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Locations and reorientations of multi-ring-fused 2-Pyridones in Ganglioside GM1 Micelles
Umeå University, Faculty of Science and Technology, Department of Chemistry. (J. Heyrovsk"y Institute of Physical Chemistry of the Academy of Sciences of the Czech Republic, Dolejškova 3, 182 23 Prague 8, Czech Republic)
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2011 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, no 5, 1662-1667 p.Article in journal (Refereed) Published
Abstract [en]

Fluorescent multi-ring-fused 2-pyridones, with chemical resemblance to other biologically active 2-pyridone systems, were solubilized in spherical micelles formed by the gangloiside GM1 and studied with respect to their spatial localization and rotational mobility. For this, electronic energy transfer between the multi-ring-fused 2-pyridone (donor) and BODIPY-FL-labeled GM1 was determined, as well as their fluorescence depolarization. From the obtained efficiency of energy transfer to the acceptor group (BODIPY-FL), either localized in the polar or in the nonpolar part of the ganglioside, it has been possible to estimate the most likely localization of the multi-ring-fused 2-pyridones. The center of mass of the studied multi-ring-fused 2-pyridones are located at approximately 33 Å from the micellar center of mass, which corresponds to the internal hydrophobic-hydrophilic interfacial region. At this location, the reorienting rates of the multi-ring-fused 2-pyridones are surprisingly slow with typical correlation times of 35-55 ns. No evidence was found for the formation of ground and excited state dimers, even when two monomers were forced to be near each other via a short covalent linker.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2011. Vol. 27, no 5, 1662-1667 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-40167DOI: 10.1021/la104051zOAI: oai:DiVA.org:umu-40167DiVA: diva2:398044
Note
Publication Date on Web January 6, 2011 Available from: 2011-02-16 Created: 2011-02-16 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Optical characterization of potential drugs and drug delivery systems
Open this publication in new window or tab >>Optical characterization of potential drugs and drug delivery systems
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This Thesis is a characterization study on substances having potency as drugs as well as on a lipid based drug-delivery matrix. The optical properties of newly synthesized molecules with proven pilicide properties have been characterized with several spectroscopic methods. These methods include optical absorption and fluorescence as well as time-resolved fluorescence. Upon covalently linking compounds with high quantum yields of fluorescence to specific parts of the pilicide, the biological impact was found to increase for some of the derivatives. Furthermore, by expanding the aromatic part of the pilicide molecule, a significant increase in the inherent fluorescence was obtained. The S0-S1 absorption band for these molecules was found to originate from an impure electronic transition, vibronically promoted by intensity borrowing from higher electronic states.

Included in this Thesis is the measurement of how deeply some in this class of newly synthesized molecules become situated when placed inside ganglioside GM1 micelles, and how the molecules’ reorientation is affected. By means of radiation-less energy transfer, it was shown that the molecules place themselves close to the hydrophobic-hydrophilic interface inside the GM1 micelles. As a consequence they are exposed to a densely packed environment, which inhibits the free tumbling of the molecule. This restricted tumbling could be measured by means of time-resolved depolarization experiments.

The release of drug-like fluorescent molecules is investigated from a lipid mixture, which upon equilibrium with water forms a mixture of inverted hexagonal and cubic phases. The lipid matrix displayed an extended release over the course of weeks, in vitro, for molecules having a large variation in hydrophobicity.

Place, publisher, year, edition, pages
Umeå: Kemiska institutionen, Umeå universitet, 2011. 35 p.
Keyword
Pilicide, Ganglioside GM1 micelles, Drug Delivery, Elecronic Energy Transfer, UV-Vis Absorption, Fluorescence Spectroscopy
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-40177 (URN)978-91-7459-157-6 (ISBN)
Public defence
2011-03-11, KBC-huset, KB3A9, Umeå Universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2011-02-18 Created: 2011-02-16 Last updated: 2011-02-18Bibliographically approved
2. Localisation of Fluorescent Probes and the estimation of Lipid Nanodomain sizes by modern fluorescence techniques
Open this publication in new window or tab >>Localisation of Fluorescent Probes and the estimation of Lipid Nanodomain sizes by modern fluorescence techniques
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[cs]
Lokalizace fluorescenčních značek a určování velikostí lipidových nanodomén pomocí moderních fluorescenčních metod
Abstract [en]

The thesis is divided into two major parts. The first part focuses on the localisation of probes in lipid/polymeric bilayers and in GM1 micelles. Included in this thesis is a new approach based on electronic energy transfer/migration (FRET/DDEM), which efficiently determines transversal positions of fluorescent molecules in lipid bilayers. This approach has been used to locate newly synthesized lipid probes in DOPC bilayers. The label was introduced at the end of sn-2 acyl chains of variable length.

