Martin Luther University Halle-Wittenberg

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Research projects

Primary focuses of our research are:

  • synthesis of artificial phospholipids,
  • study their biophysics (especially the aggregation behaviour in aqueous suspension and the miscibility with naturally occuring membrane lipids), and
  • probe their potential applications in pharmaceutical technology and protein analysis

The particular projects:

Bipolar Amphiphiles (bolalipids)

Bipolar amphiphiles (bolalipids) are a special type of lipids. These bolalipids are composed of two hydrophilic headgroups that are connected with one or two hydrophobic alkyl chains. They originate in the membrane lipids (tetraether lipids) of certain Archaebacteria, e.g., thermoacidophiles, where they are responsible for the outstanding stability of those bacteria against extreme living conditions, such as high temperatures or low pH values.

With the synthesis of archaebacterial model lipids we try to mimic the stabilising properties of the tetraether lipids by keeping the chemical structure of the bolalipids as simple as possible in order to maintain the syntheses 'practicable'. These novel bolalipids will firstly be investigated with regard to their aggregation behaviour in aqueous suspension. Subsequently, the mixing behaviour of these bolalipids with different, naturally occuring, liposome-forming phospholipids will be elucidated.
The main target is to identify a bolalipid that is able to stabilise liposomes - which will finally lead to a liposomal formulation that can be used as drug delivery system for oral application.

Furthermore, we are interested in the question: how to control the aggregation behaviour of bipolar amphiphiles by selective modifications of the chemical structure.

To characterise the aggregate structures built by bolalipids in aqueous suspension and to investigate the miscibility of bolalipids with conventional phospholipids, the following methods are used:

  • calorimetric methods (DSC, ITC)
  • scattering methods (DLS, neutron scattering SANS, X-ray scattering SAXS and WAXS)
  • spectroscopic methods (FT-IR, NMR, fluorescence)
  • imaging methods (electron microscopy TEM, cryo-EM, freeze-fracture EM)
  • simulation (Monte Carlo)

Bolalipid-Hydrogele als potentielle drug delivery Systeme:

In diesem Kooperationsprojekt erforschen wir die Eignung von zwei speziellen Bolalipiden zur gezielten Abgabe von Wirkstoffen. Die Gelbildung der Bolalipide in wässriger Dispersion wird dabei als Trägersystem ausgenutzt. Da die Stabilität der Gele nicht hoch genug ist, um direkt als Matrix zur Wirkstoffreisetzung eingesetzt zu werden, nutzen wir die Technik der Lyophilisation, um Xerogele zu erhalten. Bei einer Anwendung können sich dann in situ die Gele bilden und einen eingeschlossenen Arzneistoff kontrolliert freisetzten.

Zum Nachweis der Biokompatibilität und des Verhaltens der Applikationsform Xerogel nach der Anwendung, nutzen wir dazu das chorioallantiosche Membranmodell (CAM-Modell). Ein befruchtetes Hühnerei bildet eine gut zugängliche, stark durchblutete Membran. An dieser können die Reaktionen auf das Trägersystem direkt mittels Mikroskop beobachtet werden. Die befruchteten Hühnereier sind zu diesem Zweck an einem Ende geöffnet und über mehrere Tage bebrütet worden. Anschließend können die Bolalipidgele direkt auf die Oberfläche der Membran gegeben und über einige Tage beobachtet werden. Eine direkte Reaktion auf freigesetzte Arzneistoffe kann man z.B. mit anti- oder pro-angiogenetischen Substanzen erzielen.

Der Effekt der verschiedenen Bolalipide und verschiedener Konzentrationen der Lipide auf die Freisetzung der Wirkstoffe ist hierbei, neben der guten Biokompatibilität, der Hauptfokus dieses Projektes.

