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- ItemDendritic 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, BrigitteIn 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.
- ItemSynergistic effects of anionic/cationic dendrimers and levofloxacin on antibacterial activities(Basel : MDPI, 2019) Wrońska, Natalia; Majoral, Jean Pierre; Appelhans, Dietmar; Bryszewska, Maria; Lisowska, KatarzynaDespite 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.
- ItemPoly(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, OxanaPoly(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
- ItemAnti-Prion Drug mPPIg5 Inhibits PrPC Conversion to PrPSc(San Francisco, CA : Public Library of Science, 2013) McCarthy, J.M.; Franke, M.; Resenberger, U.K.; Waldron, S.; Simpson, J.C.; Tatzelt, J.; Appelhans, D.; Rogers, M.S.Prion diseases, also known as transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. The 'protein only hypothesis' advocates that PrPSc, an abnormal isoform of the cellular protein PrPC, is the main and possibly sole component of prion infectious agents. Currently, no effective therapy exists for these diseases at the symptomatic phase for either humans or animals, though a number of compounds have demonstrated the ability to eliminate PrPSc in cell culture models. Of particular interest are synthetic polymers known as dendrimers which possess the unique ability to eliminate PrPSc in both an intracellular and in vitro setting. The efficacy and mode of action of the novel anti-prion dendrimer mPPIg5 was investigated through the creation of a number of innovative bio-assays based upon the scrapie cell assay. These assays were used to demonstrate that mPPIg5 is a highly effective anti-prion drug which acts, at least in part, through the inhibition of PrPC to PrPSc conversion. Understanding how a drug works is a vital component in maximising its performance. By establishing the efficacy and method of action of mPPIg5, this study will help determine which drugs are most likely to enhance this effect and also aid the design of dendrimers with anti-prion capabilities for the future.
- ItemCytotoxicity of dendrimers(Basel : MDPI, 2019) Janaszewska, Anna; Lazniewska, Joanna; Trzepiński, Przemysław; Klajnert-Maculewicz, BarbaraDrug delivery systems are molecular platforms in which an active compound is packed into or loaded on a biocompatible nanoparticle. Such a solution improves the activity of the applied drug or decreases its side effects. Dendrimers are promising molecular platforms for drug delivery due to their unique properties. These macromolecules are known for their defined size, shape, and molecular weight, as well as their monodispersity, the presence of the void space, tailorable structure, internalization by cells, selectivity toward cells and intracellular components, protection of guest molecules, and controllable release of the cargo. Dendrimers were tested as carriers of various molecules and, simultaneously, their toxicity was examined using different cell lines. It was discovered that, in general, dendrimer cytotoxicity depended on the generation, the number of surface groups, and the nature of terminal moieties (anionic, neutral, or cationic). Higher cytotoxicity occurred for higher-generation dendrimers and for dendrimers with positive charges on the surface. In order to decrease the cytotoxicity of dendrimers, scientists started to introduce different chemical modifications on the periphery of the nanomolecule. Dendrimers grafted with polyethylene glycol (PEG), acetyl groups, carbohydrates, and other moieties did not affect cell viability, or did so only slightly, while still maintaining other advantageous properties. Dendrimers clearly have great potential for wide utilization as drug and gene carriers. Moreover, some dendrimers have biological properties per se, being anti-fungal, anti-bacterial, or toxic to cancer cells without affecting normal cells. Therefore, intrinsic cytotoxicity is a comprehensive problem and should be considered individually depending on the potential destination of the nanoparticle. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemCounterion condensation and effective charge of PAMAM dendrimers(Basel : MDPI AG, 2011) Böhme, U.; Klenge, A.; Hänel, B.; Scheler, U.PAMAM dendrimers are used as a model system to investigate the effects of counterion condensation and the effective charge for spherical polyelectrolytes. Because of their amino groups, PAMAM dendrimers are weak polyelectrolytes. Lowering the pH results in an increasing protonation of the amino groups which is monitored via the proton chemical shifts of the adjacent CH2 groups. The effective charge is determined from a combination of diffusion and electrophoresis NMR. The fraction of the charges, which are effective for the interaction with an external electric field or other charges, decreases with increasing generation (size) of the dendrimers.
- ItemIn situ identification and G4-PPI-His-Mal-dendrimer-induced reduction of early-stage amyloid aggregates in Alzheimer’s disease transgenic mice using synchrotron-based infrared imaging([London] : Macmillan Publishers Limited, part of Springer Nature, 2021) Benseny-Cases, Núria; Álvarez-Marimon, Elena; Aso, Ester; Carmona, Margarita; Klementieva, Oxana; Appelhans, Dietmar; Ferrer, Isidre; Cladera, JosepAmyloid plaques composed of Aβ amyloid peptides and neurofibrillary tangles are a pathological hallmark of Alzheimer Disease. In situ identification of early-stage amyloid aggregates in Alzheimer’s disease is relevant for their importance as potential targets for effective drugs. Synchrotron-based infrared imaging is here used to identify early-stage oligomeric/granular aggregated amyloid species in situ in the brain of APP/PS1 transgenic mice for the first time. Also, APP/PS1 mice show fibrillary aggregates at 6 and 12 months. A significant decreased burden of early-stage aggregates and fibrillary aggregates is obtained following treatment with poly(propylene imine) dendrimers with histidine-maltose shell (a neurodegenerative protector) in 6-month-old APP/PS1 mice, thus demonstrating their putative therapeutic properties of in AD models. Identification, localization, and characterization using infrared imaging of these non-fibrillary species in the cerebral cortex at early stages of AD progression in transgenic mice point to their relevance as putative pharmacological targets. No less important, early detection of these structures may be useful in the search for markers for non-invasive diagnostic techniques.