Chemical Lipidology Group
University of Fribourg

Marzia Buscema, Sofiya Matviykiv, Tamas Meszaros, Gabriela Gerganova, Andreas Weinberger, Ute Mettal, Dennis Mueller, Frederik Neuhaus, Etienne Stalder, Takashi Ishikawa, Rudolf Urbanics, Till Saxer, Thomas Pfohl, Janos Szebeni, Andreas Zumbuehl, Bert Müller
Immunological response to nitroglycerin-loaded shear-responsive liposomes in vitro and in vivo
Journal of Controlled Release 2017264, 14–23.

Liposomes formulated from the 1,3-diamidophospholipid Pad-PC-Pad are shear-responsive and thus promising nano-containers to specifically release a vasodilator at stenotic arteries. The recommended preclinical safety tests for therapeutic liposomes of nanometer size include the in vitro assessment of complement activation and the evaluation of the associated risk of complement activation-related pseudo-allergy (CARPA) in vivo. For this reason, we measured complement activation by Pad-PC-Pad formulations in human and porcine sera, along with the nanopharmaceutical-mediated cardiopulmonary responses in pigs. The evaluated formulations comprised of Pad-PC-Pad liposomes, with and without polyethylene glycol on the surface of the liposomes, and nitroglycerin as a model vasodilator. The nitroglycerin incorporation efficiency ranged from 25% to 50%. In human sera, liposome formulations with 20 mg/mL phospholipid gave rise to complement activation, mainly via the alter- native pathway, as reflected by the rises in SC5b-9 and Bb protein complex concentrations. Formulations having a factor of ten lower phospholipid content did not result in measurable complement activation. The weak complement activation induced by Pad-PC-Pad liposomal formulations was confirmed by the results obtained by performing an in vivo study in a porcine model, where hemodynamic parameters were monitored continuously. Our study suggests that, compared to FDA-approved liposomal drugs, Pad-PC-Pad exhibits less or similar risks of CARPA.


Frederik Neuhaus, Fabio Zobi, Gerald Brezesinski, Marta Dal Molin, Stefan Matile, Andreas Zumbuehl
Correlation of surface pressure and hue of planarizable push-pull chromophores at the air/water interface
Beilstein Journal of Organic Chemistry 201713, 1099–1105.

It is currently not possible to directly measure the lateral pressure of a biomembrane. Mechanoresponsive fluorescent probes are an elegant solution to this problem but it requires first the establishment of a direct correlation between the membrane surface pressure and the induced color change of the probe. Here, we analyze planarizable dithienothiophene push–pull probes in a monolayer at the air/water interface using fluorescence microscopy, grazing-incidence angle X-ray diffraction, and infrared reflection–absorption spectroscopy. An increase of the lateral membrane pressure leads to a well-packed layer of the ‘flipper’ mechanophores and a clear change in hue above 18 mN/m. The fluorescent probes had no influence on the measured isotherm of the natural phospholipid DPPC suggesting that the flippers probe the lateral membrane pressure without physically changing it. This makes the flipper probes a truly useful addition to the membrane probe toolbox.


Frederik Neuhaus, Dennis Mueller, Radu Tanasescu, Sandor Balog, Takashi Ishikawa, Gerald Brezesinski, and Andreas Zumbuehl
Vesicle Origami: Cuboid Phospholipid Vesicles Formed by Template-Free Self-Assembly
Angewandte Chemie 201756, 6515–6518.

Phospholipid liposomes are archetypical self-assembled structures. To minimize the surface tension, the vesicles typically are spherical. Deciphering the bilayer code, the basic physical interactions between phospholipids would allow these molecules to be utilized as building blocks for novel, non-spherical structures. A 1,2-diamidophospholipid is presented that self-assembles into a cuboid structure. Owing to intermolecular hydrogen bonding, the bilayer membranes form an exceptionally tight subgel packing, leading to a maximization of flat structural elements and a minimization of any edges. These conditions are optimized in the geometrical structure of a cube. Surprisingly, the lateral surface pressure in the membrane is only one third of the value typically assumed for a bilayer membrane, questioning a long-standing rule-of-thumb.


