Anja Traeger
University of Jena
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Publication
Featured researches published by Anja Traeger.
Nature Communications | 2014
Adrian T. Press; Anja Traeger; Christian Pietsch; Alexander Mosig; Michael Wagner; Mark G. Clemens; Nayla Jbeily; Nicole Koch; Michael Gottschaldt; Nicolas Beziere; Volodymyr Ermolayev; Vasilis Ntziachristos; Jürgen Popp; Michael M. Kessels; Britta Qualmann; Ulrich S. Schubert; Michael Bauer
Efficient delivery of short interfering RNAs reflects a prerequisite for the development of RNA interference therapeutics. Here, we describe highly specific nanoparticles, based on near infrared fluorescent polymethine dye-derived targeting moieties coupled to biodegradable polymers. The fluorescent dye, even when coupled to a nanoparticle, mimics a ligand for hepatic parenchymal uptake transporters resulting in hepatobiliary clearance of approximately 95% of the dye within 45 min. Body distribution, hepatocyte uptake and excretion into bile of the dye itself, or dye-coupled nanoparticles can be tracked by intravital microscopy or even non-invasively by multispectral optoacoustic tomography. Efficacy of delivery is demonstrated in vivo using 3-hydroxy-3-methyl-glutaryl-CoA reductase siRNA as an active payload resulting in a reduction of plasma cholesterol levels if siRNA was formulated into dye-functionalised nanoparticles. This suggests that organ-selective uptake of a near infrared dye can be efficiently transferred to theranostic nanoparticles allowing novel possibilities for personalised silencing of disease-associated genes.
Macromolecular Bioscience | 2015
Alexandra C. Rinkenauer; Lutz Tauhardt; Felix Wendler; Kristian Kempe; Michael Gottschaldt; Anja Traeger; Ulrich S. Schubert
To date, cationic polymers with high transfection efficiencies (TE) often have a high cytotoxicity. By screening an 18-membered library of cationic 2-oxazoline-based polymers, a polymer with similar TE as linear poly(ethylene imine) but no detectable cytotoxicity at the investigated concentrations could be identified. The influence of the polymer side chain hydrophobicity and the type and content of amino groups on the pDNA condensation, the TE, the cytotoxicity, the cellular membrane interaction as well as the size, charge, and stability of the polyplexes was studied. Primary amines and an amine content of at least 40% were required for an efficient TE. While polymers with short side chains were non-toxic up to an amine content of 40%, long hydrophobic side chains induced a high cytotoxicity.
Journal of Materials Chemistry B | 2015
Alexandra C. Rinkenauer; Stephanie Schubert; Anja Traeger; Ulrich S. Schubert
In 2012, the first gene therapy agent was approved by the Europe Medicines Agency leading to increased interest in this research field. Beside viruses, non-viral agents based on lipids or polymers represent aspiring alternatives to deliver the genetic material. Different hurdles have to be overcome depending on the kind of nucleic acid used, where plasmid DNA (pDNA) and small interfering RNA represent the common ones. The main challenge for transfection agents, in particular for pDNA delivery, is the transfer to the cell and into the cell nuclei. Within the group of transfection vesicles, cationic polymers show promising features and variability, as they can be synthesized with tailor-made physical and chemical properties (architectures and functionalisation). In the field of polymer-based gene delivery, the tuning potential of polymers by using different architectures like graft and star-shaped polymers as well as self-assembled block copolymers is immense. In particular, in the last few years numerous new polymer designs showed enhanced transfection properties in combination with good biocompatibility. Furthermore, new insights into the transfection mechanism demonstrated the continuous progress in this field. Polymer architecture influences the polyplex characteristics and the latter has an impact on the transfection mechanism, e.g. the interaction with the cellular membrane depends on the polyplex shape. Moreover, polyplex dissociation can be easily influenced by the polymer chemistry, thus biodegradable linkers lead to well suited polymers with reduced toxicity and high delivery potential, and are also promising for in vivo applications. This review focuses on the influence of polymer architectures for pDNA transfection in vitro, showing recent developments and insights. The theoretical background concerning the biological challenges for cationic polymers and the impact of graft- or star-shaped architectures as well as self-assembled structures will be presented in detail.
