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Author: Appelhans, Dietmar × Start date: 1990 × Has files: Yes × WGL Institute: IPF ×

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Now showing 1 - 10 of 21
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    Toward Functional Synthetic Cells: In-Depth Study of Nanoparticle and Enzyme Diffusion through a Cross-Linked Polymersome Membrane
    (Weinheim : Wiley-VCH, 2019) Gumz, Hannes; Boye, Susanne; Iyisan, Banu; Krönert, Vera; Formanek, Petr; Voit, Brigitte; Lederer, Albena; Appelhans, Dietmar
    Understanding the diffusion of nanoparticles through permeable membranes in cell mimics paves the way for the construction of more sophisticated synthetic protocells with control over the exchange of nanoparticles or biomacromolecules between different compartments. Nanoparticles postloading by swollen pH switchable polymersomes is investigated and nanoparticles locations at or within polymersome membrane and polymersome lumen are precisely determined. Validation of transmembrane diffusion properties is performed based on nanoparticles of different origin—gold, glycopolymer protein mimics, and the enzymes myoglobin and esterase—with dimensions between 5 and 15 nm. This process is compared with the in situ loading of nanoparticles during polymersome formation and analyzed by advanced multiple-detector asymmetrical flow field-flow fractionation (AF4). These experiments are supported by complementary i) release studies of protein mimics from polymersomes, ii) stability and cyclic pH switches test for in polymersome encapsulated myoglobin, and iii) cryogenic transmission electron microscopy studies on nanoparticles loaded polymersomes. Different locations (e.g., membrane and/or lumen) are identified for the uptake of each protein. The protein locations are extracted from the increasing scaling parameters and the decreasing apparent density of enzyme-containing polymersomes as determined by AF4. Postloading demonstrates to be a valuable tool for the implementation of cell-like functions in polymersomes.
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    Photo-Cross-Linked Dual-Responsive Hollow Capsules Mimicking Cell Membrane for Controllable Cargo Post-Encapsulation and Release
    (Weinheim : Wiley-VCH, 2016) Liu, Xiaoling; Appelhans, Dietmar; Wei, Qiang; Voit, Brigitte
    Multifunctional and responsive hollow capsules are ideal candidates to establish highly sophisticated compartments mimicking cell membranes for controllable bio-inspired functions. For this purpose pH and temperature dual-responsive and photo-cross-linked hollow capsules, based on silica-templated layer-by-layer approach by using poly(N-isopropyl acrylamide)-blockpolymethacrylate) and polyallylamine, have been prepared to use them for the subsequent and easily available post-encapsulation process of proteinlike macromolecules at room temperature and pH 7.4 and their controllable release triggered by stimuli. The uptake and release properties of the hollow capsules for cargos are highly affected by changes in the external stimuli temperature (25, 37, or 45 °C) and internal stimuli pH of the phosphate-containing buffer solution (5.5 or 7.4), by the degree of photo-cross-linking, and the size of cargo. The photo-cross-linked and dual stimuli-responsive hollow capsules with different membrane permeability can be considered as attractive material for mimicking cell functions triggered by controllable uptake and release of different up to 11 nm sized biomolecules.
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    Dendritic glycopolymers based on dendritic polyamine scaffolds: view on their synthetic approaches, characteristics and potential for biomedical applications
    (London : Soc., 2014) Appelhans, Dietmar; Klajnert-Maculewicz, Barbara; Janaszewska, Anna; Lazniewska, Joanna; Voit, Brigitte
    In this review we highlight the potential for biomedical applications of dendritic glycopolymers based on polyamine scaffolds. The complex interplay of the molecular characteristics of the dendritic architectures and their specific interactions with various (bio)molecules are elucidated with various examples. A special role of the individual sugar units attached to the dendritic scaffolds and their density is identified, which govern ionic and H-bond interactions, and biological targeting, but to a large extent are also responsible for the significantly reduced toxicity of the dendritic glycopolymers compared to their polyamine scaffolds. Thus, the application of dendritic glycopolymers in drug delivery systems for gene transfection but also as therapeutics in neurodegenerative diseases has great promise.
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    Synergistic effects of anionic/cationic dendrimers and levofloxacin on antibacterial activities
    (Basel : MDPI, 2019) Wrońska, Natalia; Majoral, Jean Pierre; Appelhans, Dietmar; Bryszewska, Maria; Lisowska, Katarzyna
    Despite the numerous studies on dendrimers for biomedical applications, the antibacterial activity of anionic phosphorus dendrimers has not been explored. In our research, we evaluated the antibacterial activity of modified polycationic and polyanionic dendrimers in combination with levofloxacin (LVFX) against Gram-negative (Escherichia coli ATCC 25922, Proteus hauseri ATCC 15442) and Gram-positive (Staphylococcus aureus ATCC 6538) bacteria. In the case of Gram-negative bacteria, we concluded that a combination of dendrimers and antibiotic gave satisfactory results due to a synergistic effect. The use of fluoroquinolone antibiotics, such as LVFX, not only caused resistance in disease-causing microorganisms but also increased environmental pollution. Therefore, reduction of drug dosage is of general interest. © 2019 by the authors.