J. Thomas Hannich, Denia Mellal, Suihan Feng, Andreas Zumbuehl, and Howard Riezman
Structure and conserved function of iso-branched sphingoid bases from the nematode Caenorhabditis elegans
Chemical Science 20178, 3676–3686.

Sphingolipids are bio-active metabolites that show structural diversity among eukaryotes. They are essential for growth of all eukaryotic cells but when produced in an uncontrolled manner can lead to cell death and pathologies including auto-immune reactions, cancer, diabetes and neurodegeneration. Caenorhabditis elegans is an important genetic model organism both to find new drug-targets against parasitic nematodes and to study the conserved roles of sphingolipids in animals like their essential functions in very basic cellular processes ranging from maintenance of cell polarity and mitochondrial repair to growth and survival. C. elegans produces sphingoid bases which are structurally distinct from those of other animals as both iso- and anteiso-branched species have been reported. Using metabolic labeling we show that most worm sphingoid bases are iso-branched. We have synthesized the nematode-specific C17 iso-branched sphinganine and its 1-deoxy analogue and could show that both the iso-branch and the 1-hydroxyl group are essential to form functional nematode sphingolipids which are needed to maintain intestinal function. The organism specificity was examined by complementation experiments in Saccharomyces cerevisiae yeast cells lacking sphingoid base synthesis. We found that iso-branched sphingoid base did not support growth of mutant cells and was toxic to wild type yeast. 1-Deoxy sphingolipids have been linked to the hereditary disease HSAN1A and other metabolic disorders including diabetes. We found that in C. elegans the 1-deoxy analogue cannot rescue the intestinal phenotype caused by sphingoid base depletion. In fact, in wild-type animals with normal sphingoid base biosynthesis, exogenous 1-deoxy analogue had a disruptive effect on apical cytoskeletal organization of intestinal cells indicating that atypical bases can interfere with normal sphingolipid function.


Etienne Stalder and Andreas Zumbuehl
Liposome-Containing Mechanoresponsive Hydrogels
Macromolecular Materials and Engineering2017, 302, 1600549.


The direct injection of a drug into a joint can relieve osteoarthritic pain for a short period of time. The problem is that the drug will not stay at the allocated location. Therefore, a proof-of-concept in situ is designed forming hydrogel containing liposomes that are covalently linked to the hydrogel network. When the liposomes are filled with a cargo, the formed hydrogel is thus loaded with this cargo, too. Due to the link between the hydrogel and the liposomes, a compression or other mechanical force applied to the hydrogel will rupture the liposomes and release a small percentage of the cargo. Overall, a long-term intra-articular drug release is feasible.


Sofiya Matviykiv, Marzia Buscema, Hans Dehlye, Thomas Pfohl, Andreas Zumbuehl, Till Saxer, Bert Müller
X-ray micro computed tomography for the visualization of an atherosclerotic human coronary artery
Journal of Physics: Conference Series 2017849, 012002.

Atherosclerosis refers to narrowing or blocking of blood vessels that can lead to a heart attack, chest pain or stroke. Constricted segments of diseased arteries exhibit considerably increased wall shear stress, compared to the healthy ones. One of the possibilities to improve patient’s treatment is the application of nano-therapeutic approaches, based on shear stress sensitive nano-containers. In order to tailor the chemical composition and subsequent physical properties of such liposomes, one has to know precisely the morphology of critically stenosed arteries at micrometre resolution. It is often obtained by means of histology, which has the drawback of offering only two-dimensional information. Additionally, it requires the artery to be decalcified before sectioning, which might lead to deformations within the tissue. Micro computed tomography (μCT) enables the three-dimensional (3D) visualization of soft and hard tissues at micrometre level. μCT allows lumen segmentation that is crucial for subsequent flow simulation analysis. In this communication, tomographic images of a human coronary artery before and after decalcification are qualitatively and quantitatively compared. We analyse the cross section of the diseased human coronary artery before and after decalcification, and calculate the lumen area of both samples.


 

Sofiya Matviykiv, Marzia Buscema, Tamas Meszaros, Gabriela Gerganova, Thomas Pfohl, Andreas Zumbuehl, Janos Szebeni, Bert Müller
Liposomes: bio-inspired nano-containers for physically triggered targeted drug delivery
Proceedings of SPIE 2017, 10162, 101620A-1–101620A-14.

