114 results on '"Hoeppener S"'
Search Results
2. Microwave-assisted preparation of carbon nanofiber-functionalized graphite felts as electrodes for polymer-based redox-flow batteries
- Author
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Schwenke, A.M., Janoschka, T., Stolze, C., Martin, N., Hoeppener, S., and Schubert, U.S.
- Published
- 2016
- Full Text
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3. The electrooxidation of small organic molecules on platinum nanoparticles supported on gold: influence of platinum deposition procedure
- Author
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Scheijen, F. J. E., Beltramo, G. L., Hoeppener, S., Housmans, T. H. M., and Koper, M. T. M.
- Published
- 2008
- Full Text
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4. HD DVD substrates for surface enhanced Raman spectroscopy analysis: fabrication, theoretical predictions and practical performance.
- Author
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Radu, A. I., Ussembayev, Ye. Ye., Jahn, M., Schubert, U. S., Weber, K., Cialla-May, D., Hoeppener, S., Heisterkamp, A., and Popp, J.
- Published
- 2016
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5. Self-healing metallopolymers based on cadmium bis(terpyridine) complex containing polymer networks.
- Author
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Bode, S., Bose, R. K., Matthes, S., Ehrhardt, M., Seifert, A., Schacher, F. H., Paulus, R. M., Stumpf, S., Sandmann, B., Vitz, J., Winter, A., Hoeppener, S., Garcia, S. J., Spange, S., van der Zwaag, S., Hager, M. D., and Schubert, U. S.
- Published
- 2013
- Full Text
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6. Chemical Nanostructures of Multifunctional Self-Assembled Monolayers.
- Author
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Herzer, N., Hoeppener, S., Schubert, U. S., Fuchs, H., and Fischer, U. C.
- Published
- 2008
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7. Inkjet Printing of Luminescent CdTe Nanocrystal-Polymer Composites.
- Author
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Tekin, E., Smith, P. J., Hoeppener, S., van den Berg, A. M. J., Susha, A. S., Rogach, A. L., Feldmann, J., and Schubert, U. S.
- Published
- 2007
- Full Text
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8. Metal Nanoparticles, Nanowires, and Contact Electrodes Self-Assembled on Patterned Monolayer Templates-A Bottom-up Chemical Approach.
- Author
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Hoeppener, S., Maoz, R., Cohen, S.R., Chi, L.F., Fuchs, H., and Sagiv, J.
- Published
- 2002
- Full Text
- View/download PDF
9. Latex bead projection nanopatterns.
- Author
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Fischer, U. C., Heimel, J., Maas, H.-J., Hartig, M., Hoeppener, S., and Fuchs, H.
- Published
- 2002
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10. Inside Front Cover: Inkjet Printing of Luminescent CdTe Nanocrystal-Polymer Composites (Adv. Funct. Mater. 1/2007).
- Author
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Tekin, E., Smith, P. J., Hoeppener, S., van den Berg, A. M. J., Susha, A. S., Rogach, A. L., Feldmann, J., and Schubert, U. S.
- Published
- 2007
- Full Text
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11. Optimizing Biocompatibility and Gene Delivery with DMAEA and DMAEAm: A Niacin-Derived Copolymer Approach.
- Author
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Mapfumo PP, Reichel LS, André T, Hoeppener S, Rudolph LK, and Traeger A
- Subjects
- Humans, HEK293 Cells, Animals, Mice, Gene Transfer Techniques, Biocompatible Materials chemistry, Biocompatible Materials pharmacology, Jurkat Cells, Genetic Therapy methods, Transfection methods, Plasmids genetics, THP-1 Cells, DNA chemistry, Niacin chemistry, Niacin pharmacology, Polymers chemistry, Polymers pharmacology
- Abstract
Gene therapy is pivotal in nanomedicine, offering a versatile approach to disease treatment. This study aims to achieve an optimal balance between biocompatibility and efficacy, which is a common challenge in the field. A copolymer library is synthesized, incorporating niacin-derived monomers 2-acrylamidoethyl nicotinate (AAEN) or 2-(acryloyloxy)ethyl nicotinate (AEN) with N,N -(dimethylamino)ethyl acrylamide (DMAEAm) or hydrolysis-labile N,N -(dimethylamino)ethyl acrylate (DMAEA). Evaluation of the polymers' cytotoxicity profiles reveals that an increase in AAEN or DMAEA molar ratios correlates with improved biocompatibility. Remarkably, an increase in AAEN in both DMAEA and DMAEAm copolymers demonstrated enhanced transfection efficiencies of plasmid DNA in HEK293T cells. Additionally, the top-performing polymers demonstrate promising gene expression in challenging-to-transfect cells (THP-1 and Jurkat cells) and show no significant effect on modulating immune response induction in ex vivo treated murine monocytes. Overall, the best performing candidates exhibit an optimal balance between biocompatibility and efficacy, showcasing potential advancements in gene therapy.
- Published
- 2024
- Full Text
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12. Anti-Inflammatory Potential of Beclometasone-Loaded Filomicelles on Activated Human Monocytes.
- Author
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Gardey E, Eberhardt J, Hoeppener S, Sobotta FH, Brendel JC, and Stallmach A
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- Humans, Cytokines metabolism, Lipopolysaccharides pharmacology, Drug Liberation, Drug Carriers chemistry, Drug Carriers pharmacology, Beclomethasone pharmacology, Beclomethasone chemistry, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents chemistry, Monocytes drug effects, Monocytes metabolism, Micelles
- Abstract
Polymeric micelles with a hydrophobic core represent versatile nanostructures for encapsulation and delivery of water-insoluble drugs. Here, water-insoluble beclometasone dipropionate (BDP) which is a potent anti-inflammatory therapeutic agent but limited to topical applications so far, is encapsulated. Therefore, this work used an amphiphilic block copolymer self-assembling into flexible polymeric filomicelles, which have recently proven to selectively target inflamed areas in patients with inflammatory bowel disease (IBD). The small diameter and flexibility of these filomicelles is considered beneficial for transepithelial passages, while their length minimizes the unspecific uptake into nontargeted cells. This work successfully establishes a protocol to load the water-insoluble BDP into the core of the filomicelles, while maintaining the particle stability to prevent any premature drug release. The anti-inflammatory efficacy of BDP-loaded filomicelles is further investigated on lipopolysaccharide (LPS) stimulated human monocytes. In these ex vivo assays, the BDP-loaded filomicelles significantly reduce TNF-α, IL-6, IL-1ß, IL-12p70, IL-17a, and IL-23 release after 24 h. Additional time course study of drug-loaded filomicelles and their comparison with a common water-soluble and unspecific corticosteroid demonstrate promising results with significant immune response suppression in stimulated monocytes after 2 and 6 h. These findings demonstrate the potential of polymeric filomicelles as a vehicle for potent water-insoluble corticosteroids., (© 2024 The Author(s). Macromolecular Bioscience published by Wiley‐VCH GmbH.)
- Published
- 2024
- Full Text
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13. Biophysical investigation of liposome systems decorated with bioconjugated copolymers in the presence of amantadine.
- Author
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Pérez-Isidoro R, Valdez-Lara AG, Díaz-Salazar AJ, Hoeppener S, Guerrero-Sánchez C, Quintana-Owen P, Ruiz-Suárez JC, Schubert US, Ayora-Talavera G, De Jesús-Téllez MA, and Saldívar-Guerra E
- Subjects
- Polymers chemistry, Animals, Antiviral Agents chemistry, Antiviral Agents pharmacology, Madin Darby Canine Kidney Cells, Dogs, Liposomes chemistry, Amantadine chemistry
- Abstract
Liposome-based technologies derived from lipids and polymers ( e.g. , PEGylated liposomes) have been recognized because of their applications in nanomedicine. However, since such systems represent myriad challenges and may promote immune responses, investigation of new biomaterials is mandatory. Here, we report on a biophysical investigation of liposomes decorated with bioconjugated copolymers in the presence (or absence) of amantadine (an antiviral medication). First, copolymers of poly( N , N -dimethylacrylamide- co -fluoresceinacrylate- co -acrylic acid- N -succinimide ester)- block -poly( N -isopropylacrylamide) (PDMA- b -PNIPAM) containing a fluorescence label were biofunctionalized with short peptides that resemble the sequence of the loops 220 and 130 of the binding receptor of the hemagglutinin (HA) protein of the influenza A virus. Then, the bioconjugated copolymers were self-assembled along with liposomes composed of 1,2 dimyristoyl- sn-glycero -3-phosphocholine, sphingomyelin, and cholesterol (MSC). These biohybrid systems, with and without amantadine, were systematically characterized using differential scanning calorimetry (DSC), dynamic light scattering (DLS), and cryogenic transmission electron microscopy (cryoTEM). Finally, the systems were tested in an in vitro study to evaluate cytotoxicity and direct immunofluorescence in Madin Darbin Canine Kidney (MDCK) cells. The biohybrid systems displayed long-term stability, thermo-responsiveness, hydrophilic-hydrophobic features, and fluorescence properties and were presumable endowed with cell targeting properties intrinsically integrated into the amino acid sequences of the utilized peptides, which indeed turn them into promising nanodevices for biomedical applications.
