The effectiveness of liposomes incorporating bismuth-ethanedithiol and loaded with tobramycin (LipoBiEDT-TOB) at sub-inhibitory concentrations to inhibit the production of quorum sensing signaling molecules and virulence factors induced by P. aeruginosa was evaluated in vitro. In addition, we evaluated the efficacy and safety of free and encapsulated tobramycin in liposomal formulations administered intratracheally to rats chronically infected with P. aeruginosa. LipoBiEDT-TOB significantly reduced the production of quorum sensing signaling molecules and virulence factor secretion compared to free tobramycin. The LipoBiEDT-TOB formulation significantly reduced the bacterial count in lungs, modulated the IL-8 level in blood and minimized the nephrotoxicity that is associated with aminoglycoside treatment. These results support the hypothesis that aerosolization of liposomal aminoglycosides may enhance the management of chronic lung infections caused by resistant P. aeruginosa in patients with cystic fibrosis.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2009. / Härtill 3 uppsatser.

Thesis (Ph.D.) in Chemistry--University of Maine, 2009. / Includes vita. Includes bibliographical references (leaves 144-162).

Thesis (Ph. D.)--University of Wisconsin--Madison, 2003. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (p. 103-116).

No description available.

Μελέτες έχουν δείξει ότι το νευροστεροειδές διυδροεπιανδροστερόνη (DHEA) προστατεύουν τους νευρώνες από ανοξία και απόπτωση. Έχει επίσης αποδειχθεί ότι το DHEA ενισχύει την κινητική δραστηριότητα πιθήκων με τη νόσο του Parkinson, ενώ επίσης σε συνδυασμό με την αλλοπρεγνανολόνη προκαλεί δημιουργία νευρώνων σε αρκετά πειραματικά μοντέλα. Τα λιποσώματα είναι σφαιρικά σωματίδια αποτελούμενα από ενυδατωμένες διπλοστοιβάδες φωσφολιπιδίων οι οποίες σχηματίζονται αυθόρμητα κατά τη διασπορά λιπιδίων στο νερό, εγκλωβίζοντας υδατικό διάλυμα στο εσωτερικό τους. Οι κυκλοδεξτρίνες είναι ολιγοσακχαρίτες με ειδική δομή κώνου, που έχουν υδρόφιλη πολική επιφάνεια και μη πολική εσωτερική κοιλότητα, έχουν τη δυνατότητα να ενσωματώνουν λιπόφιλα φάρμακα στην εσωτερική τους κοιλότητα (με τη δημιουργία συμπλόκων) και να αυξάνουν την υδατική διαλυτότητά τους. Στην παρούσα μελέτη χρησιμοποιήθηκαν τρία παράγωγα του νευροστεροειδούς DHEA, που έχουν τροποποιηθεί στις θέσεις C3 και C17 με σκοπό να βελτιώσουν την αντιαποπτωτική και νευροπροστατευτική δράση τους, καθώς και την αναστολή της μετατροπής τους σε ανδρογόνα και οιστρογόνα. Τα παράγωγα αυτά είναι εξαιρετικά λιπόφιλα και έχουν μικρό μοριακό βάρος και πολύ χαμηλή διαλυτότητα, γεγονός που καθιστά αδύνατη την χορήγησή τους. Για να αντιμετωπιστεί το πρόβλημα της χαμηλής διαλυτότητας, δοκιμάστηκαν δύο μέθοδοι: (1) H παρασκευή σύμπλοκων με υδροξυ-προπυλ-β-κυκλοδεξτρίνη (HP-beta-CD), και (2) Η ενσωμάτωσν των νευροστεροειδών στη λιπιδική μεμβράνη μικρών μονοστoιβαδιακών λιποσωμάτων (SUV) διαφόρων λιπιδικών συστάσεων. Μετά από τροποποίηση μιας ειδικής τεχνικής μέτρησης των στεροειδών, υπολογίστηκαν οι συγκετρώσεις που ενσωματώθηκαν στα λιποσώματα, καθώς και στα σύμπλοκα με τη κυκλοδεξτρίνη. Οι λιποσωμικές μορφές των παραγώγων δεν είχαν την αναμενόμενη ικανότητα ενσωμάτωσης τους, με αποτέλεσμα η συγκέντρωση των λιποσωμικών διαπορών να μην είναι αρκετά υψηλή για in vivo χορήγηση. Αντίθετα η HP-β-CD έδωσε σύμπλοκα που αύξησαν την υδατική διαλυτότητα των παραγώγων θεαματικά.Τα σύμπλοκα χαρακτηρίστηκαν με διάφορες τεχνικές, για να πιστωποιηθεί ο σχηματισμός τους. Με σκοπό να παρασκευαστούν μορφές με δυνατότητα ελεγχόμενης αποδέσμευσης των στεροειδών, μελετήθηκε στο επόμενο στάδιο της διατριβής, η ανάπτυξη υβριδικών μορφών που περιλαμβάνουν τον συνδυασμό συμπλόκων κυκλοδεξτρίνης και λιποσωμάτων, δηλαδή: λιποσώματα που στην εσωτερική τους κοιλότητα εγκλωβίζουν τα υδατοδιαλυτά σύμπλοκα των παραγώγων με κυκλοδεξτρίνες. Τα υβριδικά αυτά συστήματα είχαν αυξημένη ενσωμάτωση των νευροστεροειδών σε σύγκριση με τα συμβατικά λιποσώματα και κατάλληλα χαρακτηριστικά για in vivo χορήγηση. / Studies have shown that the neuroactive steroid dehydroepiandrosterone (DHEA) protects neurons from anoxia and apoptosis. It has also been demonstrated that DHEA is able to potentiate locomotor activity of hemi – Parkinsonian monkeys, and in conjunction with allopregnanolone can induce neurogenesis in various experimental models. Liposomes are spherical particles composed of hydrated bilayers of phospholipids which are formed spontaneously during the dispersion of lipids in water, entrapping aqueous solution inside. Cyclodextrins are oligosaccharides with specific cone structure that have the ability to incorporate lipophilic drugs and increase their aqueous solubility. In the present study, three DHEA analogues were used, which have been modified at positions C3 and C17 in order to improve the antiapoptotic and neuroprotective activity, and to inhibit of their conversion into androgens and estrogens. These derivatives are highly lipophilic and have small molecular weight. In order to find a solution for their very low aqueous solubility which is a problem for their in vivo administration, two methodologies were investigated: (1) The formation of soluble complexes with hydroxy-propyl-beta-cyclodextrin (HP-β-CD), and (2) the incorporation of the steroids in the lipid bilayer of small unilamellar liposomes (SUV) of various lipid compositions. After adjusting a special measurement technique for the neurosteroids, we calculated the concentration of the neurosteroids incorporated into liposomes, as well as in complexes with the cyclodextrin.The liposomal forms of the derivatives did not have the expected integration ability, resulting in a concentration of liposomal dispersion which is not high enough for in vivo administration. On the other hand, the HP-β-CD complexes increased the aqueous solubility of the derivatives to a significant extent. The complexes were characterized by various techniques, in order to verify their existence. With the aim of preparing formulations with the ability of controlled release of steroids, we investigated in the last part of this thesis, the possibility to develop hybrid systems that consist of liposomes which entrap the highly soluble steroid-cyclodextrin complexes in their internal cavity. These hybrid systems had better integration capacity compared to conventional liposomes and were suitable for in vivo administration (for both intravenous and intravitreal administration). These hybrid systems can also ensure controlled release of the steroid analogues.