For natural scientists and engineers, learning from nature has tradition and is often driven by bio-inspired processes and materials. For example, engineers have designed multifunctional materials with hierarchical structures. Lipid bilayers, the principal components of cell membranes, can form vesicles, termed liposomes. Such liposomes are usually recognized as foreign by the immune system of a patient, which makes it challenging to use liposomes as containers for targeted drug delivery. There are, however, promising non-spherical, mechano-sensitive, artificial liposomes about 100 nm in diameter, which were recently identified. These bio-inspired containers offer a wide range of applications. In particular, the targeted release at critically stenosed arteries formed as a result of atherosclerosis significantly reduces the undesired side effects such as a drop of blood pressure. It is well known that FDA-approved liposomal drugs, currently on the market, often induce adverse immune responses. Therefore, to exclude the hypersensitivity of the recently discovered mechano-sensitive liposomes, we have performed in vitro complement activation experiments and related animal studies with pigs. Recently, it has been shown that the drug-free Pad-PC-Pad liposomes surprisingly lack any complement activation. In this study, we demonstrate that nitroglycerin-loaded liposomes with relevant human therapeutic dosage exhibit low complement activation compared to the FDA-approved phospholipid drugs, including Abelcet. Furthermore, the liposomal suspensions applied are stable for a period of more than two months. Consequently, the non-spherical liposomes of nanometer size we have developed are promising containers for physically triggered, targeted drug delivery.


Radu Tanasescu, Martin A. Lanz, Dennis Mueller, Stephanie Tassler, Takashi Ishikawa, Renate Reiter, Gerald Brezesinski, Andreas Zumbuehl
Vesicle Origami and the Influence of Cholesterol on Lipid Packing
Langmuir 201632, 4896-4903.

 


The artificial phospholipid Pad-PC-Pad was analyzed in 2D (monolayers at the air/water interface) and 3D (aqueous lipid dispersions) systems. In the gel phase, the two leaflets of a Pad-PC-Pad bilayer interdigitate completely, and the hydrophobic bilayer region has a thickness comparable to the length of a single phospholipid acyl chain. This leads to a stiff membrane with no spontaneous curvature. Forced into a vesicular structure, Pad-PC-Pad has faceted geometry, and in its extreme form, tetrahedral vesicles were found as predicted a decade ago. Above the main transition temperature, a noninterdigitated L? phase with fluid chains has been observed. The addition of cholesterol leads to a slight decrease of the main transition temperature and a gradual decrease in the transition enthalpy until the transition vanishes at 40 mol % cholesterol in the mixture. Additionally, cholesterol pulls the chains apart, and a noninterdigitated gel phase is observed. In monolayers, cholesterol has an ordering effect on liquid-expanded phases and disorders condensed phases. The wavenumbers of the methylene stretching vibration indicate the formation of a liquid-ordered phase in mixtures with 40 mol % cholesterol.


Simon Bugna, Marzia Buscema, Sofiya Matviykiv, Rudolf Urbanics, Andreas Weinberger, Tamas Meszaros, Janos Szebeni, Andreas Zumbuehl, Till Saxer, Bert Müller
Surprising lack of liposome-induced complement activation by artificial 1,3-diamidophospholipids in vitro
Nanomedicine NBM 201612, 845-849.

Cardio-vascular diseases are the main cause of death, emphasizing the need to improve patient treatment and survival. One therapeutic approach is a liposome-based drug carrier system specifically targeting constricted arteries. The recently discovered mechano-sensitive liposomes use hemodynamic shear-stress differences between healthy and constricted blood vessels as trigger for drug release. Liposomes are promising delivery containers but are being recognized as foreign by the immune system. Complement activation as essential factor of the recognition leads to adverse effects. Here, we tested complement activation by liposomes formulated from the artificial phospholipid Pad-PC-Pad in vitro. Surprisingly no complement activation was detected in human sera and porcine plasma. In in vivo experiments with three pigs, neither anaphylactic reactions nor other significant hemodynamic changes were observed even at comparably high liposome doses. The pilot study holds promise for an absence of complement-mediated adverse effects of Pad-PC-Pad liposomes in humans.