- Published
- 2024
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14. Influence of Polymer Side Chain Size and Backbone Length on the Self-Assembly of Supramolecular Polymer Bottlebrushes.
- Author
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Ulrich HF, Gruschwitz FV, Klein T, Ziegenbalg N, Anh DTN, Fujii S, Hoeppener S, Sakurai K, and Brendel JC
- Abstract
Hydrogen bonds are a versatile tool for creating fibrous, bottlebrush-like assemblies of polymeric building blocks. However, a delicate balance of forces exists between the steric repulsion of the polymer chains and these directed supramolecular forces. In this work we have systematically investigated the influence of structural parameters of the attached polymers on the assembly behaviour of benzene trisurea (BTU) and benzene tris(phenylalanine) (BTP) conjugates in water. Polymers with increasing main chain lengths and different side chain sizes were prepared by reversible addition-fragmentation chain-transfer (RAFT) polymerization of hydroxyethyl acrylate (HEA), tri(ethylene glycol) methyl ether acrylate (TEGA) and oligo(ethylene glycol) methyl ether acrylate (OEGA). The resulting structures were analyzed using small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). Both BTU and BTP formed fibres with PHEA attached, but a transition to spherical morphologies was observed at degrees of polymerisation (DP) of 70 and above. Overall, the main chain length appeared to be a dominating factor in inducing morphology transitions. Increasing the side chain size generally had a similar effect but mainly impeded any aggregation as is the case of POEGA. Interestingly, BTP conjugates still formed fibres, suggesting that the stronger intermolecular interactions can compensate partially for the steric repulsion., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)
- Published
- 2024
- Full Text
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15. Selective Uptake Into Inflamed Human Intestinal Tissue and Immune Cell Targeting by Wormlike Polymer Micelles.
- Author
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Gardey E, Cseresnyes Z, Sobotta FH, Eberhardt J, Haziri D, Grunert PC, Kuchenbrod MT, Gruschwitz FV, Hoeppener S, Schumann M, Gaßler N, Figge MT, Stallmach A, and Brendel JC
- Subjects
- Humans, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Nanoparticles chemistry, Inflammation drug therapy, Inflammation pathology, Drug Delivery Systems, Micelles, Polymers chemistry, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases metabolism, Inflammatory Bowel Diseases pathology
- Abstract
Inflammatory bowel disease (IBD) has become a globally prevalent chronic disease with no causal therapeutic options. Targeted drug delivery systems with selectivity for inflamed areas in the gastrointestinal tract promise to reduce severe drug-related side effects. By creating three distinct nanostructures (vesicles, spherical, and wormlike micelles) from the same amphiphilic block copolymer poly(butyl acrylate)-block-poly(ethylene oxide) (PBA-b-PEO), the effect of nanoparticle shape on human mucosal penetration is systematically identified. An Ussing chamber technique is established to perform the ex vivo experiments on human colonic biopsies, demonstrating that the shape of polymeric nanostructures represents a rarely addressed key to tissue selectivity required for efficient IBD treatment. Wormlike micelles specifically enter inflamed mucosa from patients with IBD, but no significant uptake is observed in healthy tissue. Spheres (≈25 nm) and vesicles (≈120 nm) enter either both normal and inflamed tissue types or do not penetrate any tissue. According to quantitative image analysis, the wormlike nanoparticles localize mainly within immune cells, facilitating specific targeting, which is crucial for further increasing the efficacy of IBD treatment. These findings therefore demonstrate the untapped potential of wormlike nanoparticles not only to selectively target the inflamed human mucosa, but also to target key pro-inflammatory cells., (© 2023 The Authors. Small published by Wiley‐VCH GmbH.)
- Published
- 2024
- Full Text
- View/download PDF
16. Improving Gene Delivery: Synergy between Alkyl Chain Length and Lipoic Acid for PDMAEMA Hydrophobic Copolymers.
- Author
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Mapfumo PP, Reichel LS, Hoeppener S, and Traeger A
- Subjects
- Gene Transfer Techniques, Polymers chemistry, Methacrylates chemistry, Transfection, Thioctic Acid pharmacology, Nylons
- Abstract
In the field of gene delivery, hydrophobic cationic copolymers hold great promise. They exhibit improved performance by effectively protecting genetic material from serum interactions while facilitating interactions with cellular membranes. However, managing cytotoxicity remains a significant challenge, prompting an investigation into suitable hydrophobic components. A particularly encouraging approach involves integrating nutrient components, like lipoic acid, which is known for its antioxidant properties and diverse cellular benefits such as cellular metabolism and growth. In this study, a copolymer library comprising 2-(dimethylamino)ethyl methacrylate (DMAEMA) and lipoic acid methacrylate (LAMA), combined with either n-butyl methacrylate (nBMA), ethyl methacrylate (EMA), or methyl methacrylate (MMA), is synthesized. This enables to probe the impact of lipoic acid incorporation while simultaneously exploring the influence of pendant acyclic alkyl chain length. The inclusion of lipoic acid results in a notable boost in transfection efficiency while maintaining low cytotoxicity. Interestingly, higher levels of transfection efficiency are achieved in the presence of nBMA, EMA, or MMA. However, a positive correlation between pendant acyclic alkyl chain length and cytotoxicity is observed. Consequently, P(DMAEMA-co-LAMA-co-MMA), emerges as a promising candidate. This is attributed to the optimal combination of low cytotoxic MMA and transfection-boosting LAMA, highlighting the crucial synergy between LAMA and MMA., (© 2024 The Authors. Macromolecular Rapid Communications published by Wiley‐VCH GmbH.)
- Published
- 2024
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17. Optimization of Mixed Micelles Based on Oppositely Charged Block Copolymers by Machine Learning for Application in Gene Delivery.
- Author
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Leer K, Reichel LS, Kimmig J, Richter F, Hoeppener S, Brendel JC, Zechel S, Schubert US, and Traeger A
- Subjects
- Polymers chemistry, Gene Transfer Techniques, Acrylamides, Micelles, Polyethylene Glycols chemistry
- Abstract
The COVID-19 mRNA vaccines represent a milestone in developing non-viral gene carriers, and their success highlights the crucial need for continued research in this field to address further challenges. Polymer-based delivery systems are particularly promising due to their versatile chemical structure and convenient adaptability, but struggle with the toxicity-efficiency dilemma. Introducing anionic, hydrophilic, or "stealth" functionalities represents a promising approach to overcome this dilemma in gene delivery. Here, two sets of diblock terpolymers are created comprising hydrophobic poly(n-butyl acrylate) (PnBA), a copolymer segment made of hydrophilic 4-acryloylmorpholine (NAM), and either the cationic 3-guanidinopropyl acrylamide (GPAm) or the 2-carboxyethyl acrylamide (CEAm), which is negatively charged at neutral conditions. These oppositely charged sets of diblocks are co-assembled in different ratios to form mixed micelles. Since this experimental design enables countless mixing possibilities, a machine learning approach is applied to identify an optimal GPAm/CEAm ratio for achieving high transfection efficiency and cell viability with little resource expenses. After two runs, an optimal ratio to overcome the toxicity-efficiency dilemma is identified. The results highlight the remarkable potential of integrating machine learning into polymer chemistry to effectively tackle the enormous number of conceivable combinations for identifying novel and powerful gene transporters., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)
- Published
- 2024
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18. PEG-Lipid-PLGA Hybrid Particles for Targeted Delivery of Anti-Inflammatory Drugs.
- Author
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Ismail J, Klepsch LC, Dahlke P, Tsarenko E, Vollrath A, Pretzel D, Jordan PM, Rezaei K, Czaplewska JA, Stumpf S, Beringer-Siemers B, Nischang I, Hoeppener S, Werz O, and Schubert US
- Abstract
Hybrid nanoparticles (HNPs) were designed by combining a PLGA core with a lipid shell that incorporated PEG-Lipid conjugates with various functionalities (-RGD, -cRGD, -NH
2 , and -COOH) to create targeted drug delivery systems. Loaded with a neutral lipid orange dye, the HNPs were extensively characterized using various techniques and investigated for their uptake in human monocyte-derived macrophages (MDMs) using FC and CLSM. Moreover, the best-performing HNPs (i.e., HNP-COOH and HNP-RGD as well as HNP-RGD/COOH mixed) were loaded with the anti-inflammatory drug BRP-201 and prepared in two size ranges (dH ~140 nm and dH ~250 nm). The HNPs were examined further for their stability, degradation, MDM uptake, and drug delivery efficiency by studying the inhibition of 5-lipoxygenase (5-LOX) product formation, whereby HNP-COOH and HNP-RGD both exhibited superior uptake, and the HNP-COOH/RGD (2:1) displayed the highest inhibition.- Published
- 2024
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19. Characterization of Drug Delivery Systems by Transmission Electron Microscopy.