The aim of this diploma thesis is the preparation of liposome nanoparticles enriched with PHA and PHA nanofibers. The nanostructures served to encapsulate extracts of lipophilic and hydrophilic nature. The characterization of the properties of nanostructures such as polydispersity, size, colloidal stability, long-term stability after exposure to various environments such as seawater, water from the Brno dam and tap water, and finally the cytotoxicity of fibers with extracts was addressed. The theoretical part is focused on different types of water, human skin, coffee and subsequently carotenoids. It continues by describing of possibilities of extraction and preparation of lipophilic and hydrophilic extracts and possibilities of their determination is discussed. Finally, it describes the possibilities of preparation and characterization of PHA based nanomaterials. The practical part deals with the preparation of liposome particles and fibers enriched with PHA with encapsulated extracts, their characterization, and their subsequent exposure to various environments. Monitoring of their long-term stability was carried out, but the release of the encapsulated extracts into the environment to which the nanoparticles and nanofibers were exposed was also measured. Finally, the interaction of nanofibers with live HaCaT cells was monitored, and cytotoxicity assays determined the viability of the cells after interaction with the nanofibers.

We investigated the effects of angiotensinogen (Ang), angiotensin I (Ang I), and angiotensin II (Ang II) on the fluidity of phosphatidylcholine vesicles. Changes in fluidity were assessed by changes in anisotopy values calculated from fluorescence polarization measurements. All three compounds produced an increase in membrane fluidity when localized inside the phosphatidylcholine vesicles. When placed outside the vesicles. Ang II increased bilayer rigidity (decreased fluidity), whereas Ang and Ang I produced no effect. These results suggest the possibility that these peptides may alter the fluidity of cell membranes by a direct action on the phospholipid bilayer, which may in turn interfere with receptor-mediated effects.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

Liposomes incorporating chlorophyll (Chl) have been used as a model system to study various aspects of photosynthesis (such as Chl photooxidation and acceptor reduction). Laser flash photolysis studies of this system have demonstrated that the Chl triplet state (Chl(t)) can transfer an electron to acceptors such as quinones, resulting in the formation of the Chl cation radical (Chl⁺.) and the semiquinone anion radical (Q¯.). Quenching of Chl(t) by quinones in liposomes is diffusion-controlled. The quenching rate is dependent upon bilayer viscosity. Chl(t) lifetimes in the absence of quinones also reflect bilayer viscosity. Radical decay occurs by reverse electron transfer. Although the decay is non-exponential, the decay rate is independent of laser intensity. This is presumably because radical pairs once formed do not become independent of one another and back react in a manner which can be likened to geminate recombination. The non-exponentiality is due to electron exchange between quinone molecules and the heterogeneity in the distribution of molecules among the vesicles. This electron exchange is also manifested in the radical formation process. At high quinone concentration the radical yield increases with quinone concentration in non-linear fashion with respect to the amount of triplet quenched. This positive cooperative effect is interpreted in terms of high quinone concentrations increasing the efficiency of radical production by providing a pathway (via electron hopping) for removal of the electron from the site of initial electron transfer. When ubiquinone is used, only a single fast decay is observed. However, when quinones which can partition between the aqueous and lipid phases are used, radical decay occurs via a fast and a slow process. This is interpreted in terms of electron transfers from Q¯. within the bilayer to Q at the bilayer-water interface which results in a stabilization of the electron transfer products and a slowly-decaying radical. The rate of this slow decay process is also quinone concentration dependent, which is a consequence of a facilitation of electron return to Chl⁺. by Q molecules within the bilayer via an electron hopping mechanism. That such a mechanism is, in fact, operative in radical production is shown also by the observation of electron transfer from UQ¯. to BQ molecules.