Andreas Weinberger, Radu Tanasescu, Cristina Stefaniu, lllya A. Fedotenko, France Favarger, Takashi Ishikawa, Gerald Brezesinski, Carlos M. Marques, and Andreas Zumbuehl
Bilayer Properties of 1,3-Diamidophospholipids
Langmuir 2015, 31, 1879-1884.


A series of 1,3-diamido phosphocholines was synthesized, and their potential to form stable bilayers was investigated. Large and giant unilamellar vesicles produced from these new lipids form a wide variety of faceted liposomes. Factors such as cooling rates and the careful choice of the liposome preparation method influence the formation of facets. Interdigitation was hypothesized as a main factor for the stabilization of facets and effectively monitored by small-angle X-ray scattering measurements.


Cristina Stefaniu, Pierre-Leonard Zaffalon, Alessio Carmine, Quentin Verolet, Samuel Fernandez, Tomasz A. Wesolowski, Gerald Brezesinski, Andreas Zumbuehl
Rigid Urea and Self-Healing Thiourea Ethanolamine Monolayers
Langmuir 2015, 31, 1296–1302.


A series of long-tail alkyl ethanolamine analogs containing amide-, urea-, and thiourea moieties was synthesized and the behavior of the corresponding monolayers was assessed on the Langmuir–Pockels trough combined with grazing incidence X-ray diffraction experiments and complemented by computer simulations. All compounds form stable monolayers at the soft air/water interface. The phase behavior is dominated by strong intermolecular headgroup hydrogen bond networks. While the amide analog forms well-defined monolayer structures, the stronger hydrogen bonds in the urea analogs lead to the formation of small three-dimensional crystallites already during spreading due to concentration fluctuations. The hydrogen bonds in the thiourea case form a two-dimensional network, which ruptures temporarily during compression and is recovered in a self-healing process, while in the urea clusters the hydrogen bonds form a more planar framework with gliding planes keeping the structure intact during compression. Because the thiourea analogs are able to self-heal after rupture, such compounds could have interesting properties as tight, ordered, and self-healing monolayers.


Bert Müller, Andreas Zumbuehl, Martin A. Walter, Thomas Pfohl, Philippe C. Cattin, Jörg Huwyler, and Simone E. Hieber
Translational Medicine: Nanoscience and Nanotechnology to Improve Patient Care
Chapter 15 in: The Nano-Micro Interface: Bridging the Micro and Nano Worlds, 2nd Edition. Wiley VCH, 2014, ISBN: 978-3-527-33633-3.

The present chapter focuses on selected clinically relevant challenges that can realistically be overcome by nanomedicine approaches in the near future. The four most prevalent diseases in Europe are cancer, cardiovascular and neurodegenera- tive diseases, as well as disorders of the musculoskeletal system. Here, we will focus on selected solutions to cardiovascular diseases and musculoskeletal disorders. In these fields, therapeutic strategies are based upon quantitative understanding of the nanostructure and mechanical properties of human hard and soft tissues. Deeper understanding of diseases based on nanometer- and micrometer-scale mechanical characterization methods and, above all, structural imaging down to the molecular scale help in clarifying the roots of underlying pathological pro- cesses, allowing for elaborating preventive strategies and enabling the develop- ment of adaptive local drug delivery. For instance, one main focus is the design of mechanosensitive nanocarriers and nanocontainers to deliver active substances at target locations in predefined doses.


Andreas Zumbuehl, Bodo Dobner, Gerald Brezesinski
Phase Behavior of selected Artificial Lipids
Current Opinion in Colloid & Interface Science 2014, 19, 17-24.

The flexibility of biomembranes is based on the physical-chemical properties of their main components - glycerophospholipids. The structure of these modular amphiphilic molecules can be modified through organic synthesis making it possible to study specific physical-chemical effects in detail. In particular, the roles of the hydrophobic tails of the phospholipids and their hydrophobic/hydrophilic interfacial backbone on the phase behaviour are highlighted. The spatial orientation of the glycerol backbone changes from sn-1,2 to sn-1,3 phospholipids leading to an increase of the in-plane area of the molecule. The larger distance between the hydrophobic tails can lead to membrane leaflet interdigitation. The introduction of methyl side groups in the hydrophobic tails increases the fluidity of the bilayer. Depending on the position of the methyl branches partial interdigitation is observed. In the case of bolaamphiphiles, methyl side groups have a similar effect on the fluidity, but interdigitation cannot occur.


