Functionalized Polymers and Regenerative Agents

Objectives

We focus on the development of new polymers based on biomacromolecules as well as on chemical polymerization. In doing so we optimize the polymer phase with respect to polymer size and degree of cross linking and affect the polymer properties (solubility, degradability). Also we develop facile chemical functionalization methods for modifying existing polymers with respect immunological properties and create anchor groups for attaching (bio)molecules with e.g. cell adhesion properties. In addition our group provides small molecular drugs used within the rebirth consortium.

Major projects:

a) Polysaccharide-based  hydrogels based on functionalized building blocks – a versatile toolbox for tissue engineering

We developed a synthetic tool box for functionalizing polysaccharides (hyaluronic acid, alginate, dextran, pullulan, glycogen, lentinan and carboxymethyl cellulose) with “clickable” aldehydo and hydrazido groups. They allow in vivo hydrogel formation upon mixing. Furthermore, functionalization of clickable polysaccharide strands with bioactive ligands such as cyclic RGD pentapeptides as cell adhesion factors has been achieved in an orthogonal manner. In that way libraries of polysaccharide-based hydrogels were created including those that are based on different polysaccharide backbones.

These studies are complemented with studies on their biophysical properties, biocompatibility and biodegradability as well as substitutes for extracellular matrices. 

 

b) Nanoparticle-drug conjugates

In close collaboration with the group of Michael Ott we designed novel drug-nanoparticle conjugates based on the toxin ansamitocin and iron oxide nanoparticles. The therapeutic effect is initiated by controlled release of ansamitocin from the nanoparticle and by hyperthermia. After injection an external electromagnetic field serves as a release trigger. As major physicotechnical issues energy density as well as the frequency of the electromagnetic field were encountered and solved by redesigning the inductor coil combined with a stronger HF-generator. The efficacy of heating and drug release was improved for use in in vivo studies. The linker architecture between the nanoparticle and the toxin turned out to be a chemical challenge.

Collaborations

Further Research Projects

Teaching

  • Mass spectrometry, lectures and tutorials in organic chemistry, glycochemistry, biosynthesis, lab classes in organic chemistry

Publications

2013 - ongoing

2017

Kirschning A, Dibbert N, Drager G. Chemical Functionalization of Polysaccharides-Towards Biocompatible Hydrogels for Biomedical Applications. Chemistry. 2017/08/15 ed2017.

Massai D, Bolesani E, Diaz DR, Kropp C, Kempf H, Halloin C, Martin U, Braniste T, Isu G, Harms V, Morbiducci U, Drager G, Zweigerdt R. Sensitivity of human pluripotent stem cells to insulin precipitation induced by peristaltic pump-based medium circulation: considerations on process development. Sci Rep. 2017/06/24 ed2017. p. 3950.

Seidel K, Balakrishnan A, Alexiou C, Janko C, Komoll RM, Wang LL, Kirschning A, Ott M. Synthesis of Magnetic-Nanoparticle/Ansamitocin Conjugates-Inductive Heating Leads to Decreased Cell Proliferation In Vitro and Attenuation Of Tumour Growth In Vivo. Chemistry. 2017/06/07 ed2017. p. 12326-37.

Jara-Avaca M, Kempf H, Ruckert M, Robles-Diaz D, Franke A, de la Roche J, Fischer M, Malan D, Sasse P, Solodenko W, Drager G, Kirschning A, Martin U, Zweigerdt R. EBIO Does Not Induce Cardiomyogenesis in Human Pluripotent Stem Cells but Modulates Cardiac Subtype Enrichment by Lineage-Selective Survival. Stem cell reports. 2017.

2016

Wang LL, Balakrishnan A, Bigall NC, Candito D, Miethe JF, Seidel K, Xie Y, Ott M, Kirschning A. A Bio-Chemosynthetic Approach to Superparamagnetic Iron Oxide-Ansamitocin Conjugates for Use in Magnetic Drug Targeting. Chemistry. 2016.