Collaborations

Recent publication

An Asymmetrical Glycerol Diether Bolalipid with Protonable Phosphodimethylethanolamine Headgroup: The impact of pH on Aggregation Behavior and Miscibility with DPPC.
T. Markowski, S. Müller, B. Dobner, A. Meister, A. Blume, and S. Drescher
Polymers 2017, 9, 573. [LINK]   


Modified membrane lipids

In this project we will synthesise and modify common phospholipids, e.g., dipalmitoyl phosphocholine (DPPC), in order to address particular problems.

One project is focused on the synthesis of membrane lipids that can be photo-activated. Such lipids include specific structural elements (e.g., diazirine) at a certain position of the long alkyl chain. This diazirine can be activated using UV light producing highly reactive carbene species, which further reacts with membrane proteins. After proteolytic processing of those proteins and mass spectrometric analysis - one should be able to elucidate the structure of membrane proteins.

Another project is focused on the synthesis of deuterated phospholipids, in particular of oxidised variations of these lipids, used for solid-state NMR high resolution studies.

Collaborations

Recent publication

Azide-modified Membrane Lipids: Synthesis, Properties, and Reactivity.
S. Lindner, K. Gruhle, R. Schwarz, V.M. Garamus, D. Ramsbeck, G. Hause,
A. Meister, A. Sinz, and S. Drescher
Langmuir 2017, 33, 4960-4973. [LINK]   


Previous work

Stable organic radicals as EPR probes

In this project we characterised EPR probes that are synthesised in the group of Prof. Peter Imming. These spin probes - triarylmethyl(TAM) radicals - are characterised by remarkable stability under physiological conditions. They allow in vivo monitoring of physico-chemical parameters in the tissue, in which they reside or accumulate. Local oxygen content and the pH value of tissues play an important role in the assessment of pathophysiological processes, particularly in tumor tissues. Investigation were performed in cooperation with Prof. Dr. Karsten Mäder and Prof. Dr. Dariush Hinderberger.

Synthesis and EPR-spectroscopic characterization of the perchlorotriarylmethyl tricarboxylic acid radical (PTMTC) and its 13C labelled analogue (13C-PTMTC).
M. Elewa, N. Maltar-Strmecki, M.M. Said, H.A. El Shihawy, M. El-Sadek, J. Frank, S. Drescher, M. Drescher, K. Mäder, D. Hinderberger, and P. Imming
Phys. Chem. Chem. Phys. 2017, 19, 6688-6697. [LINK]   

Amino-functionalised lipids

This project was focused on the physico-chemical characterisation of amino-functionalised lipids that are synthesised under the responsibility of Dr. Christian Wölk.
Special attention was paid on the investigation of the aggregate structures of those lipids in aqueous suspension using imaging methods, such as electron microscopy.

Investigation of Binary Lipid Mixtures of a Three-Chain Cationic Lipid with Phospholipids Suitable for Gene Delivery.
C. Wölk, C. Janich, A. Meister, S. Drescher, A. Langner, G. Brezesinski, and U. Bakowsky
Bioconjugate Chem. 2015, 26, 2461-2473. [LINK]   

Synthesis of heterocyclic compounds with potential biological activity

Hetercyclic compounds represent still the majority of established drugs. In addition to their relevance as biologically active substances, they represent at the same time very interesting chemical building blocks that can be used as initial point for further preparative modifications. Specific, highly functionalised heterocyclic compounds allow ring transformation and substitution reactions leading to novel heterocyclic systems in only a few synthetic steps. Using this methodology, highly functionalised pyrimidines can be converted into basically substituted pyrimidines or condensated thieno[2.3-d]pyrimidines. In collaboration with other groups, we will test these compounds with respect to their inhibition of tyrosin kinases.

Selective Nucleophilic Substitution Reactions in 2,4,6-Trisulfanyl-substituted Pyrimidin-5-carbonitriles by Secondary Amines.
S. Drescher, D. Ramsbeck, D. Briel, and B. Dobner
J. Het. Chem. 2007, 44, 757-763. [LINK]   

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