Denia Mellal, Andreas Zumbuehl
Exit-strategies - smart ways to release phospholipid vesicle cargo
Journal of Materials Chemistry B 2014, 2, 247-252.

This highlight describes recent trends in fundamental phospholipid research towards possible future drug delivery technology. In particular it focuses on synthetic phospholipids and their vesicular constructs and describes selected “smart” ways to release cargo from liposomes. Various chemical and physical release triggers are discussed such as temperature changes, application of ultrasound, enzyme degradation, changes in pH, redox reactions, photochemical reactions, as well as the effects of shear stress on vesicles.  


Illya A. Fedotenko, Cristina Stefaniu, Gerald Brezesinski, Andreas Zumbuehl
Monolayer Properties of 1,3-Diamidophospholipids
Langmuir 2013, 29, 9428-9435.

While nature provides an endless variety of phospholipids presenting hydrolysable ester linkages for the 1,2 positioned hydrocarbon tails, we designed and synthesized 1,3-diamidophospholipids which contain stable fatty acid amides. These new phospholipids form faceted unilamellar vesicles with mechanosensitive properties. Aiming to understand the mechanism responsible for this behavior at a molecular level we investigated the 1,3-diamidophospholipid family in monolayers, a simplified model membrane system. Langmuir isotherms combined with in situ Grazing Incidence X-Ray Diffraction (GIXD), specular X-ray reflectivity (XR) and Infrared Reflection Absorption Spectroscopy (IRRAS) allowed the characterization of the monolayers from a structural and thermodynamical point of view. The existence of strong head group interactions due to the formation of a hydrogen-bonding network was clearly revealed by IRRAS and by the high rigidity of the monolayers. GIXD showed that only the longer chain compounds of the series (Pad-PC-Pad and Sad-PC-Sad) were able to form ordered monolayers. The chains are strongly tilted in a rigid lattice formed due to these hydrogen-bonding interactions between the head groups. The thermodynamical analysis leads to a critical temperature of the monolayer which is clearly different from the main phase transition temperature in bulk indicating that there must be a different structural arrangement of the 1,3-diamidophospholipids in monolayers and in bilayers. 


Etienne Stalder, Andreas Zumbuehl
Phosphate Test 2.0
Chimia 2013, 67, 819-821.

The accurate measurement of the phosphate content of a liposomal suspension is important when working with differential scanning calorimetry. Standard phosphate tests date back several decades and require extended hands-on time. Here, we present a rapid version of a phosphate test taking advantage of microwave assisted chemical digestion and multiwell plate reading technology allowing for the fast and accurate testing of many samples in parallel. 


Till Saxer, Andreas Zumbuehl, Bert Müller
The Use of Shear Stress for Targeted Drug Delivery
Cardiovascular Research 2013, 99, 328-333.

Stenosed segments of arteries significantly alter the blood flow known from healthy vessels. In particular, the wall shear stress at critically stenosed arteries is at least an order of magnitude higher than in healthy situations. This alteration represents a change in physical force and might be used as a trigger signal for drug delivery. Mechanosensitive drug delivery systems, that preferentially release their payload under increased shear stress, are discussed. Therefore, besides biological or chemical markers, physical triggers are a further principle approach for targeted drug delivery. We hypothesize that such physical trigger is much more powerful to release drugs for vasodilation, plaque stabilization or clot lysis at stenosed arteries than any known biological or chemical ones. 


Pierre-Léonard Zaffalon, Vincenza D'Anna, Hans Hagemann, Andreas Zumbuehl
Study of Surfactant Alcohols with various Chemical Motives at the Hydrophilic/Hydrophobic Interface
RSC Advances 20133, 7237-7244.