- Author
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Hoeppener S
- Subjects
- Humans, Microscopy, Electron, Transmission, Drug Delivery Systems
- Abstract
The contribution of electron microscopy, and here, in particular transmission electron microscopy (TEM), to the formulation and understanding of the biological action of drug delivery systems has led to a better insight into the design principles of drug delivery systems. TEM can be applied for particle characterization, for the visualization of the uptake and intracellular pathways of drug vehicles in cells and tissues and more recently can be also applied for the high-resolution investigation of drug-receptor interactions with near-atomic resolution. This chapter introduces basic techniques to optimize imaging quality of soft matter samples, highlights possibilities to study certain aspects of drug delivery applications, and finally provides a short introduction to high-resolution characterization possibilities which recently emerged., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
- Published
- 2024
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20. Electronic and Photochemical Passivation by a Classic Sunscreen Material Leading to Reduced V oc Losses and Enhanced Stability in Organic Solar Cells.
- Author
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Xu Z, Islam MM, Meitzner R, Anand A, Djoumessi AS, Stumpf S, Hoeppener S, Neumann C, Turchanin A, Schubert US, and Hoppe H
- Abstract
Organic solar cells (OSCs) have been a popular topic of research for a long time. As a well-known electron transport layer (ETL) material for inverted device architecture, sol-gel-derived zinc oxide (ZnO) displays certain defective surfaces that cause excessive charge recombination and lower device performance. While ultraviolet (UV)-light soaking is sometimes necessary for the ZnO layer to function properly, the latter can also cause the photodegradation of conjugated organic semiconductors. The photostability of OSCs has always been a hot research topic, as the radiation of UV light may cause changes in the material's properties, and that, in turn, may cause rapid attenuation of the devices. Herein, ZnO is modified by inserting the commonly used sunscreen ingredient benzophenone-3 (BP-3) between the photoactive layer, consisting of a PM6:Y6 blend, and ZnO to reduce the impact of UV radiation on the photosensitive layer. The addition of BP-3 successfully enhances the photovoltaic parameters, and a remarkable open-circuit voltage ( V
oc loss as small as 0.547 V. Finally, the application of this strategy increases the device's power conversion efficiency from 12.44 to 13.71% and provides improved UV stability.Voc loss as small as 0.547 V. Finally, the application of this strategy increases the device's power conversion efficiency from 12.44 to 13.71% and provides improved UV stability.- Published
- 2023
- Full Text
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21. PEG-Lipids: Quantitative Study of Unimers and Aggregates Thereof by the Methods of Molecular Hydrodynamics.
- Author
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Anufriev I, Hoeppener S, and Nischang I
- Subjects
- Humans, Hydrodynamics, SARS-CoV-2, Polyethylene Glycols chemistry, Solvents, Polymers, Water chemistry, Lipids chemistry, Ethanol, Micelles, COVID-19
- Abstract
Understanding the polymorphism of lipids in solution is the key to the development of intracellular delivery systems. Here, we study the dynamics of poly(ethylene glycol)-lipid (PEG-Lipid) conjugates aiming at a better understanding of their molecular properties and aggregation behavior in solution. Those PEG-Lipids are used as components of lipid nanoparticles (LNPs). LNPs are gaining increased popularity, e.g., by their utilization in modern vaccination strategies against SARS-CoV-2. Characterization of the systems is conducted by the classical methods of hydrodynamics in different solvents, such as ethanol and water, which are also commonly used for LNP formulation. We were able to elucidate the structurally associated hydrodynamic properties of isolated PEG-Lipids in ethanol, revealing the typically expected values of the hydrodynamic invariant for random coil polymers. By virtue of the same experimental setting, the PEG-Lipids' behavior in water was as well studied, which is a less good solvent than ethanol for the PEG-Lipids. Our experiments demonstrate that PEG-Lipids dissolved in water form well-defined micelles that can quantitatively be characterized in terms of their degree of aggregation of PEG-Lipid polymer unimers, their hydrodynamic size, and solvation, i.e., the quantitative determination of water contained or associated to the identified micelles. Quantitative results obtained from classical hydrodynamic analyses are fully supported by studies with standard dynamic light scattering (DLS). The obtained diffusion coefficients and hydrodynamic sizes are in excellent agreement with numerical results derived from analytical ultracentrifugation (AUC) data. Cryo-transmission electron microscopy (cryo-TEM) supports the structural insight from hydrodynamic studies, particularly, in terms of the observed spherical structure of the formed micelles. We demonstrate experimentally that the micelle systems can be considered as solvent-permeable, hydrated spheres.
- Published
- 2023
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22. Guided-deconvolution for correlative light and electron microscopy.
- Author
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Ma F, Kaufmann R, Sedzicki J, Cseresnyés Z, Dehio C, Hoeppener S, Figge MT, and Heintzmann R
- Subjects
- Humans, Microscopy, Electron, HeLa Cells, Organelles
- Abstract
Correlative light and electron microscopy is a powerful tool to study the internal structure of cells. It combines the mutual benefit of correlating light (LM) and electron (EM) microscopy information. The EM images only contain contrast information. Therefore, some of the detailed structures cannot be specified from these images alone, especially when different cell organelle are contacted. However, the classical approach of overlaying LM onto EM images to assign functional to structural information is hampered by the large discrepancy in structural detail visible in the LM images. This paper aims at investigating an optimized approach which we call EM-guided deconvolution. This applies to living cells structures before fixation as well as previously fixed sample. It attempts to automatically assign fluorescence-labeled structures to structural details visible in the EM image to bridge the gaps in both resolution and specificity between the two imaging modes. We tested our approach on simulations, correlative data of multi-color beads and previously published data of biological samples., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
- Full Text
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23. Tuning the corona-core ratio of polyplex micelles for selective oligonucleotide delivery to hepatocytes or hepatic immune cells.
- Author
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Foo W, Cseresnyés Z, Rössel C, Teng Y, Ramoji A, Chi M, Hauswald W, Huschke S, Hoeppener S, Popp J, Schacher FH, Sierka M, Figge MT, Press AT, and Bauer M
- Subjects
- Tissue Distribution, Endothelial Cells, Polyethylene Glycols chemistry, RNA, Small Interfering genetics, Hepatocytes, Micelles, Oligonucleotides
- Abstract
Targeted delivery of oligonucleotides or small molecular drugs to hepatocytes, the liver's parenchymal cells, is challenging without targeting moiety due to the highly efficient mononuclear phagocyte system (MPS) of the liver. The MPS comprises Kupffer cells and specialized sinusoidal endothelial cells, efficiently clearing nanocarriers regardless of their size and surface properties. Physiologically, this non-parenchymal shield protects hepatocytes; however, these local barriers must be overcome for drug delivery. Nanocarrier structural properties strongly influence tissue penetration, in vivo pharmacokinetics, and biodistribution profile. Here we demonstrate the in vivo biodistribution of polyplex micelles formed by polyion complexation of short interfering (si)RNA with modified poly(ethylene glycol)-block-poly(allyl glycidyl ether) (PEG-b-PAGE) diblock copolymer that carries amino moieties in the side chain. The ratio between PEG corona and siRNA complexed PAGE core of polyplex micelles was chemically varied by altering the degree of polymerization of PAGE. Applying Raman-spectroscopy and dynamic in silico modeling on the polyplex micelles, we determined the corona-core ratio (CCR) and visualized the possible micellar structure with varying CCR. The results for this model system reveal that polyplex micelles with higher CCR, i.e., better PEG coverage, exclusively accumulate and thus allow passive cell-type-specific targeting towards hepatocytes, overcoming the macrophage-rich reticuloendothelial barrier of the liver., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
