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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

THE DEVELOPMENT OF INTRACELLULAR NANOSENSORS: ACID-DEGRADABLE POLYMERIZED PHOSPHOLIPID VESICLES AND FLUORESCENT LABELS

Roberts, David January 2010 (has links)
Phospholipid vesicles are biocompatible, and have potential for intracellular applications, but minimal membrane integrity limits their use in membrane-rich environments. Stabilized membranes overcome this limitation while maintaining biocompatible surface structures. Additionally, the modularity of phospholipid bilayer makes them ideal components when designing biologically inspired sensors. Membrane composition can be tailored to specific applications, transmembrane proteins can provide added functionalities, and the isolated interior can prevent cytotoxic and interfering detection chemistries from altering the cellular environment. This work has focused on expanding the capabilities of stabilized phospholipid membranes, and determining which formulations hold promise in developing stabilized phospholipid vesicle nanosensors.Current membrane stabilization methods suffer from either incomplete stabilization, or irreversible stabilization limiting the applications of vesicle nanosensors. Therefore, a facile method to prepare robust phospholipid vesicles using commonly available phospholipids stabilized via the formation of an interpenetrating, acid-labile, cross-linked polymer network that imparts controlled polymer destabilization and subsequent vesicle degradation was developed. Upon exposure to acidic conditions, the highly cross-linked polymer network was converted to linear polymers, substantially reducing vesicle stability upon exposure to chemical and physical insults. The resultant transiently stabilized vesicles have potential for enhanced drug delivery and chemical sensing applications requiring minimal membrane defects, and allow for improved physiological clearance.Some vesicle nanosensor schemes may require the passive diffusion of low molecular weight species across the membrane in addition to controllable degradation. Therefore, the acid-degradable, polymer-stabilized, phospholipid vesicle production method was extended to bis-SorbPC membranes by simultaneously polymerizing the vesicle with an acetal-containing cross-linker. The vesicles display prolonged stability under physiological conditions, and significant additional stability compared to vesicles composed of naturally occurring phospholipids. The vesicles demonstrated potential utility for sensing and therapeutic applications.Phospholipid vesicles can also serve as labels to observe movement in macromolecular biological assemblies, but a dearth of caged fluorescent labels limits design and function. Therefore, the first caged fluorescent thiol was synthesized, shown to label amines rapidly, and demonstrated the required photolytic properties. The caged fluorescent thiol has potential as a label in observing the movement of macromolecular biological assemblies and as a fluorescent probe for observing endosomal trafficking and release.
2

Biodegradable polymeric delivery systems for protein subunit vaccines

Heffernan, Michael John 17 June 2008 (has links)
The prevention and treatment of cancer and infectious diseases requires vaccines that can mediate cytotoxic T lymphocyte-based immunity. A promising strategy is protein subunit vaccines composed of purified protein antigens and immunostimulatory adjuvants, such as Toll-like receptor (TLR) agonists. In this research, we developed two new biodegradable polymeric delivery vehicles for protein antigens and TLR agonists, as model vaccine delivery systems. This work was guided by the central hypothesis that an effective vaccine delivery system would have stimulus-responsive degradation and release, biodegradability into excretable non-acidic degradation products, and the ability to incorporate various TLR-inducing adjuvants. The first vaccine delivery system is a cross-linked polyion complex micelle which efficiently encapsulates proteins, DNA, and RNA. The micelle-based delivery system consists of a block copolymer of poly(ethylene glycol) (PEG) and poly(L-lysine), cross-linked by dithiopyridyl side groups to provide transport stability and intracellular release. The second delivery system consists of solid biodegradable microparticles encapsulating proteins, nucleic acids, and hydrophobic compounds. The microparticles are composed of pH-sensitive polyketals, which are a new family of hydrophobic, linear polymers containing backbone ketal linkages. Polyketals are synthesized via a new polymerization method based on the acetal exchange reaction and degrade into non-acidic, excretable degradation products. In addition, the technique of hydrophobic ion pairing was utilized to enhance the encapsulation of ovalbumin, DNA, and RNA in polyketal microparticles via a single emulsion method. Using in vitro and in vivo immunological models, we demonstrated that the micelle- and polyketal-based vaccine delivery systems enhanced the cross-priming of cytotoxic T lymphocytes. The model vaccines were composed of ovalbumin antigen and various TLR-inducing adjuvants including CpG-DNA, monophosphoryl lipid A, and dsRNA. The results demonstrate that the cross-linked micelles and polyketal microparticles have considerable potential as delivery systems for protein-based vaccines.
3

Nouveaux polymères issus de la polymérisation par étapes organocatalysée de monomères aldéhydiques : polyaldols et polybenzoïnes linéaires et polyacétals hyperramifiés / New polymers synthesis by organocatalyzed step-growth polymerization of aldehydic monomers : polyaldols, linear polybenzoin and hyperbranched polyacetals

Liu, Na 11 July 2013 (has links)
A partir des mêmes briques élémentaires portant des fonctions aldéhydes et mettant en jeu des catalyseurs différents, trois types de nouveaux polymères ont été synthétisés par la polymérisation par étape dans ce travail. Dans la première partie, bis-cétone et bis-aldéhyde monomères ont directement polymérisé dans des conditions stoechiométriques par ce processus offrant polyaldols. Divers catalyseurs et des effets de la nature du solvant ont ensuite été étudiés. Dans la deuxième partie, nous avons travaillé sur la polymérisation organo-catalysée de monomères bis-aldéhydes par des précurseurs de carbènes N-hétérocycliques chiraux et achiraux pour synthétiser les polymères chiraux. Enfin, la directe polymérisation des monomères de type AB2 avec une fonction aldéhyde fournit une facile synthétique approche à polyacétals hyperbrramifiés portant nombreux périphéries aldehyiques. Ces polyacétals hyperramifiés sans défauts structuraux ont ensuit été introduirsé par des chaines de PEO par réaction de « PEGylation ». L’utilisation de la postpolymymérisation permet d’offre un large varité de la propriété du polymère, à l’aide ces périphéries aldéhydiques. Enplus, les polyacétals hyperramifiés sont dégradables, et facilement hydrolysés en milieu acide. / Using the same building blocks carrying aldehyde function with different catalysts, three types of new polymers were synthesized by step-growth polymerization in this work. In the fist part, bis-ketone and bis-aldehyde monomers have been directly polymerized under stoichiometric conditions by this process affording polyaldols. The effects of different catalysts and solvent nature have also been studied. In the second part, we have studied the organo-catalyzed polymerization of bis-aldehyde monomers by precursors of chiral and achiral N-heterocyclic carbene for synthesis of chiral polymer. Finally, polymerization of AB2-type monomers with one function of aldehyde provides a facile synthetic approach to hyperbranched polyacetals carrying numerous peripheral aldehydes. These defect free hyperbranched polyacetals have been introduced PEO chains by "PEGylation" reaction. A wide variety of other functional moieties could be introduced by postpolymerization with peripheral aldehydes. Besides, the hyperbranched polyacetals are degradable in essence, being readily hydrolyzed under acidic condition.

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