The melting behavior, the solubility, and the influence of hydrogen bonds were analyzed for a series of single- and double-tailed surfactant alcohols. Various effects such as the presence of free amides or the intermolecular spacing were found to be important factors for increasing or decreasing the melting temperature of a surfactant. Furthermore, we present a model for the packing of diamido-lipids and study the temperature-dependence of the IR signals. 


Pierre-Léonard Zaffalon, Andreas Zumbuehl
New Trends in Phosholipid Research
in: Colloid and Interface Chemistry for Nanotechnology, Taylor & Francis, Boca Raton, FL, 2013. Edited by Peter Kralchevsky, Reinhard Miller, Francesca Ravera.

This book describes highlights in the very modern scientific world of nanotechnology. The contributions are all based on state-of-the-art principles in colloid and interface science and show how great progress in the various branches of nanotechnology can be reached. The chapters give examples of the synthesis of nanoparticles for specific applications as well as their characterization in bulk phases and at interfaces. The application of the colloid and interfacial science principles allows also developing new experimental and theoretical tools.


Margaret Holme, Georg Schulz, Hans Deyhle, Simone Elke Hieber, Timm Weitkamp, Felix Beckmann, Julia Herzen, Johannes A Lobrinus, Fabrizio Montecucco, François Mach, Andreas Zumbuehl, Till Saxer, and Bert Müller.
Morphology of atherosclerotic coronary arteries.
Proceedings of SPIE 2012, 8506, 850609. 

Atherosclerosis, the narrowing of vessel diameter and build-up of plaques in coronary arteries, leads to an increase in the shear stresses present, which can be used as a physics-based trigger for targeted drug delivery. In order to develop appropriate nanometer-size containers, one has to know the morphology of the critical stenoses with isotropic micrometer resolution. Micro computed tomography in absorption and phase contrast mode provides the necessary spatial resolution and contrast. The present communication describes the pros and cons of the conventional and synchrotron radiation-based approaches in the visualization of diseased human and murine arteries. Using registered datasets, it also demonstrates that multi-modal imaging, including established histology, is even more powerful. The tomography data were evaluated with respect to cross-section, vessel radius and maximal constriction. The average cross-section of the diseased human artery (2.31 mm2) was almost an order of magnitude larger than the murine one (0.27 mm2), whereas the minimal radius differs only by a factor of two (0.51 mm versus 0.24 mm). The maximal constriction, however, was much larger for the human specimen (85% versus 49%). We could also show that a plastic model used for recent experiments in targeted drug delivery represents a very similar morphology, which is, for example, characterized by a maximal constriction of 82%. The tomography data build a sound basis for flow simulations, which allows for conclusions on shear stress distributions in stenosed blood vessels.


Margaret N. Holme, Illya A. Fedotenko, Daniel Abegg, Jasmin Althaus, Lucille Babel, France Favarger, Renate Reiter, Radu Tanasescu, Pierre-Léonard Zaffalon, André Ziegler, Bert Müller, Till Saxer, Andreas Zumbuehl. 
Shear-stress sensitive lenticular vesicles for targeted drug delivery.
Nature Nanotechnology 2012, 7, 536-543.

Atherosclerosis results in the narrowing of arterial blood vessels and this causes significant changes in the endogenous shear stress between healthy and constricted arteries. Nanocontainers that can release drugs locally with such rheological changes can be very useful. Here, we show that vesicles made from an artificial 1,3-diaminophospholipid are stable under static conditions but release their contents at elevated shear stress. These vesicles have a lenticular morphology, which potentially leads to instabilities along their equator. Using a model cardiovascular system based on polymer tubes and an external pump to represent shear stress in healthy and constricted vessels of the heart, we show that drugs preferentially release from the vesicles in constricted vessels that have high shear stress. 


Frédéric Loosli, David Alonso Doval, David Grassi, Pierre-Léonard Zaffalon, France Favarger, Andreas Zumbuehl.
Clickosomes—using triazole-linked phospholipid connectors to fuse vesicles.
Chemical Communications 2012, 48, 1604-1606.

Two complementary artificial diether phospholipids were synthe- sized that can undergo a Cu(I)-catalyzed Huisgen–Sharpless click reaction. The resulting lipid can bridge the membranes of large unilamellar vesicles and cause their aggregation and ultimately their fusion.