Journal of Controlled Release | 2015
Alexandra C. Rinkenauer; Adrian T. Press; Martin Raasch; Christian Pietsch; Simon Schweizer; Simon Schwörer; Karl Lenhard Rudolph; Alexander Mosig; Michael Bauer; Anja Traeger; Ulrich S. Schubert
Polymer-based nanoparticles are promising drug delivery systems allowing the development of new drug and treatment strategies with reduced side effects. However, it remains a challenge to screen for new and effective nanoparticle-based systems in vitro. Important factors influencing the behavior of nanoparticles in vivo cannot be simulated in screening assays in vitro, which still represent the main tools in academic research and pharmaceutical industry. These systems have serious drawbacks in the development of nanoparticle-based drug delivery systems, since they do not consider the highly complex processes influencing nanoparticle clearance, distribution, and uptake in vivo. In particular, the transfer of in vitro nanoparticle performance to in vivo models often fails, demonstrating the urgent need for novel in vitro tools that can imitate aspects of the in vivo situation more accurate. Dynamic cell culture, where cells are cultured and incubated in the presence of shear stress has the potential to bridge this gap by mimicking key-features of organs and vessels. Our approach implements and compares a chip-based dynamic cell culture model to the common static cell culture and mouse model to assess its capability to predict the in vivo success more accurately, by using a well-defined poly((methyl methacrylate)-co-(methacrylic acid)) and poly((methyl methacrylate)-co-(2-dimethylamino ethylmethacrylate)) based nanoparticle library. After characterization in static and dynamic in vitro cell culture we were able to show that physiological conditions such as cell-cell communication of co-cultured endothelial cells and macrophages as well as mechanotransductive signaling through shear stress significantly alter cellular nanoparticle uptake. In addition, it could be demonstrated by using dynamic cell cultures that the in vivo situation is simulated more accurately and thereby can be applied as a novel system to investigate the performance of nanoparticle systems in vivo more reliable.
Polymer Chemistry | 2014
Michael Wagner; Markus J. Barthel; Robert R. A. Freund; Stephanie Hoeppener; Anja Traeger; Felix H. Schacher; Ulrich S. Schubert
A well-defined ABC triblock terpolymer, poly(ethylene oxide)-block-poly(furfuryl glycidyl ether)-block-poly(allyl glycidyl ether) (PEO-b-PFGE-b-PAGE), was synthesized via sequential living anionic ring-opening polymerization, and subsequently functionalized by thiol–ene click chemistry. In that way, either a fluorocarbon chain or carboxy groups were introduced into the C segment (PAGE). The self-assembly of the resulting materials in water as selective solvent was studied in detail by asymmetric flow field-flow fractionation (AF4) coupled to multi-angle laser light scattering and dynamic light scattering (DLS). The obtained results were compared with batch DLS and cryogenic transmission electron microscopy (cryo-TEM) results. The influence of the separation conditions on the retention behavior of the triblock terpolymers was evaluated to reveal possible limitations associated with AF4 measurements. The influence of pH value and ionic strength on the solution behavior of the materials, in particular for PEO-b-PFGE-b-PAGECOOH, was investigated as well. Crosslinking of the PAGECOOH by chelating metal ions (Fe3+) was studied under different conditions. In case of PEO-b-PFGE-b-PAGE, spherical micelles of approximately 20 nm (Rh) were observed, whereas the introduction of a fluorocarbon chain led to an increase in size (30 nm, Rh) and the formation of worm-like structures. Carboxy functionalization rendered small (5 nm) disk-like structures. In the latter case, subsequent addition of FeCl3 resulted in the formation of spherical nanostructures ranging from 10 to 60 nm in size, depending on the pH value and the polymer/metal ion ratio.
Journal of Materials Chemistry B | 2017
Tanja Bus; Christoph Englert; Martin Reifarth; Philipp Borchers; Matthias Hartlieb; Antje Vollrath; Stephanie Hoeppener; Anja Traeger; Ulrich S. Schubert
Cationic polymers play a crucial role within the field of gene delivery offering the possibility to circumvent (biological) barriers in an elegant way. However, polymers are accompanied either by a high cytotoxicity or low efficiency. In this study, a series of high molar mass poly(2-oxazoline)-based copolymers was synthesized introducing 2-ethyl-2-oxazoline, ethylene imine, and primary amine bearing monomer units representing a new generation of poly(ethylene imine) (PEI). The potential of these modified PEIs as non-viral gene delivery agents was assessed and compared to linear PEI by studying the cytotoxicity, the polyplex characteristics, the transfection efficiency, and the cellular uptake using plasmid DNA (pDNA) as well as small interfering RNA (siRNA). High transfection efficiencies, even in serum containing media, were achieved using pDNA without revealing any cytotoxic effects on the cell viability at concentrations up to 1 mg mL-1. The delivery potential for siRNA was further investigated showing the importance of polymer composition for different genetic materials. To elucidate the origins for this superior performance, super-resolution and electron microscopy of transfected cells were used, identifying the endosomal release of the polymers as well as a reduced protein interaction as the main difference to PEI-based transfection processes. In this respect, the investigated copolymers represent remarkable alternatives as non-viral gene delivery agents.