24. Polymer-based particles against pathogenic fungi: A non-uptake delivery of compounds.
- Author
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Orasch T, Gangapurwala G, Vollrath A, González K, Alex J, De San Luis A, Weber C, Hoeppener S, Cseresnyés Z, Figge MT, Guerrero-Sanchez C, Schubert US, and Brakhage AA
- Subjects
- Humans, Polymers pharmacology, Fluorescent Dyes, Candida albicans, Antifungal Agents pharmacology, Itraconazole pharmacology
- Abstract
The therapy of life-threatening fungal infections is limited and needs urgent improvement. This is in part due to toxic side effects of clinically used antifungal compounds or their limited delivery to fungal structures. Until today, it is a matter of debate how drugs or drug-delivery systems can efficiently reach the intracellular lumen of fungal cells and how this can be improved. Here, we addressed both questions by applying two different polymeric particles for delivery of compounds. Their formulation was based on two biocompatible polymers, i.e., poly(lactic-co-glycolic acid)
50:50 and poly(methyl methacrylate-stat-methacrylic acid)90:10 yielding particles with hydrodynamic diameters ranging from 100 to 300 nm. The polymers were covalently labeled with the fluorescent dye DY-550 to monitor the interaction between particles and fungi by confocal laser scanning microscopy. Furthermore, the fluorescent dye coumarin-6 and the antifungal drug itraconazole were successfully encapsulated in particles to study the fate of both the cargo and the particle when interacting with the clinically most important human-pathogenic fungi Aspergillus fumigatus, A. terreus, Candida albicans, and Cryptococcus neoformans. While the polymers were exclusively located on the fungal surface, the encapsulated cargo was efficiently transported into fungal hyphae, indicated by increased intracellular fluorescence signals due to coumarin-6. In accordance with this finding, compared to the pristine drug a reduced minimal inhibitory concentration for itraconazole was determined, when it was encapsulated. Together, the herein used polymeric particles were not internalized by pathogenic fungi but were able to efficiently deliver hydrophobic cargos into fungal cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)- Published
- 2023
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25. Ethoxy acetalated dextran nanoparticles for drug delivery: A comparative study of formulation methods.
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Behnke M, Klemm P, Dahlke P, Shkodra B, Beringer-Siemers B, Czaplewska JA, Stumpf S, Jordan PM, Schubert S, Hoeppener S, Vollrath A, Werz O, and Schubert US
- Abstract
Dextran-based polymers, such as ethoxy acetalated dextran (Ace-DEX), are increasingly becoming the focus of research as they offer great potential for the development of polymer-based nanoparticles as drug delivery vehicles. Their major advantages are the facile synthesis, straightforward particle preparation and the pH-dependent degradation of the particles that can be fine-tuned by the degree of acetalation of the polymer. In this study we have shown that Ace-DEX can not only compete against the commonly used and FDA-approved polymer poly(lactic- co -glycolic acid) (PLGA), but even has the potential to outperform it in its encapsulation properties, e.g. , for the herein used anti-inflammatory leukotriene biosynthesis inhibitor BRP-187. We used three different methods (microfluidics, batch nanoprecipitation and emulsion solvent evaporation) for the preparation of BRP-187-loaded Ace-DEX nanoparticles to investigate the influence of the formulation technique on the physicochemical properties of the particles. Finally, we evaluated which production method offers the greatest potential for achieving the demands for a successful translation from research into pharmaceutical production by fulfilling the basic requirements, such as reaching a high loading capacity of the particles and excellent reproducibility while being simple and affordable., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)
- Published
- 2023
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26. Intestinal epithelial barrier integrity investigated by label-free techniques in ulcerative colitis patients.
- Author
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Quansah E, Gardey E, Ramoji A, Meyer-Zedler T, Goehrig B, Heutelbeck A, Hoeppener S, Schmitt M, Waldner M, Stallmach A, and Popp J
- Subjects
- Humans, Intestines pathology, Intestinal Mucosa diagnostic imaging, Intestinal Mucosa pathology, Colitis, Ulcerative pathology, Inflammatory Bowel Diseases pathology, Colitis pathology
- Abstract
The intestinal epithelial barrier, among other compartments such as the mucosal immune system, contributes to the maintenance of intestinal homeostasis. Therefore, any disturbance within the epithelial layer could lead to intestinal permeability and promote mucosal inflammation. Considering that disintegration of the intestinal epithelial barrier is a key element in the etiology of ulcerative colitis, further assessment of barrier integrity could contribute to a better understanding of the role of epithelial barrier defects in ulcerative colitis (UC), one major form of chronic inflammatory bowel disease. Herein, we employ fast, non-destructive, and label-free non-linear methods, namely coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG), two-photon excited fluorescence (TPEF), and two-photon fluorescence lifetime imaging (2P-FLIM), to assess the morpho-chemical contributions leading to the dysfunction of the epithelial barrier. For the first time, the formation of epithelial barrier gaps was directly visualized, without sophisticated data analysis procedures, by the 3D analysis of the colonic mucosa from severely inflamed UC patients. The results were compared with histopathological and immunofluorescence images and validated using transmission electron microscopy (TEM) to indicate structural alterations of the apical junction complex as the underlying cause for the formation of the epithelial barrier gaps. Our findings suggest the potential advantage of non-linear multimodal imaging is to give precise, detailed, and direct visualization of the epithelial barrier in the gastrointestinal tract, which can be combined with a fiber probe for future endomicroscopy measurements during real-time in vivo imaging., (© 2023. The Author(s).)
- Published
- 2023
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27. Targeting of phagolysosomes containing conidia of the fungus Aspergillus fumigatus with polymeric particles.
- Author
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González K, Gangapurwala G, Alex J, Vollrath A, Cseresnyés Z, Weber C, Czaplewska JA, Hoeppener S, Svensson CM, Orasch T, Heinekamp T, Guerrero-Sánchez C, Figge MT, Schubert US, and Brakhage AA
- Subjects
- Humans, Spores, Fungal, Macrophages microbiology, Phagocytosis, Aspergillus fumigatus, Phagosomes
- Abstract
Conidia of the airborne human-pathogenic fungus Aspergillus fumigatus are inhaled by humans. In the lung, they are phagocytosed by alveolar macrophages and intracellularly processed. In macrophages, however, conidia can interfere with the maturation of phagolysosomes to avoid their elimination. To investigate whether polymeric particles (PPs) can reach this intracellular pathogen in macrophages, we formulated dye-labeled PPs with a size allowing for their phagocytosis. PPs were efficiently taken up by RAW 264.7 macrophages and were found in phagolysosomes. When macrophages were infected with conidia prior to the addition of PPs, we found that they co-localized in the same phagolysosomes. Mechanistically, the fusion of phagolysosomes containing PPs with phagolysosomes containing conidia was observed. Increasing concentrations of PPs increased fusion events, resulting in 14% of phagolysosomes containing both conidia and PPs. We demonstrate that PPs can reach conidia-containing phagolysosomes, making these particles a promising carrier system for antimicrobial drugs to target intracellular pathogens. KEY POINTS: • Polymer particles of a size larger than 500 nm are internalized by macrophages and localized in phagolysosomes. • These particles can be delivered to Aspergillus fumigatus conidia-containing phagolysosomes of macrophages. • Enhanced phagolysosome fusion by the use of vacuolin1 can increase particle delivery., (© 2022. The Author(s).)
- Published
- 2023
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28. Targeted Suppression of Peptide Degradation in Ag-Based Surface-Enhanced Raman Spectra by Depletion of Hot Carriers.
- Author
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Yao X, Höppener C, Schneidewind H, Hoeppener S, Tang Z, Buchholz A, König A, Mogavero S, Diegel M, Dellith J, Turchanin A, Plass W, Hube B, and Deckert V
- Subjects
- Microscopy, Atomic Force, Iodides, Spectrum Analysis, Raman methods
- Abstract
Sample degradation, in particular of biomolecules, frequently occurs in surface-enhanced Raman spectroscopy (SERS) utilizing supported silver SERS substrates. Currently, thermal and/or photocatalytic effects are considered to cause sample degradation. This paper establishes the efficient inhibition of sample degradation using iodide which is demonstrated by a systematic SERS study of a small peptide in aqueous solution. Remarkably, a distinct charge separation-induced surface potential difference is observed for SERS substrates under laser irradiation using Kelvin probe force microscopy. This directly unveils the photocatalytic effect of Ag-SERS substrates. Based on the presented results, it is proposed that plasmonic photocatalysis dominates sample degradation in SERS experiments and the suppression of typical SERS sample degradation by iodide is discussed by means of the energy levels of the substrate under mild irradiation conditions. This approach paves the way toward more reliable and reproducible SERS studies of biomolecules under physiological conditions., (© 2022 The Authors. Small published by Wiley-VCH GmbH.)
- Published
- 2022
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29. Efficient Gene Delivery of Tailored Amphiphilic Polypeptides by Polyplex Surfing.