Illya A. Fedotenko, Margaret N. Holme, Radu Tanasescu, Pierre-Léonard Zaffalon, Andreas Zumbuehl.
Putting the 'P' into Phospholipids.
Chimia 2011, 65, 859-862


Miwa Takahashi-Umebayashi, Ludovic Pineau, Thomas Hannich, Andreas Zumbuehl, David Alonso Doval, Stefan Matile, Christian Heinis, Gerardo Turcatti, Robbie Loewith, Aurelien Roux, Luc Reymond, Kai Johnsson, Howard Riezman.
Chemical Biology Approaches to Membrane Homeostasis and Function.
Chimia 2011, 65, 849-852. 


Pierre-Léonard Zaffalon, Etienne Stalder, Illya A. Fedotenko, France Favarger, Andreas Zumbuehl.
The Synthesis of an Amine-bearing Polymerizable Phospholipid.
Tetrahedron Letters 2011, 52, 4215-4217. 


Pierre-Léonard Zaffalon, Andreas Zumbuehl. 
BODP - A Versatile Reagent for Phospholipid Synthesis.
Synthesis 2011, 778-782.


Illya Fedotenko, Pierre-Leonard Zaffalon, France Favarger, Andreas Zumbuehl. 
The Synthesis of 1,3-Diamidophospholipids.
Tetrahedron Letters 2010, 51, 5382-5384.


Clément Mazet, Andreas Zumbuehl, Damien Jeannerat, Jiri Mareda, Alexandre Alexakis, E. Peter Kündig, Jérôme Lacour, Stefan Matile.
Organic Chemistry à la Genevoise.
Chimia 2009, 63, 816-821. 


Barbara Winter-Werner, Hermann Wegner, Andreas Zumbuehl. 
Motivation, Politics and Funding at the Second ‘Young Faculty Meeting’. 
Chimia 2009, 63, 586-587.


Lino Ferreira, Andreas Zumbuehl. 
Non-leaching surfaces capable of killing microorganisms on contact. 
Journal of Materials Chemistry 2009, 19, 7796-7806.


Andreas Zumbuehl, Pasquale Stano, Marc Sohrmann, Rolf Dietiker, Mathias Peter, Erick M. Carreira. 
Synthesis and Investigation of Tryptophan-Amphotericin B Conjugates. 
ChemBioChem 2009, 10, 1617-1620.


Andreas Zumbuehl. 
Recent Advances in Nonviral Gene Transfection – A Decade of Research into Poly-(β-amino esters). 
Chimia 2009, 63, 288-290.


Andreas Zumbuehl.
Nonnatural Phospholipids: Probing Nature's Modular Platform. 
Chimia 2009, 63, 63-65.


Christian P. R. Hackenberger, Hermann A. Wegner, Andreas Zumbuehl. 
Stereochemistry at Bürgenstock: Chemical Biology and Organic Synthesis in Focus. 
Angewandte Chemie, Int. Ed. Engl. 2008, 47, 5496-5499.


Hermann Wegner, Andreas Zumbuehl. 
The 43rd EUCHEM Conference on Stereochemistry (Bürgenstock Conference 2008) Fürigen, April 12–18, 2008. 
Chimia 2008, 62, 525-528.


Akin Akinc, Andreas Zumbuehl, Michael Goldberg, Elizaveta S. Leshchiner, Valentina Busini, Sergio A. Bacallado, Naushad Hossain, Rene Alvarez, Anna Borodovsky, Todd Borland, Rainer Constien, Antonin de Fougerolles, J. Robert Dorkin, K. Narayanannair Jayaprakash, Muthusamy Jayaraman, Matthias John, Victor Koteliansky, Muthiah Manoharan, Lubomir Nechev, June Qin, Timothy Racie, Denitza Raitcheva, Kallanthottathil G. Rajeev, Dinah W.Y. Sah, Jürgen Soutschek, Ivanka Toudjarska, Hans-Peter Vornlocher, Tracy S. Zimmermann, Robert Langer, Daniel G. Anderson.
A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. 
Nature Biotechnology 2008, 26, 561-569.