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    Poly(propylene imine) dendrimers and amoxicillin as dual-action antibacterial agents
    (Basel : MDPI, 2015) Wrońska, Natalia; Felczak, Aleksandra; Zawadzka, Katarzyna; Poszepczyńska, Martyna; Różalska, Sylwia; Bryszewska, Maria; Appelhans, Dietmar; Lisowska, Katarzyna
    Besides acting as antimicrobial compounds, dendrimers can be considered as agents that improve the therapeutic effectiveness of existing antibiotics. In this work we present a new approach to using amoxicillin (AMX) against reference strains of common Gram-negative pathogens, alone and in combination with poly(propylene imine) (PPI) dendrimers, or derivatives thereof, in which 100% of the available hydrogen atoms are substituted with maltose (PPI 100%malG3). The concentrations of dendrimers used remained in the range non-toxic to eukaryotic cells. The results indicate that PPI dendrimers significantly enhance the antibacterial effect of amoxicillin alone, allowing antibiotic doses to be reduced. It is important to reduce doses of amoxicillin because its widespread use in medicine could lead to the development of bacterial resistance and environmental pollution. This is the first report on the combined antibacterial activity of PPI surface-modified maltose dendrimers and amoxicillin.
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    Hydrogel microvalves as control elements for parallelized enzymatic cascade reactions in microfluidics
    (Basel : MDPI, 2020) Obst, Franziska; Beck, Anthony; Bishayee, Chayan; Mehner, Philipp J.; Richter, Andreas; Voit, Brigitte; Appelhans, Dietmar
    Compartmentalized microfluidic devices with immobilized catalysts are a valuable tool for overcoming the incompatibility challenge in (bio) catalytic cascade reactions and high-throughput screening of multiple reaction parameters. To achieve flow control in microfluidics, stimuli-responsive hydrogel microvalves were previously introduced. However, an application of this valve concept for the control of multistep reactions was not yet shown. To fill this gap, we show the integration of thermoresponsive poly(N-isopropylacrylamide) (PNiPAAm) microvalves (diameter: 500 and 600 µm) into PDMS-on-glass microfluidic devices for the control of parallelized enzyme-catalyzed cascade reactions. As a proof-of-principle, the biocatalysts glucose oxidase (GOx), horseradish peroxidase (HRP) and myoglobin (Myo) were immobilized in photopatterned hydrogel dot arrays (diameter of the dots: 350 µm, amount of enzymes: 0.13-2.3 µg) within three compartments of the device. Switching of the microvalves was achieved within 4 to 6 s and thereby the fluid pathway of the enzyme substrate solution (5 mmol/L) in the device was determined. Consequently, either the enzyme cascade reaction GOx-HRP or GOx-Myo was performed and continuously quantified by ultraviolet-visible (UV-Vis) spectroscopy. The functionality of the microvalves was shown in four hourly switching cycles and visualized by the path-dependent substrate conversion. © 2020 by the authors.
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    Hydrogel patterns in microfluidic devices by do-it-yourself UV-photolithography suitable for very large-scale integration
    (Basel : MDPI, 2020) Beck, Anthony; Obst, Franziska; Busek, Mathias; Grünzner, Stefan; Mehner, Philipp J.; Paschew, Georgi; Appelhans, Dietmar; Voit, Brigitte; Richter, Andreas
    The interest in large-scale integrated (LSI) microfluidic systems that perform highthroughput biological and chemical laboratory investigations on a single chip is steadily growing. Such highly integrated Labs-on-a-Chip (LoC) provide fast analysis, high functionality, outstanding reproducibility at low cost per sample, and small demand of reagents. One LoC platform technology capable of LSI relies on specific intrinsically active polymers, the so-called stimuli-responsive hydrogels. Analogous to microelectronics, the active components of the chips can be realized by photolithographic micro-patterning of functional layers. The miniaturization potential and the integration degree of the microfluidic circuits depend on the capability of the photolithographic process to pattern hydrogel layers with high resolution, and they typically require expensive cleanroom equipment. Here, we propose, compare, and discuss a cost-efficient do-it-yourself (DIY) photolithographic set-up suitable to micro-pattern hydrogel-layers with a resolution as needed for very large-scale integrated (VLSI) microfluidics. The achievable structure dimensions are in the lower micrometer scale, down to a feature size of 20 µm with aspect ratios of 1:5 and maximum integration densities of 20,000 hydrogel patterns per cm. Furthermore, we demonstrate the effects of miniaturization on the efficiency of a hydrogel-based microreactor system by increasing the surface area to volume (SA:V) ratio of integrated bioactive hydrogels. We then determine and discuss a correlation between ultraviolet (UV) exposure time, cross-linking density of polymers, and the degree of immobilization of bioactive components. © 2020 by the authors.
