name title fuMetaTitel body fuDCcreator fuDCcreatorLinks fuDCpublisher fuDCpublisherLocation fuDCSizeOrDuration fuDCdateYear fuDCdateMonth fuDCdateDay fuDCsubject fuDCrelationPartOf fuDCrelation fuDClanguage fuDCsource fuDCcontributor fuDCtype fuDCformat fuDCidentifier fuDCcoverage fuDCrights fuDCdescriptionDE fuDCdescriptionEN fuDCIdentifierBibliographicCitation fuBild fuDCBibtex fuLinksZumThema KA940 Self-degrading graphene sheets for tumor therapy "Donskyi, I. S.; Chen, Y.; Nickl, P.; Guday, G.; Qiao, H.; Achazi, K.; Lippitz, A.; Unger, W. E. S.; Bottcher, C.; Chen, W.; Adeli, M.; Haag, R." Nanoscale 2020 7 14 "*Graphite; Coloring Agents; Doxorubicin/pharmacology" https://doi.org/10.1039/d0nr02159h journalArticle 2040-3372 (Electronic) 2040-3364 (Linking) Low biodegradability of graphene derivatives and related health risks are the main limiting factors for their in vivo biomedical applications. Here, we present the synthesis of enzyme-functionalized graphene sheets with self-degrading properties under physiological conditions and their applications in tumor therapy. The synergistic enzyme cascade glucose oxidase and myeloperoxidase are covalently conjugated to the surface of graphene sheets and two-dimensional (2D) platforms are obtained that can produce sodium hypochlorite from glucose. The enzyme-functionalized graphene sheets with up to 289 nm average size are degraded into small pieces (90% cells (HeLa or MDA-MB-231) were found to be alive after 96 h of incubation with a polymer concentration of up to 1.0 mg/mL, which was further validated by the hemolysis assay. Cytotoxicity assay of the Dox-loaded polymersome exhibited time and dose-dependent sustained killing of HeLa as well as MDA-MB-231 cells wherein after 48 h of incubation >50% cell killing was noticed with a Dox concentration of approximately 4.0 and approximately 8.7 mug/mL, respectively, while the free Dox showed faster cell killing. Flow cytometry and live cell fluorescence microscopy studies revealed time-dependent cellular uptake of the drug-loaded polymersome followed by diffusion of the drug to the nucleus. Cells with artificially enhanced GSH were killed at a much faster rate indicating that intracellular GSH-triggered disassembly is the key drug release mechanism. KA943 One-Pot Synthesis of Poly(glycerol- co-succinic acid) Nanogels for Dermal Delivery "Zabihi, F.; Koeppe, H.; Achazi, K.; Hedtrich, S.; Haag, R." Biomacromolecules 2019 5 13 "*Drug Carriers; *Skin Absorption; Administration, Cutaneous; Drug Delivery Systems; Glycerol/*chemical synthesis; Nanogels/*chemistry; Polymers/*chemical synthesis; Succinates/*chemical synthesis" https://doi.org/10.1021/acs.biomac.8b01741 journalArticle 1526-4602 (Electronic) 1525-7797 (Linking) Polyglycerol nanogels are three-dimensional polymeric networks with a few hundred nanometer sizes and the ability to encapsulate and deliver cargos for a wide range of biomedical applications. However, time-consuming and multistep synthetic routes as well as milligram-scale production have hindered further development of these nanomaterials. In this work, we report on a straightforward synthetic method for the production of polyglycerol nanoarchitectures. Enzymatic ring-opening copolymerization of a mixture of glycidol and succinic anhydride resulted in polyglycerol nanogels with succinic acid segments in their backbone. Novozyme 435 was used as a dual catalytic agent to support ring-opening polymerization of the above-mentioned cyclic monomers as well as esterification of the produced oligomers to obtain nanogels. While succinic acid segments improved the biodegradability and loading capacity of nanogels, polyglycerol caused water solubility, high functionality, and biocompatibility. Nanogels were loaded with tacrolimus and photosensitizer 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (mTHPP)-a close congener of the approved photosensitizer temoporfin (mTHPC)-and their ability to improve the skin penetration of these therapeutic agents was investigated. mTHPP delivery experiments on human skin, which were quantified by fluorescence microscopy, showed that these nanogels deposit in the stratum corneum and release the loaded