Analytical models accounting for FRET exist for a limited number of basic geometries. Here, a combination of FRET and Monte Carlo simulations enables the localisation of probes in bicelles and in bilayers containing pores, i.e. in lipid systems with variable curvature, or in non-homogenous lipid systems. This approach has been used to test whether conical-like fluorescence probes have an increased affinity to highly curved regions, which would enable preferential labelling of membrane pores.

A simplified FRET model has been applied to localize 2-pyridones, a class of potential drugs, in GM1 micelles. Since the localisation of drugs within nanoparticles might influence the release kinetics and loading efficiency, knowledge about the drug location is highly relevant. It turned out that all derivatives were localised at the core-shell interface of GM1 micelles.

The second part of the thesis focuses mainly on the estimation of lipid nanodomain size by means of FRET, which still remains the most powerful method in this field. Limitations of FRET in the determination of domain size have been explored. We showed that the limitations of FRET are mainly caused by a low probes affinity to either the liquid-ordered or liquid-disordered phase. In the continuing work we provided a detailed dynamic and structural study of crosslinker-triggered formation of nanodomains. Here, two different domains have been revealed, i.e. i) domains whose size grows with increasing amount of added cholera toxin (CTxB), and to which CTxB binds tightly; ii) domains formed in membranes containing a slightly increased amount of sphingomyelin (as compared to i) whose size does not change during titration by additional CTxB and to which CTxB binds less tightly.

Abstract [cs]

Disertace je rozdělena do dvou hlavníchčástí. Prvníčást se zabývá lokalizací značek v lipidových/polymerních dvojvrstvách a v GM1micelách. V práci prezentujeme nový přístup založený na přenosu/migraci elektronické energie (FRET/DDEM), jež umožňuje efektivně určovat vertikální pozici fluorescenčních molekul uvnitř lipidové dvojvrstvy. Tato metoda byla použita k lokalizaci nově syntetizovaných lipidových značek značených na konci sn-2 acylového řetězce s různou délkou v DOPC dvojvrstvách.

Analytické modely popisující FRET existují pouze pro limitovaný počet základních geometrií. Kombinace FRETu s Monte Carlo simulacemi nicméně umožňuje lokalizaci značek v bicelách a v dvojvrstvách obsahujících póry, tj. v lipidových systémech s proměnlivým zakřivením a v nehomogenních lipidových útvarech. Tento přístup umožnil např. zjistit, zda kuželovitětvarované značky mají zvýšenou afinitu k vysoce zakřiveným oblastem dvojvrstvy, což by umožnilo preferenční značení pórů.

Lokalizovány byly rovněž tři deriváty 2-pyridonů(potencionálních léčiv) v GM1micelách za použití jednoduchého modelu zohledňujícího FRET mezi donory a akceptory nacházejícími se v micelách. Lokalizace léčiv v nanočásticích ovlivňuje kinetiku uvolňování (release kinetics) a množství látky solubilizované v micelách (loading efficiency).

Druhá část se především zabývá určováním velikostí lipidových nanodomén pomocí FRETu, který stále zůstává nejvíce výkonnou metodou v této oblasti. Zkoumány byly limitace FRETu v určování lipidových nanodomén. Ukázalo se, že tato omezení jsou především způsobena nízkou afinitou značek buď k Lonebo k Ldfázi. V navazující studii jsme poskytnuli detailní dynamickou a strukturní studii formace nanodomén indukované crosslinkerem. Objevili jsme dva typy domén: a) domény, jejichž velikost se zvětšuje s rostoucím množstvím přidaného cholera toxinu (CTxB) a k nimž se CTxB váže pevně a b) domény vzniklé v membránách se zvýšeným množstvím sfingomyelinu (ve srovnání s a)), jejichž velikost se nemění během titrace dodatečným CTxB a k nimž se CTxB váže méně pevně.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. 46 p.
Keyword
Electronic energy transfer, fluorescence, rafts, lipid bilayer, bicelles, micelles
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-52619 (URN)978-91-7459-390-7 (ISBN)
Public defence
2012-03-27, KBC-huset, KB3A9, Umeå Universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Note
This thesis has been elaborated within the framework of the Agreement on Joint Supervision (co-tutelle) of an International Doctoral Degree Programme between Charles University in Prague, Czech Republic and the Department of Chemistry at Umeå University, Sweden.Available from: 2012-03-06 Created: 2012-02-28 Last updated: 2012-02-28Bibliographically approved

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Sachl, RadekRosenbaum, ErikSellstedt, MagnusAlmqvist, FredrikJohansson, Lennart B-Å

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