Alborz Mahdavi, Lino Ferreira, Cathryn Sundback, Jason W. Nichol, Edwin P. Chan, David J. D. Carter, Chris J. Bettinger, Siamrut Patanavanich, Loice Chignozha, Eli Ben-Joseph, Alex Galakatos, Howard Pryor, Irina Pomerantseva, Peter T. Masiakos, William Faquin, Andreas Zumbuehl, Seungpyo Hong, Jeffrey Borenstein, Joseph Vacanti, Robert Langer, Jeffrey M. Karp. 
A biodegradable and biocompatible Gecko-inspired tissue adhesive. 
Proceedings of the National Academy of Sciences U.S.A. 2008, 105, 2307-2312.


Andreas Zumbuehl, Pasquale Stano, Marc Sohrmann, Mathias Peter, Peter Walde, Erick M. Carreira. 
A Novel Strategy for Bioconjugation: Synthesis and Preliminary Evaluation with Amphotericin B. 
Organic and Biomolecular Chemistry 2007, 5, 1339-1342.


Andreas Zumbuehl, Lino Ferreira, Duncan Kuhn, Anna Astashkina, Lisa Lon, Yoon Yeo, Tiffany Iaconis, Mahmoud Ghannoum, Gerald R. Fink, Robert Langer, Daniel S. Kohane. 
Antifungal hydrogels.
Proceedings of the National Academy of Sciences U.S.A. 2007, 104, 12994-12998. 


Christiaan L. E. Nijst, Joost P. Bruggeman, Jeffrey M. Karp, Lino Ferreira, Andreas Zumbuehl, Christopher J. Bettinger, Robert Langer. 
Synthesis and Characterization of Photocurable Elastomers from Poly(glycerol-co-sebacate). 
Biomacromolecules 2007, 8, 3067-3073.


Gregory T. Zugates, Weidan Peng, Andreas Zumbuehl, Siddharth Jhunjhunwala, Yu-Hung Huang, Robert Langer, Janet A. Sawicki, Daniel G. Anderson. 
Rapid Optimization of Gene Delivery by Parallel End-modification of Poly(β-amino ester)s. 
Molecular Therapy 2007, 15, 1306-1312.


Gregory T. Zugates, Nathan C. Tedford, Andreas Zumbuehl, Siddharth Jhunjhunwala, Christina S. Kang, Linda G. Griffith, Douglas A. Lauffenburger, Robert Langer, Daniel G. Anderson. 
Gene Delivery Properties of End-Modified Poly(β-amino ester)s. 
Bioconjugate Chemistry 2007, 18, 1887-1896.


Valerie Paquet, Andreas Zumbuehl, Erick M. Carreira. 
Biologically Active Amphotericin B-Calix[4]arene Conjugates. 
Bioconjugate Chemistry 2006, 17, 1460-1463.


Andreas Zumbuehl, Damien Jeannerat, Scott E. Martin, Marc Sohrmann, Pasquale Stano, Tamas Vigassy, Daniel D. Clark, Stephen L. Hussey, Mathias Peter, Blake R. Peterson, Ernö Pretsch, Peter Walde, Erick M. Carreira. 
An Amphotericin B-Fluorescein Conjugate as a Powerful Probe for Biochemical Studies of the Membrane. 
Angewandte Chemie, Int. Ed. Engl. 2004, 43, 5181-5185.


Andreas Zumbuehl, Pasquale Stano, Dominik Heer, Peter Walde, Erick M. Carreira. 
Amphotericin B as a Potential Probe of the Physical State of Vesicle Membranes. 
Organic Letters 2004, 6, 3683-3686.


Jürgen Gallus, Qiong Lin, Andreas Zumbühl, Sebastian D. Friess, Rudolf Hartmann, Erich C. Meister. 
Binary Solid-Liquid Phase Diagrams of Selected Organic Compounds - A Complete Listing of 15 Binary Phase Diagrams. 
Journal of Chemical Education 2001, 78, 961-964.

Department of Chemistry - Chemin du Musée 9 - CH-1700 Fribourg - Tel +41 26 / 300 8794
andreas.zumbuehl [at] unifr.ch - Swiss University