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Klemm P, Solomun JI, Rodewald M, Kuchenbrod MT, Hänsch VG, Richter F, Popp J, Hertweck C, Hoeppener S, Bonduelle C, Lecommandoux S, Traeger A, and Schubert S
- Subjects
- Genetic Therapy, Transfection, Cations, Peptides, Glutamine, Gene Transfer Techniques
- Abstract
Within this study, an amphiphilic and potentially biodegradable polypeptide library based on poly[(4-aminobutyl)-l-glutamine- stat -hexyl-l-glutamine] [P(AB-l-Gln- stat -Hex-l-Gln)] was investigated for gene delivery. The influence of varying proportions of aliphatic and cationic side chains affecting the physicochemical properties of the polypeptides on transfection efficiency was investigated. A composition of 40 mol% Hex-l-Gln and 60 mol % AB-l-Gln ( P3 ) was identified as best performer over polypeptides with higher proportions of protonatable monomers. Detailed studies of the transfection mechanism revealed the strongest interaction of P3 with cell membranes, promoting efficient endocytic cell uptake and high endosomal release. Spectrally, time-, and z -resolved fluorescence microscopy further revealed the crucial role of filopodia surfing in polyplex-cell interaction and particle internalization in lamellipodia regions, followed by rapid particle transport into cells. This study demonstrates the great potential of polypeptides for gene delivery. The amphiphilic character improves performance over cationic homopolypeptides, and the potential biodegradability is advantageous toward other synthetic polymeric delivery systems.
- Published
- 2022
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30. Inkjet Printing and 3D Printing Strategies for Biosensing, Analytical, and Diagnostic Applications.
- Author
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Zub K, Hoeppener S, and Schubert US
- Subjects
- Printing, Three-Dimensional
- Abstract
Inkjet printing and 3D inkjet printing have found many applications in the fabrication of a great variety of devices, which have been developed with the aim to improve and simplify the design, fabrication, and performance of sensors and analytical platforms. Here, developments of these printing technologies reported during the last 10 years are reviewed and their versatile applicability for the fabrication of improved sensing platforms and analytical and diagnostic sensor systems is demonstrated. Illustrative examples are reviewed in the context of particular advantages provided by inkjet printing technologies. Next to aspects of device printing and fabrication strategies, the utilization of inkjet dispensing, which can be implemented into common analytical tools utilizing customized inkjet printing equipment as well as state-of-the-art consumer inkjet printing devices, is highlighted. This review aims to providing a comprehensive overview of examples integrating inkjet and 3D inkjet printing technologies into device layout fabrication, dosing, and analytical applications to demonstrate the versatile applicability of these technologies, and furthermore, to inspire the utilization of inkjet printing for future developments., (© 2022 The Authors. Advanced Materials published by Wiley-VCH GmbH.)
- Published
- 2022
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31. pH-sensitive packaging of cationic particles by an anionic block copolymer shell.
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Solomun JI, Martin L, Mapfumo P, Moek E, Amro E, Becker F, Tuempel S, Hoeppener S, Rudolph KL, and Traeger A
- Subjects
- Animals, Cations, HEK293 Cells, Humans, Hydrogen-Ion Concentration, Mice, Transfection, Polyethylene Glycols chemistry, Polymers chemistry
- Abstract
Cationic non-viral vectors show great potential to introduce genetic material into cells, due to their ability to transport large amounts of genetic material and their high synthetic versatility. However, designing materials that are effective without showing toxic effects or undergoing non-specific interactions when applied systemically remains a challenge. The introduction of shielding polymers such as polyethylene glycol (PEG) can enhance biocompatibility and circulation time, however, often impairs transfection efficiency. Herein, a multicomponent polymer system is introduced, based on cationic and hydrophobic particles (P(nBMA
46 -co-MMA47 -co-DMAEMA90 ), (PBMD)) with high delivery performance and a pH-responsive block copolymer (poly((N-acryloylmorpholine)-b-(2-(carboxy)ethyl acrylamide)) (P(NAM72 -b-CEAm74 ), PNC)) as shielding system, with PNAM as alternative to PEG. The pH-sensitive polymer design promotes biocompatibility and excellent stability at extracellular conditions (pH 7.4) and also allows endosomal escape and thus high transfection efficiency under acidic conditions. PNC shielded particles are below 200 nm in diameter and showed stable pDNA complexation. Further, interaction with human erythrocytes at extracellular conditions (pH 7.4) was prevented, while acidic conditions (pH 6) enabled membrane leakage. The particles demonstrate transfection in adherent (HEK293T) as well as difficult-to-transfect suspension cells (K-562), with comparable or superior efficiency compared to commercial linear poly(ethylenimine) (LPEI). Besides, the toxicity of PNC-shielded particles was significantly minimized, in particular in K-562 cells and erythrocytes. In addition, a pilot in vivo experiment on bone marrow blood cells of mice that were injected with PNC-shielded particles, revealed slightly enhanced cell transfection in comparison to naked pDNA. This study demonstrates the applicability of cationic hydrophobic polymers for transfection of adherent and suspension cells in culture as well as in vivo by co-formulation with pH-responsive shielding polymers, without substantially compromising transfection performance., (© 2022. The Author(s).)- Published
- 2022
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32. Encapsulation of the Anti-inflammatory Dual FLAP/sEH Inhibitor Diflapolin Improves the Efficiency in Human Whole Blood.
- Author
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Grune C, Kretzer C, Zergiebel S, Kattner S, Thamm J, Hoeppener S, Werz O, and Fischer D
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Drug Carriers, Drug Delivery Systems, Female, Humans, Particle Size, Polyethylene Glycols, Chickens, Nanoparticles
- Abstract
Diflapolin is a dual FLAP/sEH inhibitor with potent anti-inflammatory efficiency in cellular assays and experimental in vivo studies. Despite these outstanding characteristics, its high lipophilicity and plasma protein binding hamper the bioactivity in blood. To overcome these limitations, diflapolin was encapsulated in poly(lactic-co-glycolic acid) nanoparticles to develop an efficient and biocompatible drug delivery system. Two different cosolvent approaches were tested showing the possibility to exchange dimethyl sulfoxide in the organic phase by the sustainable 400 g/mol poly(ethylene glycol). A particle size of 220 nm and the amorphous encapsulation of diflapolin in high amounts rendered the nanoparticles appropriate for the intended application. Excellent biocompatibility of the nanoparticles was demonstrated in an ex ovo hen's egg model. The potent suppression of FLAP-dependent 5-lipoxygenase product formation by the nanoparticles in human whole blood, superior to the free drug, makes them to a promising drug delivery system to improve the bioactivity of diflapolin., Competing Interests: Declaration of Interest The authors declare that they have no competing personal relationships or financial interests that could have appeared to influence this study., (Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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33. Triazole-Functionalized Mesoporous Materials Based on Poly(styrene- block -lactic acid): A Morphology Study of Thin Films.
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Trejo-Maldonado M, Womiloju A, Stumpf S, Hoeppener S, Schubert US, Elizalde LE, and Guerrero-Sanchez C
- Abstract
We report the synthesis of poly(styrene- block -lactic acid) (PS- b -PLA) copolymers with triazole rings as a junction between blocks. These materials were prepared via a 'click' strategy which involved the reaction between azide-terminated poly(styrene) (PS-N
3 ) and acetylene-terminated poly(D,L-lactic acid) (PLA-Ac), accomplished by copper-catalyzed azide-alkyne cycloaddition reaction. This synthetic approach has demonstrated to be effective to obtain specific copolymer structures with targeted self-assembly properties. We observed the self-assembly behavior of the PS- b -PLA thin films as induced by solvent vapor annealing (SVA), thermal annealing (TA), and hydrolysis of the as-spun substrates and monitored their morphological changes by means of different microscopic techniques. Self-assembly via SVA and TA proved to be strongly dependent on the pretreatment of the substrates. Microphase segregation of the untreated films yielded a pore size of 125 nm after a 45-min SVA. After selectively removing the PLA microdomains, the as-spun substrates exhibited the formation of pores on the surface, which can be a good alternative to form an ordered pattern of triazole functionalized porous PS at the mesoscale. Finally, as revealed by scanning electron microscopy-energy dispersive X-ray spectroscopy, the obtained triazole-functionalized PS-porous film exhibited some affinity to copper (Cu) in solution. These materials are suitable candidates to further study its metal-caption properties.- Published
- 2022
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34. Ethoxy acetalated dextran-based nanocarriers accomplish efficient inhibition of leukotriene formation by a novel FLAP antagonist in human leukocytes and blood.