Journal of Controlled Release | 2016
Christoph Englert; Anne-Kristin Trützschler; Martin Raasch; Tanja Bus; Philipp Borchers; Alexander Mosig; Anja Traeger; Ulrich S. Schubert
The targeted drug delivery to the central nervous system represents one of the major challenges in pharmaceutical formulations since it is strictly limited through the highly selective blood-brain barrier (BBB). l-Glutathione (GSH), a tripeptide and well-known antioxidant, has been studied in the last years as potential candidate to facilitate the receptor-mediated transcytosis of nanocarriers. We thus tested whether GSH decoration of a positively charged polymer, poly(ethylene imine), with this vector enables the transport of genetic material and, simultaneously, the passage through the BBB. In this study, we report the synthesis of GSH conjugated cationic poly(ethylene imine)s via ecologically desirable thiol-ene photo-addition. The copolymers, containing 80% primary or secondary amine groups, respectively, were investigated concerning their bio- and hemocompatibility as well as their ability to cross a hCMEC/D3 endothelial cell layer mimicking the BBB within microfluidically perfused biochips. We demonstrate that BBB passage depends on the used amino-groups and on the GSH ratio. Thereby the copolymer containing secondary amines showed an enhanced performance. We thus conclude that GSH-coupling represents a feasible and promising approach for the functionalization of nanocarriers intended to cross the BBB for the delivery of drugs to the central nervous system.
Polymer Chemistry | 2016
Ilknur Yildirim; Tanja Bus; Martin Sahn; Turgay Yildirim; Diana Kalden; Stephanie Hoeppener; Anja Traeger; Matthias Westerhausen; Christine Weber; Ulrich S. Schubert
A series of amphiphilic heterografted comb polymers comprising various ratios of oligomeric polylactide (PLA) and poly(2-ethyl-2-oxazoline) (PEtOx) side chains was synthesized via the grafting-through method employing the reversible addition–fragmentation chain transfer copolymerization. Two well-defined PLA macromonomers were prepared via ring opening polymerization (ROP) of L-lactide using a calcium-based pre-catalyst, pyrenebutanol as an initiator and methacryloyl chloride as an end-capping agent. The PEtOx macromonomer was obtained from the cationic ROP of EtOx and end-capping with methacrylic acid. The amphiphilic comb polymers self-assembled in aqueous solution to form spherical and worm-like micelles, vesicles and more complex morphologies as a function of the composition, as is evident from dynamic light scattering and cryo-transmission electron microscopy studies. All polymers were found to be non-toxic to L929 cells up to a concentration of 200 μg mL−1. Cellular uptake studies with HEK-293 cells by live cell confocal fluorescence microscopy revealed localization in the cytosol after 4 h and suggest an energy-driven cellular uptake mechanism.
Macromolecular Bioscience | 2017
Christoph Englert; Michael Pröhl; Justyna A. Czaplewska; Carolin Fritzsche; Elisabeth Preußger; Ulrich S. Schubert; Anja Traeger; Michael Gottschaldt
The high affinity of GLUT5 transporter for d-fructose in breast cancer cells has been discussed intensely. In this contribution, high molar mass linear poly(ethylene imine) (LPEI) is functionalized with d-fructose moieties to combine the selectivity for the GLUT5 transporter with the delivery potential of PEI for genetic material. The four-step synthesis of a thiol-group bearing d-fructose enables the decoration of a cationic polymer backbone with d-fructose via thiol-ene photoaddition. The functionalization of LPEI is confirmed by 2D NMR techniques, elemental analysis, and size exclusion chromatography. Importantly, a d-fructose decoration of 16% renders the polymers water-soluble and eliminates the cytotoxicity of PEI in noncancer L929 cells, accompanied by a reduced unspecific cellular uptake of the genetic material. In contrast, the cytotoxicity as well as the cell specific uptake is increased for triple negative MDA-MB-231 breast cancer cells. Therefore, the introduction of d-fructose shows superior potential for cell targeting, which can be assumed to be GLUT5 dependent.
Angewandte Chemie | 2018
Christoph Englert; Ivo Nischang; Cornelia Bader; Philipp Borchers; Julien Alex; Michael Pröhl; Martin Hentschel; Matthias Hartlieb; Anja Traeger; Georg Pohnert; Stephanie Schubert; Michael Gottschaldt; Ulrich S. Schubert
A benzoin-derived diol linker was synthesized and used to generate biocompatible polyesters that can be fully decomposed on demand upon UV irradiation. Extensive structural optimization of the linker unit was performed to enable the defined encapsulation of diverse organic compounds in the polymeric structures and allow for a well-controllable polymer cleavage process. Selective tracking of the release kinetics of encapsulated model compounds from the polymeric nano- and microparticle containers was performed by confocal laser scanning microscopy in a proof-of-principle study. The physicochemical properties of the incorporated and released model compounds ranged from fully hydrophilic to fully hydrophobic. The demonstrated biocompatibility of the utilized polyesters and degradation products enables their use in advanced applications, for example, for the smart packaging of UV-sensitive pharmaceuticals, nutritional components, or even in the area of spatially selective self-healing processes.