Kempf H, Olmer R, Haase A, Franke A, Bolesani E, Schwanke K, Robles-Diaz D, Coffee M, Gohring G, Drager G, Potz O, Joos T, Martinez-Hackert E, Haverich A, Buettner FF, Martin U, Zweigerdt R. Bulk cell density and Wnt/TGFbeta signalling regulate mesendodermal patterning of human pluripotent stem cells. Nature communications. 2016;7:13602.

Hoepfner J, Kleinsorge M, Papp O, Ackermann M, Alfken S, Rinas U, Solodenko W, Kirschning A, Sgodda M, Cantz T. Biphasic modulation of Wnt signaling supports efficient foregut endoderm formation from human pluripotent stem cells. Cell Biol Int. 2016;40(5):534-48.

Dibbert N, Krause A, Rios-Camacho JC, Gruh I, Kirschning A, Drager G. A Synthetic Toolbox for the In Situ Formation of Functionalized Homo- and Heteropolysaccharide-Based Hydrogel Libraries. Chemistry. 2016;22(52):18777-86.

2015

Williams S, Neumann A, Bremer I, Su Y, Drager G, Kasper C, Behrens P. Nanoporous Silica Nanoparticles as Biomaterials: Evaluation of Different Strategies for the Functionalization with Polysialic Acid by Step-by-Step Cytocompatibility Testing. J Mater Sci Mater Med. 2015;26(3):125. Epub 2015/02/19.

Hermane J, Bułyszko I, Eichner S, Sasse F, Collisi W, Poso A, Schax E, Walter J-G, Scheper T, Kock K, Herrmann C, Aliuos P, Reuter G, Zeilinger C, Kirschning A. New, Non-Quinone Fluorogeldanamycin Derivatives Strongly Inhibit Hsp90. ChemBioChem. 2015;16(2):302-11.

Stumpp N, Premnath P, Schmidt T, Ammermann J, Drager G, Reck M, Jansen R, Stiesch M, Wagner-Dobler I, Kirschning A. Synthesis of New Carolacton Derivatives and Their Activity against Biofilms of Oral Bacteria. Org Biomol Chem. 2015;13(20):5765-74. Epub 2015/04/23.

2014

Mikhova, B., Janevska, V., Stambolizska, B., Draeger, G., Popovski, E. Synthesis and structure of some novel dicoumarinamines. Bulgarian Chemical Communications. 2014; 46:135-140.

Mancuso L, Knobloch T, Buchholz J, Hartwig J, Moller L, Seidel K, Collisi W, Sasse F, Kirschning A. Preparation of Thermocleavable Conjugates Based on Ansamitocin and Superparamagnetic Nanostructured Particles by a Chemobiosynthetic Approach. Chemistry. 2014;20(52):17541-51.

Jirawutthiwongchai J, Draeger G, Chirachanchai S. Rapid Hybridization of Chitosan-Gold-Antibodies Via Metal-Free Click in Water-Based Systems: A Model Approach for Naked-Eye Detectable Antigen Sensors. Macromol Rapid Commun. 2014;35(13):1204-10.

Jashari A, Imeri F, Ballazhi L, Shabani A, Mikhova B, Drager G, Popovski E, Huwiler A. Synthesis and Cellular Characterization of Novel Isoxazolo- and Thiazolohydrazinylidene-Chroman-2,4-Diones on Cancer and Non-Cancer Cell Growth and Death. Bioorg Med Chem. 2014;22(9):2655-61.

2013

Su Y, Paleček J, Kirschning A, Dräger G. Copper Mediated and Copper Free “Click” Decoration of Polysialic Acid for Rgd-Modification and Hydrogel Formation. Macromolecular Symposia. 2013;334(1):82-91.