- Author
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Kretzer C, Shkodra B, Klemm P, Jordan PM, Schröder D, Cinar G, Vollrath A, Schubert S, Nischang I, Hoeppener S, Stumpf S, Banoglu E, Gladigau F, Bilancia R, Rossi A, Eggeling C, Neugebauer U, Schubert US, and Werz O
- Subjects
- Animals, Female, Healthy Volunteers, Humans, Male, Mice, Leukotriene Antagonists pharmacology, Leukotrienes biosynthesis, Leukotrienes metabolism, Nanoparticles chemistry
- Abstract
Leukotrienes are pro-inflammatory lipid mediators generated by 5-lipoxygenase aided by the 5-lipoxygenase-activating protein (FLAP). BRP-201, a novel benzimidazole-based FLAP antagonist, inhibits leukotriene biosynthesis in isolated leukocytes. However, like other FLAP antagonists, BRP-201 fails to effectively suppress leukotriene formation in blood, which limits its therapeutic value. Here, we describe the encapsulation of BRP-201 into poly(lactide-co-glycolide) (PLGA) and ethoxy acetalated dextran (Ace-DEX) nanoparticles (NPs), aiming to overcome these detrimental pharmacokinetic limitations and to enhance the bioactivity of BRP-201. NPs loaded with BRP-201 were produced via nanoprecipitation and the physicochemical properties of the NPs were analyzed in-depth using dynamic light scattering (size, dispersity, degradation), electrophoretic light scattering (effective charge), NP tracking analysis (size, dispersity), scanning electron microscopy (size and morphology), UV-VIS spectroscopy (drug loading), an analytical ultracentrifuge (drug release, degradation kinetics), and Raman spectroscopy (chemical attributes). Biological assays were performed to study cytotoxicity, cellular uptake, and efficiency of BRP-201-loaded NPs versus free BRP-201 to suppress leukotriene formation in primary human leukocytes and whole blood. Both PLGA- and Ace-DEX-based NPs were significantly more efficient to inhibit leukotriene formation in neutrophils versus free drug. Whole blood experiments revealed that encapsulation of BRP-201 into Ace-DEX NPs strongly increases its potency, especially upon pro-longed (≥ 5 h) incubations and upon lipopolysaccharide-challenge of blood. Finally, intravenous injection of BRP-201-loaded NPs significantly suppressed leukotriene levels in blood of mice in vivo. These results reveal the feasibility of our pharmacological approach using a novel FLAP antagonist encapsulated into Ace-DEX-based NPs with improved efficiency in blood to suppress leukotriene biosynthesis., (© 2021. The Author(s).)
- Published
- 2021
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35. Tuneable Time Delay in the Burst Release from Oxidation-Sensitive Polymersomes Made by PISA.
- Author
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Sobotta FH, Kuchenbrod MT, Gruschwitz FV, Festag G, Bellstedt P, Hoeppener S, and Brendel JC
- Abstract
Reactive polymersomes represent a versatile artificial cargo carrier system that can facilitate an immediate release in response to a specific stimulus. The herein presented oxidation-sensitive polymersomes feature a time-delayed release mechanism in an oxidative environment, which can be precisely adjusted by either tuning the membrane thickness or partial pre-oxidation. These polymeric vesicles are conveniently prepared by PISA allowing the straightforward and effective in situ encapsulation of cargo molecules, as shown for dyes and enzymes. Kinetic studies revealed a critical degree of oxidation causing the destabilization of the membrane, while no release of the cargo is observed beforehand. The encapsulation of glucose oxidase directly transforms these polymersomes into glucose-sensitive vesicles, as small molecules including sugars can passively penetrate their membrane. Considering the ease of preparation, these polymersomes represent a versatile platform for the confinement and burst release of cargo molecules after a precisely adjustable time span in the presence of specific triggers, such as H
2 O2 or glucose., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)- Published
- 2021
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- View/download PDF
36. Adjusting the length of supramolecular polymer bottlebrushes by top-down approaches.
- Author
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Klein T, Gruschwitz FV, Kuchenbrod MT, Nischang I, Hoeppener S, and Brendel JC
- Abstract
Controlling the length of one-dimensional (1D) polymer nanostructures remains a key challenge on the way toward the applications of these structures. Here, we demonstrate that top-down processing facilitates a straightforward adjustment of the length of polyethylene oxide (PEO)-based supramolecular polymer bottlebrushes (SPBs) in aqueous solutions. These cylindrical structures self-assemble via directional hydrogen bonds formed by benzenetrisurea (BTU) or benzenetrispeptide (BTP) motifs located within the hydrophobic core of the fiber. A slow transition from different organic solvents to water leads first to the formation of µm-long fibers, which can subsequently be fragmented by ultrasonication or dual asymmetric centrifugation. The latter allows for a better adjustment of applied shear stresses, and thus enables access to differently sized fragments depending on time and rotation rate. Extended sonication and scission analysis further allowed an estimation of tensile strengths of around 16 MPa for both the BTU and BTP systems. In combination with the high kinetic stability of these SPBs, the applied top-down methods represent an easily implementable technique toward 1D polymer nanostructures with an adjustable length in the range of interest for perspective biomedical applications., (Copyright © 2021, Klein et al.)
- Published
- 2021
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37. Targeted delivery of a phosphoinositide 3-kinase γ inhibitor to restore organ function in sepsis.
- Author
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Press AT, Babic P, Hoffmann B, Müller T, Foo W, Hauswald W, Benecke J, Beretta M, Cseresnyés Z, Hoeppener S, Nischang I, Coldewey SM, Gräler MH, Bauer R, Gonnert F, Gaßler N, Wetzker R, Figge MT, Schubert US, and Bauer M
- Subjects
- Animals, Mice, Neutrophil Infiltration, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Liver Diseases, Sepsis drug therapy
- Abstract
Jaundice, the clinical hallmark of infection-associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3-kinase-γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here, we demonstrate that nanocarriers functionalized through DY-635, a fluorescent polymethine dye, and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed the PI3Kγ-dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2021
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38. The impact of anionic polymers on gene delivery: how composition and assembly help evading the toxicity-efficiency dilemma.
- Author
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Richter F, Leer K, Martin L, Mapfumo P, Solomun JI, Kuchenbrod MT, Hoeppener S, Brendel JC, and Traeger A
- Subjects
- Acrylic Resins, Animals, Cations, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Mice, Micelles, Plasmids, Polymerization, Transfection, Gene Transfer Techniques, Genetic Therapy, Polymers
- Abstract
Cationic polymers have been widely studied for non-viral gene delivery due to their ability to bind genetic material and to interact with cellular membranes. However, their charged nature carries the risk of increased cytotoxicity and interaction with serum proteins, limiting their potential in vivo application. Therefore, hydrophilic or anionic shielding polymers are applied to counteract these effects. Herein, a series of micelle-forming and micelle-shielding polymers were synthesized via RAFT polymerization. The copolymer poly[(n-butyl acrylate)-b-(2-(dimethyl amino)ethyl acrylamide)] (P(nBA-b-DMAEAm)) was assembled into cationic micelles and different shielding polymers were applied, i.e., poly(acrylic acid) (PAA), poly(4-acryloyl morpholine) (PNAM) or P(NAM-b-AA) block copolymer. These systems were compared to a triblock terpolymer micelle comprising PAA as the middle block. The assemblies were investigated regarding their morphology, interaction with pDNA, cytotoxicity, transfection efficiency, polyplex uptake and endosomal escape. The naked cationic micelle exhibited superior transfection efficiency, but increased cytotoxicity. The addition of shielding polymers led to reduced toxicity. In particular, the triblock terpolymer micelle convinced with high cell viability and no significant loss in efficiency. The highest shielding effect was achieved by layering micelles with P(NAM-b-AA) supporting the colloidal stability at neutral zeta potential and completely restoring cell viability while maintaining moderate transfection efficiencies. The high potential of this micelle-layer-combination for gene delivery was illustrated for the first time., (© 2021. The Author(s).)
- Published
- 2021
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39. Effect of Crystallinity on the Properties of Polycaprolactone Nanoparticles Containing the Dual FLAP/mPEGS-1 Inhibitor BRP-187.
- Author
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Vollrath A, Kretzer C, Beringer-Siemers B, Shkodra B, Czaplewska JA, Bandelli D, Stumpf S, Hoeppener S, Weber C, Werz O, and Schubert US
- Abstract
Seven polycaprolactones (PCL) with constant hydrophobicity but a varying degree of crystallinity prepared from the constitutional isomers ε-caprolactone (εCL) and δ-caprolactone (δCL) were utilized to formulate nanoparticles (NPs). The aim was to investigate the effect of the crystallinity of the bulk polymers on the enzymatic degradation of the particles. Furthermore, their efficiency to encapsulate the hydrophobic anti-inflammatory drug BRP-187 and the final in vitro performance of the resulting NPs were evaluated. Initially, high-throughput nanoprecipitation was employed for the εCL and δCL homopolymers to screen and establish important formulation parameters (organic solvent, polymer and surfactant concentration). Next, BRP-187-loaded PCL nanoparticles were prepared by batch nanoprecipitation and characterized using dynamic light scattering, scanning electron microscopy and UV-Vis spectroscopy to determine and to compare particle size, polydispersity, zeta potential, drug loading as well as the apparent enzymatic degradation as a function of the copolymer composition. Ultimately, NPs were examined for their potency in vitro in human polymorphonuclear leukocytes to inhibit the BRP-187 target 5-lipoxygenase-activating protein (FLAP). It was evident by Tukey's multi-comparison test that the degree of crystallinity of copolymers directly influenced their apparent enzymatic degradation and consequently their efficiency to inhibit the drug target.