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    Poly(propylene imine) dendrimers with histidine-maltose shell as novel type of nanoparticles for synapse and memory protection
    (Basel : MDPI, 2019) Aso, Ester; Martinsson, Isak; Appelhans, Dietmar; Effenberg, Christiane; Benseny-Cases, Nuria; Cladera, Josep; Gouras, Gunnar; Ferrer, Isidre; Klementieva, Oxana
    Poly(propylene imine) dendrimers have been shown to be promising 3-dimensional polymers for the use in the pharmaceutical and biomedical applications. Our aims of this study were first, to synthesize a novel type of dendrimer with poly(propylene imine) core and maltose-histidine shell (G4HisMal) assessing if maltose-histidine shell can improve the biocompatibility and the ability to cross the blood-brain barrier, and second, to investigate the potential of G4HisMal to protect Alzheimer disease transgenic mice from memory impairment. Our data demonstrate that G4HisMal has significantly improved biocompatibility and ability to cross the blood-brain barrier in vivo. Therefore, we suggest that a maltose-histidine shell can be used to improve biocompatibility and ability to cross the blood-brain barrier of dendrimers. Moreover, G4HisMal demonstrated properties for synapse and memory protection when administered to Alzheimer disease transgenic mice. Therefore, G4HisMal can be considered as a promising drug candidate to prevent Alzheimer disease via synapse protection. © 2019 The Authors
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    Long-Term Retarded Release for the Proteasome Inhibitor Bortezomib through Temperature-Sensitive Dendritic Glycopolymers as Drug Delivery System from Calcium Phosphate Bone Cement
    (Weinheim : Wiley-VCH, 2021) Lai, Thu Hang; Keperscha, Bettina; Qiu, Xianping; Voit, Brigitte; Appelhans, Dietmar
    For the local treatment of bone defects, highly adaptable macromolecular architectures are still required as drug delivery system (DDS) in solid bone substitute materials. Novel DDS fabricated by host–guest interactions between β-cyclodextrin-modified dendritic glycopolymers and adamantane-modified temperature-sensitive polymers for the proteasome inhibitor bortezomib (BZM) is presented. These DDS induce a short- and long-term (up to two weeks) retarded release of BZM from calcium phosphate bone cement (CPC) in comparison to a burst release of the drug alone. Different release parameters of BZM/DDS/CPC are evaluated in phosphate buffer at 37 °C to further improve the long-term retarded release of BZM. This is achieved by increasing the amount of drug (50–100 µg) and/or DDS (100–400 µg) versus CPC (1 g), by adapting the complexes better to the porous bone cement environment, and by applying molar ratios of excess BZM toward DDS with 1:10, 1:25, and 1:100. The temperature-sensitive polymer shells of BZM/DDS complexes in CPC, which allow drug loading at room temperature but are collapsed at body temperature, support the retarding long-term release of BZM from DDS/CPC. Thus, the concept of temperature-sensitive DDS for BZM/DDS complexes in CPC works and matches key points for a local therapy of osteolytic bone lesions.
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    Multivalent Protein-Loaded pH-Stable Polymersomes: First Step toward Protein Targeted Therapeutics
    (Weinheim : Wiley-VCH, 2021) Moreno, Silvia; Boye, Susanne; Ajeilat, Hane George Al; Michen, Susanne; Tietze, Stefanie; Voit, Brigitte; Lederer, Albena; Temme, Achim; Appelhans, Dietmar
    Synthetic platforms for mimicking artificial organelles or for designing multivalent protein therapeutics for targeting cell surface, extracellular matrix, and tissues are in the focus of this study. Furthermore, the availability of a multi-functionalized and stimuli-responsive carrier system is required that can be used for sequential in situ and/or post loading of different proteins combined with post-functionalization steps. Until now, polymersomes exhibit excellent key characteristics to fulfill those requirements, which allow specific transport of proteins and the integration of proteins in different locations of polymeric vesicles. Herein, different approaches to fabricate multivalent protein-loaded, pH-responsive, and pH-stable polymersomes are shown, where a combination of therapeutic action and targeting can be achieved, by first choosing two model proteins such as human serum albumin and avidin. Validation of the molecular parameters of the multivalent biohybrids is performed by dynamic light scattering, cryo-TEM, fluorescence spectroscopy, and asymmetrical flow-field flow fractionation combined with light scattering techniques. To demonstrate targeting functions of protein-loaded polymersomes, avidin post-functionalized polymersomes are used for the molecular recognition of biotinylated cell surface receptors. These versatile protein-loaded polymersomes present new opportunities for designing sophisticated biomolecular nanoobjects in the field of (extracellular matrix) protein therapeutics.