug is releases, and understanding which factors that trigger this transition is thus of great interest for the pharmaceutical industry. In this study the micelle-to-vesicle transition in water and the effect of salt were studied for the systems 95 mol% SDS/DDAB and 95 mol% SDeS/DDAB with different total concentrations. The static light scattering measurements showed that the micelle-to-vesicle transition for the system 95 mol% SDS/DDAB was shifted to lower total concentrations both when 50 mM NaBr and 100 mM NaBr were added, and that the transition was unaffected by changing the anionic surfactant from SDS to SDeS when no salt had been added. A phase separation was observed when 50 mM NaBr was added to 95 mol% SDeS/DDAB (the Krafft point was probably reached), and when 100 mM NaBr was added to the same system the sample remained opaque one week after mixing the sample and also after heating it to 40°C in a water bath. The curve for sample 95 mol% SDS/DDAB 1/8192 mM + 100 mM NaBr was oscillating implying possible defects in the vesicle membrane. The cryo-TEM images confirmed the light scattering results and additionally showed that at higher total concentrations agglomeration occurred, while whenever salt was added less vesicles seemed to appear, while both discs and broken vesicles were present suggesting that the disc structure is preferred over the spherical structure when salt is present. Also a vesicle inside another vesicle was discovered for the sample 0.95 SDS/DDAB 3.75 mM + 50 mM NaBr. The mole fraction of anionic surfactant in the aggregates (x) was calculated using a MATLAB code based on the Poisson-Boltzmann theory. The results from the calculations showed that a higher amount of SOS was needed for the system 0.95 SOS/CTAB than the amount of SDS and SDeS needed for the systems 0.95 SDS/DDAB and 0.95 SDeS/DDAB when forming aggregates, indicating that a shorter chain of the anion and the higher spontaneous curvature of the cation leads to a higher curvature. Also a larger amount of cation was needed when the tail was single than when it was double in order to form stable spherical structures. Finally, as the total concentration decreased the x value also decreased in all cases, thus the spontaneous curvature was decreased.
10

Correlations among surfactant drag reduction additive chemical structures, rheological properties and microstructures in water and water/co-solvent systems

Zhang, Ying 12 September 2005 (has links)
No description available.

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