- Published
- 2021
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40. Stealth Effect of Short Polyoxazolines in Graft Copolymers: Minor Changes of Backbone End Group Determine Liver Cell-Type Specificity.
- Author
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Muljajew I, Huschke S, Ramoji A, Cseresnyés Z, Hoeppener S, Nischang I, Foo W, Popp J, Figge MT, Weber C, Bauer M, Schubert US, and Press AT
- Subjects
- Polymers chemistry, Hydrophobic and Hydrophilic Interactions, Liver, Micelles, Drug Carriers chemistry
- Abstract
Dye-loaded micelles of 10 nm diameter formed from amphiphilic graft copolymers composed of a hydrophobic poly(methyl methacrylate) backbone and hydrophilic poly(2-ethyl-2-oxazoline) side chains with a degree of polymerization of 15 were investigated concerning their cellular interaction and uptake in vitro as well as their interaction with local and circulating cells of the reticuloendothelial system in the liver by intravital microscopy. Despite the high molar mass of the individual macromolecules ( M
n ≈ 20 kg mol-1 ), backbone end group modification by attachment of a hydrophilic anionic fluorescent probe strongly affected the in vivo performance. To understand these effects, the end group was additionally modified by the attachment of four methacrylic acid repeating units. Although various micelles appeared similar in dynamic light scattering and cryo-transmission electron microscopy, changes in the micelles were evident from principal component analysis of the Raman spectra. Whereas an efficient stealth effect was found for micelles formed from polymers with anionically charged or thiol end groups, a hydrophobic end group altered the micelles' structure sufficiently to adapt cell-type specificity and stealth properties in the liver.- Published
- 2021
- Full Text
- View/download PDF
41. Kinetically Controlling the Length of Self-Assembled Polymer Nanofibers Formed by Intermolecular Hydrogen Bonds.
- Author
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Gruschwitz FV, Klein T, Kuchenbrod MT, Moriyama N, Fujii S, Nischang I, Hoeppener S, Sakurai K, Schubert US, and Brendel JC
- Subjects
- Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Polymers chemistry, Water chemistry, Nanofibers chemistry, Nanostructures chemistry
- Abstract
Strong directional hydrogen bonds represent a suitable supramolecular force to drive the one-dimensional (1D) aqueous self-assembly of polymeric amphiphiles resulting in cylindrical polymer brushes. However, our understanding of the kinetics in these assembly processes is still limited. We here demonstrate that the obtained morphologies for our recently reported benzene tris-urea and tris-peptide conjugates are strongly pathway-dependent. A controlled transfer from solutions in organic solvents to aqueous environments enabled a rate-dependent formation of kinetically trapped but stable nanostructures ranging from small cylindrical or spherical objects (<50 nm) to remarkably large fibers (>2 μm). A detailed analysis of the underlying assembly mechanism revealed a cooperative nature despite the steric demands of the polymers. Nucleation is induced by hydrophobic interactions crossing a critical water content, followed by an elongation process due to the strong hydrogen bonds. These findings open an interesting new pathway to control the length of 1D polymer nanostructures.
- Published
- 2021
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42. On the stability of microwave-fabricated SERS substrates - chemical and morphological considerations.
- Author
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Wang L, Womiloju AA, Höppener C, Schubert US, and Hoeppener S
- Abstract
The stability of surface-enhanced Raman spectroscopy (SERS) substrates in different organic solvents and different buffer solutions was investigated. SERS substrates were fabricated by a microwave-assisted synthesis approach and the morphological as well as chemical changes of the SERS substrates were studied. It was demonstrated that the SERS substrates treated with methanol, ethanol, or N , N -dimethylformamide (DMF) were comparable and showed overall good stability and did not show severe morphological changes or a strong decrease in their Raman activity. Toluene treatment resulted in a strong decrease in the Raman activity whereas dimethyl sulfoxide (DMSO) treatment completely preserved or even slightly improved the Raman enhancement capabilities. SERS substrates immersed into phosphate-buffered saline (PBS) solutions were observed to be rather instable in low and neutral pH buffer solutions. Other buffer systems showed less severe influences on the SERS activity of the substrates and a carbonate buffer at pH 10 was found to even improve SERS performance. This study represents a guideline on the stability of microwave-fabricated SERS substrates or other SERS substrates consisting of non-stabilized silver nanoparticles for the application of different organic solvents and buffer solutions., (Copyright © 2021, Wang et al.)
- Published
- 2021
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- View/download PDF
43. Surface chemical reactions on self-assembled silane based monolayers.
- Author
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Wang L, Schubert US, and Hoeppener S
- Abstract
In this review, we aim to update our review "Chemical modification of self-assembled silane-based monolayers by surface reactions" which was published in 2010 and has developed into an important guiding tool for researchers working on the modification of solid substrate surface properties by chemical modification of silane-based self-assembled monolayers. Due to the rapid development of this field of research in the last decade, the utilization of chemical functionalities in self-assembled monolayers has been significantly improved and some new processes were introduced in chemical surface reactions for tailoring the properties of solid substrates. Thus, it is time to update the developments in the surface functionalization of silane-based molecules. Hence, after a short introduction on self-assembled monolayers, this review focuses on a series of chemical reactions, i.e., nucleophilic substitution, click chemistry, supramolecular modification, photochemical reaction, and other reactions, which have been applied for the modification of hydroxyl-terminated substrates, like silicon and glass, which have been reported during the last 10 years.
- Published
- 2021
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- View/download PDF
44. Sustainable preparation of anti-inflammatory atorvastatin PLGA nanoparticles.
- Author
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Grune C, Zens C, Czapka A, Scheuer K, Thamm J, Hoeppener S, Jandt KD, Werz O, Neugebauer U, and Fischer D
- Subjects
- Animals, Anti-Inflammatory Agents, Atorvastatin, Chickens, Drug Carriers, Female, Humans, Lactic Acid, Particle Size, Polyethylene Glycols, Polylactic Acid-Polyglycolic Acid Copolymer, Nanoparticles, Polyglycolic Acid
- Abstract
In the present study, the anti-inflammatory lipophilic drug atorvastatin was encapsulated in poly(D,L-lactide-co-glycolide) (PLGA) using a sustainable method in comparison to the standard emulsion-diffusion-evaporation technique. For the sustainable method the organic solvent ethyl acetate was fully replaced by 400 g/mol poly(ethylene glycol) (PEG 400). Both techniques led to the formation of nanoparticles with comparable sizes of about 170 to 247 nm depending on the polymer type, with monomodal size distribution and negative zeta potential. All nanoparticles demonstrated a high biocompatibility in a shell-less hen's egg model and displayed an anti-inflammatory effect in human monocytes. The use of PEG 400 resulted in plasticizing effects and a lower crystallinity of the PLGA nanoparticles as determined by differential scanning calorimetry and Raman spectroscopy, which correlated with a faster drug release. Interestingly, the particles prepared by the sustainable method showed a crystallinity and drug release kinetics similar to nanoparticles made of PEG-PLGA using the standard method. Conclusively, the sustainable method is a fast and easy to perform technique suitable to prepare atorvastatin-loaded PLGA nanoparticles avoiding toxic and environmentally damaging drawbacks frequently associated with classical organic solvents., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2021
- Full Text
- View/download PDF
45. Overcoming the Necessity of a Lateral Aggregation in the Formation of Supramolecular Polymer Bottlebrushes in Water.
- Author
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Klein T, Ulrich HF, Gruschwitz FV, Kuchenbrod MT, Takahashi R, Hoeppener S, Nischang I, Sakurai K, and Brendel JC
- Subjects
- Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Micelles, Polymers, Water
- Abstract
The assembly of supramolecular polymer bottlebrushes in aqueous systems is, in most cases, associated with a lateral aggregation of the supramolecular building blocks in addition to their axial stacking. Here, it is demonstrated that this limitation can be overcome by attaching three polymer chains to a central supramolecular unit that possesses a sufficiently high number of hydrogen bonding units to compensate for the increased steric strain. Therefore, a 1,3,5-benzenetrisurea-polyethylene oxide conjugate is modified with different peptide units located next to the urea groups which should facilitate self-assembly in water. For a single amino acid per arm, spherical micelles are obtained for all three tested amino acids (alanine, leucine, and phenylalanine) featuring different hydrophobicities. Only a slight increase in size and solution stability of spherical micelles is observed with increasing hydrophobicity of amino acid unit. In contrast, introducing two amino acid units per arm and thus increasing the number of hydrogen bonds per unimer molecule results in the formation of cylindrical structures, that is, supramolecular polymer bottlebrushes, despite a suppressed lateral aggregation. Consequently, it can be concluded that the number of hydrogen bonds has a more profound impact on the resulting solution morphology than the hydrophobicity of the amino acid unit., (© 2020 The Authors. Macromolecular Rapid Communications published by Wiley-VCH GmbH.)