Schmeckebier S, Mauritz C, Katsirntaki K, Sgodda M, Puppe V, Duerr J, Schubert SC, Schmiedl A, Lin Q, Palecek J, Draeger G, Ochs M, Zenke M, Cantz T, Mall MA, Martin U. Keratinocyte Growth Factor and Dexamethasone Plus Elevated Camp Levels Synergistically Support Pluripotent Stem Cell Differentiation into Alveolar Epithelial Type Ii Cells. Tissue Eng Part A. 2013;19(7-8):938-51.

Moller L, Hess C, Palecek J, Su Y, Haverich A, Kirschning A, Drager G. Towards a Biocompatible Artificial Lung: Covalent Functionalization of Poly(4-Methylpent-1-Ene) (Tpx) with Crgd Pentapeptide. Beilstein J Org Chem. 2013;9:270-7.

Kensah G, Roa Lara A, Dahlmann J, Zweigerdt R, Schwanke K, Hegermann J, Skvorc D, Gawol A, Azizian A, Wagner S, Maier LS, Krause A, Drager G, Ochs M, Haverich A, Gruh I, Martin U. Murine and Human Pluripotent Stem Cell-Derived Cardiac Bodies Form Contractile Myocardial Tissue in Vitro. Eur Heart J. 2013;34(15):1134-46.

Jirawutthiwongchai J, Krause A, Draeger G, Chirachanchai S. Chitosan-Oxanorbornadiene: A Convenient Chitosan Derivative for Click Chemistry without Metal Catalyst Problem. ACS Macro Letters. 2013;2(3):177-80.

Dahlmann J, Krause A, Moller L, Kensah G, Mowes M, Diekmann A, Martin U, Kirschning A, Gruh I, Drager G. Fully Defined in Situ Cross-Linkable Alginate and Hyaluronic Acid Hydrogels for Myocardial Tissue Engineering. Biomaterials. 2013;34(4):940-51.

Dahlmann J, Kensah G, Kempf H, Skvorc D, Gawol A, Elliott DA, Dräger G, Zweigerdt R, Martin U, Gruh I. The Use of Agarose Microwells for Scalable Embryoid Body Formation and Cardiac Differentiation of Human and Murine Pluripotent Stem Cells. Biomaterials. 2013;34(10):2463-71.

2006 - 2012

2012

Krause A, Kirschning A, Drager G. Bioorthogonal Metal-Free Click-Ligation of Crgd-Pentapeptide to Alginate. Org Biomol Chem. 2012;10(29):5547-53.

Knobloch T, Drager G, Collisi W, Sasse F, Kirschning A. Unprecedented Deoxygenation at C-7 of the Ansamitocin Core During Mutasynthetic Biotransformations. Beilstein J Org Chem. 2012;8:861-9.

2011

Palecek J, Zweigerdt R, Olmer R, Martin U, Kirschning A, Drager G. A Practical Synthesis of Rho-Kinase Inhibitor Y-27632 and Fluoro Derivatives and Their Evaluation in Human Pluripotent Stem Cells. Org Biomol Chem. 2011;9(15):5503-10.

Paleček J, Dräger G, Kirschning A. A Practical Large-Scale Synthesis of Cyclic Rgd Pentapeptides Suitable for Further Functionalization through ‘Click’ Chemistry. Synthesis. 2011;2011(04):653-61. Epub 11.01.2011.

Ovsianikov A, Deiwick A, Van Vlierberghe S, Dubruel P, Moller L, Drager G, Chichkov B. Laser Fabrication of Three-Dimensional Cad Scaffolds from Photosensitive Gelatin for Applications in Tissue Engineering. Biomacromolecules. 2011;12(4):851-8.

Möller L, Krause A, Bartsch I, Kirschning A, Witte F, Dräger G. Preparation and in Vivo Imaging of Lucifer Yellow Tagged Hydrogels. Macromolecular Symposia. 2011;309-310(1):222-8.

Dräger G, Krause A, Möller L, Dumitriu S. Carbohydrates. Handbook of Biodegradable Polymers: Wiley-VCH Verlag GmbH & Co. KGaA; 2011. p. 155-93.