- Published
- 2021
- Full Text
- View/download PDF
46. Improved gene delivery to K-562 leukemia cells by lipoic acid modified block copolymer micelles.
- Author
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Richter F, Mapfumo P, Martin L, Solomun JI, Hausig F, Frietsch JJ, Ernst T, Hoeppener S, Brendel JC, and Traeger A
- Subjects
- Animals, Antioxidants, Cations, Cell Line, Tumor, DNA chemistry, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Methacrylates chemistry, Mice, Plasmids, Transfection, Gene Transfer Techniques, Leukemia genetics, Leukemia therapy, Micelles, Polymers chemistry, Thioctic Acid chemistry, Thioctic Acid pharmacology
- Abstract
Although there has been substantial progress in the research field of gene delivery, there are some challenges remaining, e.g. there are still cell types such as primary cells and suspension cells (immune cells) known to be difficult to transfect. Cationic polymers have gained increasing attention due to their ability to bind, condense and mask genetic material, being amenable to scale up and highly variable in their composition. In addition, they can be combined with further monomers exhibiting desired biological and chemical properties, such as antioxidative, pH- and redox-responsive or biocompatible features. By introduction of hydrophobic monomers, in particular as block copolymers, cationic micelles can be formed possessing an improved chance of transfection in otherwise challenging cells. In this study, the antioxidant biomolecule lipoic acid, which can also be used as crosslinker, was incorporated into the hydrophobic block of a diblock copolymer, poly{[2-(dimethylamino)ethyl methacrylate]
101 -b-[n-(butyl methacrylate)124 -co-(lipoic acid methacrylate)22 ]} (P(DMAEMA101 -b-[nBMA124 -co-LAMA22 ])), synthesized by RAFT polymerization and assembled into micelles (LAMA-mic). These micelles were investigated regarding their pDNA binding, cytotoxicity mechanisms and transfection efficiency in K-562 and HEK293T cells, the former representing a difficult to transfect, suspension leukemia cell line. The LAMA-mic exhibited low cytotoxicity at applied concentrations but demonstrated superior transfection efficiency in HEK293T and especially K-562 cells. In-depth studies on the transfection mechanism revealed that transfection efficiency in K-562 cells does not depend on the specific oncogenic fusion gene BCR-ABL alone. It is independent of the cellular uptake of polymer-pDNA complexes but correlates with the endosomal escape of the LAMA-mic. A comparison of the transfection efficiency of the LAMA-mic with structurally comparable micelles without lipoic acid showed that lipoic acid is not solely responsible for the superior transfection efficiency of the LAMA-mic. More likely, a synergistic effect of the antioxidative lipoic acid and the micellar architecture was identified. Therefore, the incorporation of lipoic acid into the core of hydrophobic-cationic micelles represents a promising tailor-made transfer strategy, which can potentially be beneficial for other difficult to transfect cell types.- Published
- 2021
- Full Text
- View/download PDF
47. Revisiting staining of biological samples for electron microscopy: perspectives for recent research.
- Author
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Kuchenbrod MT, Schubert US, Heintzmann R, and Hoeppener S
- Subjects
- Staining and Labeling, Microscopy, Electron
- Abstract
This review revisits essential staining protocols for electron microscopy focussing on the visualization of active sites, i.e. enzymes, metabolites or proteins, in cells and tissues, which have been developed 50 to 60 years ago, however, never were established as standard protocols being used in electron microscopy in a routine fashion. These approaches offer numerous possibilities to expand the knowledge of cellular function and specifically address the localization of active compounds of these systems. It is our conviction, that many of these techniques are still useful, in particular when applied in conjunction with correlative light and electron microscopy. Revisiting specialized classical electron microscopy staining protocols for use in correlative microscopy is particularly promising, as some of these protocols were originally developed as staining methods for light microscopy. To account for this history, rather than summarizing the most recent achievements in literature, we instead first provide an overview of techniques that have been used in the past. While some of these techniques have been successfully implemented into modern microscopy techniques during recent years already, more possibilities are yet to be re-discovered and provide exciting new perspectives for their future use.
- Published
- 2021
- Full Text
- View/download PDF
48. Effect of Hydrophilic Monomer Distribution on Self-Assembly of a pH-Responsive Copolymer: Spheres, Worms and Vesicles from a Single Copolymer Composition.
- Author
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Zhang J, Farias-Mancilla B, Kulai I, Hoeppener S, Lonetti B, Prévost S, Ulbrich J, Destarac M, Colombani O, Schubert US, Guerrero-Sanchez C, and Harrisson S
- Abstract
A series of copolymers containing 50 mol % acrylic acid (AA) and 50 mol % butyl acrylate (BA) but with differing composition profiles ranging from an AA-BA diblock copolymer to a linear gradient poly(AA-grad-BA) copolymer were synthesized and their pH-responsive self-assembly behavior was investigated. While assemblies of the AA-BA diblock copolymer were kinetically frozen, the gradient-like compositions underwent reversible changes in size and morphology in response to changes in pH. In particular, a diblock copolymer consisting of two random copolymer segments of equal length (16 mol % and 84 mol % AA content, respectively) formed spherical micelles at pH >5, a mix of spherical and wormlike micelles at pH 5 and vesicles at pH 4. These assemblies were characterized by dynamic light scattering, cryo-transmission electron microscopy and small angle neutron scattering., (© 2020 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
- Published
- 2021
- Full Text
- View/download PDF
49. Solely aqueous formulation of hydrophobic cationic polymers for efficient gene delivery.
- Author
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Solomun JI, Cinar G, Mapfumo P, Richter F, Moek E, Hausig F, Martin L, Hoeppener S, Nischang I, and Traeger A
- Subjects
- Cations, HEK293 Cells, Humans, Transfection, Gene Transfer Techniques, Polymers
- Abstract
Cationic polymers are promising gene delivery vectors due to their ability to bind and protect genetic material. The introduction of hydrophobic moieties into cationic polymers can further improve the vector efficiency, but common formulations of hydrophobic polymers involve harsh conditions such as organic solvents, impairing intactness and loading efficiency of the genetic material. In this study, a mild, aqueous formulation method for the encapsulation of high amounts of genetic material is presented. A well-defined pH-responsive hydrophobic copolymer, i.e. poly((n-butylmethacrylate)-co-(methylmethacrylate)-co-(2-(dimethylamino) ethylmethacrylate)), (PBMD) was synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. Exploiting the pH-dependent solubility behavior of the polymer, stable pDNA loaded nanoparticles were prepared and characterized using analytical ultracentrifugation (AUC), cryo-transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS). This novel formulation approach showed high transfection efficiencies in HEK293T cells, while requiring 5- to 10-fold less pDNA compared to linear polyethylenimine (LPEI), in particular at short incubation times and in serum-containing media. Furthermore, the formulation was successfully adopted for siRNA and mRNA encapsulation and the commercially approved polymer Eudragit® E(PO/100). Overall, the aqueous formulation approach, accompanied by a tailor-made hydrophobic polymer and detailed physicochemical and application studies, led to improved gene delivery vectors with high potential for further applications., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
50. Emulsion Polymerizations for a Sustainable Preparation of Efficient TEMPO-based Electrodes.
- Author
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Muench S, Gerlach P, Burges R, Strumpf M, Hoeppener S, Wild A, Lex-Balducci A, Balducci A, Brendel JC, and Schubert US
- Abstract
Organic polymer-based batteries represent a promising alternative to present-day metal-based systems and a valuable step toward printable and customizable energy storage devices. However, most scientific work is focussed on the development of new redox-active organic materials, while straightforward manufacturing and sustainable materials and production will be a necessary key for the transformation to mass market applications. Here, a new synthetic approach for 2,2,6,6-tetramethyl-4-piperinidyl-N-oxyl (TEMPO)-based polymer particles by emulsion polymerization and their electrochemical investigation are reported. The developed emulsion polymerization protocol based on an aqueous reaction medium allowed the sustainable synthesis of a redox-active electrode material, combined with simple variation of the polymer particle size, which enabled the preparation of nanoparticles from 35 to 138 nm. Their application in cell experiments revealed a significant effect of the size of the active-polymer particles on the performance of poly(2,2,6,6-tetramethyl-4-piperinidyl-N-oxyl methacrylate) (PTMA)-based electrodes. In particular rate capabilities were found to be reduced with larger diameters. Nevertheless, all cells based on the different particles revealed the ability to recover from temporary capacity loss due to application of very high charge/discharge rates., (© 2020 The Authors. ChemSusChem published by Wiley-VCH GmbH.)
- Published
- 2021
- Full Text
- View/download PDF
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