2010

Su Y, Kasper C, Kirschning A, Drager G, Berski S. Synthesis of New Polysialic Acid Derivatives. Macromol Biosci. 2010;10(9):1028-33.

Olmer R, Haase A, Merkert S, Cui W, Palecek J, Ran C, Kirschning A, Scheper T, Glage S, Miller K, Curnow EC, Hayes ES, Martin U. Long Term Expansion of Undifferentiated Human Ips and Es Cells in Suspension Culture Using a Defined Medium. Stem Cell Res. 2010;5(1):51-64.

Harmrolfs K, Brunjes M, Drager G, Floss HG, Sasse F, Taft F, Kirschning A. Cyclization of Synthetic Seco-Proansamitocins to Ansamitocin Macrolactams by Actinosynnema Pretiosum as Biocatalyst. Chembiochem. 2010;11(18):2517-20.

Haastert-Talini K, Schaper-Rinkel J, Schmitte R, Bastian R, Muhlenhoff M, Schwarzer D, Draeger G, Su Y, Scheper T, Gerardy-Schahn R, Grothe C. In Vivo Evaluation of Polysialic Acid as Part of Tissue-Engineered Nerve Transplants. Tissue Eng Part A. 2010;16(10):3085-98. Epub 2010/05/22.

Assmann U, Szentivanyi A, Stark Y, Scheper T, Berski S, Drager G, Schuster RH. Fiber Scaffolds of Polysialic Acid Via Electrospinning for Peripheral Nerve Regeneration. J Mater Sci Mater Med. 2010;21(7):2115-24.

2008

Hartlieb S, Gunzel A, Gerardy-Schahn R, Munster-Kuhnel AK, Kirschning A, Drager G. Chemoenzymatic Synthesis of Cmp-N-Acetyl-7-Fluoro-7-Deoxy-Neuraminic Acid. Carbohydr Res. 2008;343(12):2075-82.

Haile Y, Berski S, Drager G, Nobre A, Stummeyer K, Gerardy-Schahn R, Grothe C. The Effect of Modified Polysialic Acid Based Hydrogels on the Adhesion and Viability of Primary Neurons and Glial Cells. Biomaterials. 2008;29(12):1880-91.

Berski S, van Bergeijk J, Schwarzer D, Stark Y, Kasper C, Scheper T, Grothe C, Gerardy-Schahn R, Kirschning A, Drager G. Synthesis and Biological Evaluation of a Polysialic Acid-Based Hydrogel as Enzymatically Degradable Scaffold Material for Tissue Engineering. Biomacromolecules. 2008;9(9):2353-9.

2007

Haile Y, Haastert K, Cesnulevicius K, Stummeyer K, Timmer M, Berski S, Drager G, Gerardy-Schahn R, Grothe C. Culturing of Glial and Neuronal Cells on Polysialic Acid. Biomaterials. 2007;28(6):1163-73.

Drager G, Kiss C, Kunz U, Kirschning A. Enzyme-Purification and Catalytic Transformations in a Microstructured Passflow Reactor Using a New Tyrosine-Based Ni-Nta Linker System Attached to a Polyvinylpyrrolidinone-Based Matrix. Org Biomol Chem. 2007;5(22):3657-64.

Dräger G, Jeske F, Kunst E, Lopez EG, Sanchez HV, Tsichritzis F, Kirschning A, Jakupovic J. Tonantzitlolone and Other Diterpenes from Stillingia Sanguinolenta. European Journal of Organic Chemistry. 2007;2007(36):6128-.

Bruns S, Stark Y, Roker S, Wieland M, Drager G, Kirschning A, Stahl F, Kasper C, Scheper T. Collagen Biomaterial Doped with Colominic Acid for Cell Culture Applications with Regard to Peripheral Nerve Repair. J Biotechnol. 2007;131(3):335-45.

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