drug to viable epidermis of skin efficiently in comparison with commercially available base cream. Taking advantage of the straightforward synthesis as well as biodegradability, biocompatibility, high loading capacity, and efficient skin penetration, the synthesized nanogels could be used as future topical delivery systems. KA944 Reductively cleavable polymer-drug conjugates based on dendritic polyglycerol sulfate and monomethyl auristatin E as anticancer drugs "Rades, N.; Achazi, K.; Qiu, M.; Deng, C.; Haag, R.; Zhong, Z.; Licha, K." J Control Release 2019 4 28 "A549 Cells; Animals; Anticancer; Antineoplastic Agents/*administration & dosage/chemistry; Caco-2 Cells; Cell Proliferation/drug effects; Cell Survival/drug effects; Dendritic polyglycerol; Drug Carriers/*administration & dosage/chemistry; Drug Liberation; Glycerol/*administration & dosage/chemistry; Humans; Maximum Tolerated Dose; MCF-7 Cells; Mice, Inbred BALB C; Monomethyl auristatin E; Oligopeptides/*administration & dosage/chemistry; Polymer drug conjugates; Polymers/*administration & dosage/chemistry; Stimuli-responsive" https://doi.org/10.1016/j.jconrel.2019.01.035 journalArticle 1873-4995 (Electronic) 0168-3659 (Linking) Stimuli-responsive polymer-drug conjugates (PDCs) provide promising approaches in anticancer treatment. Here, we report the synthesis and biological evaluation of PDCs made of the highly potent antimitotic agent monomethyl auristatin E conjugated to dendritic polyglycerol and dendritic polyglycerol sulfate via a reductively cleavable, self-immolative disulfide linker. Cell viability assays with the human cancer cell lines A549 (lung carcinoma) and HeLa (cervix carcinoma) revealed that the drug's cytotoxicity was reduced by conjugation to the polymers, with the sulfated conjugates being more effective than the non-sulfated ones. Kinetic studies using real-time cell analysis indicated a retarded drug release from the polymers, with a much later cytotoxic response after treatment with the non-sulfated conjugates due to less cellular uptake, as confirmed by flow cytometry and confocal laser scanning microscopy. In contrast, the non-cleavable dPGS-MMAE conjugate that was synthesized for comparison was not cytotoxic under the same conditions. Overall, reductively cleavable dPGS-SS-MMAE conjugates showed promising results in vitro and good tolerability in vivo. Further in vivo studies are planned. KA945 Design and Synthesis of PEG-Oligoglycerol Sulfates as Multivalent Inhibitors for the Scavenger Receptor LOX-1 "Kumari, S.; Achazi, K.; Dey, P.; Haag, R.; Dernedde, J." Biomacromolecules 2019 3 11 "*Drug Design; Binding Sites; Glycerol/*chemistry; HEK293 Cells; Humans; Ligands; Polyethylene Glycols/*chemistry; Scavenger Receptors, Class E/*antagonists & inhibitors; Sulfates/*chemistry" https://doi.org/10.1021/acs.biomac.8b01416 journalArticle 1526-4602 (Electronic) 1525-7797 (Linking) "Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a cell surface scavenger receptor. The protein is involved in binding and internalization of oxidized low-density lipoprotein (oxLDL), which leads under pathophysiological circumstances to plaque formation in arteries and initiation of atherosclerosis. A structural feature of LOX-1 relevant to oxLDL binding is the ""basic spine"" motif consisting of linearly aligned arginine residues stretched over the dimer surface. Inhibition of LOX-1 can be done by blocking these positively charged motifs. Here we report on the design, synthesis, and evaluation of a series of novel LOX-1 inhibitors having different numbers of sulfates and polyethylene glycerol (PEG) spacer. Two molecules, compounds 6b and 6d, showed binding affinity in the low nM range, i.e. 45.8 and 47.4 nM, respectively. The in vitro biological studies reveal that these molecules were also able to block the interaction of LOX-1 with its cognate ligands oxLDL, aged RBC, and bacteria." KA946 Hyperbranched Polyglycerol Loaded with (Zinc-)Porphyrins: Photosensitizer Release Under Reductive and Acidic Conditions for Improved Photodynamic Therapy "Staegemann, M. H.; Grafe, S.; Gitter, B.; Achazi, K.; Quaas, E.; Haag, R.; Wiehe, A." Biomacromolecules 2018 1 8 "*Photochemotherapy; Acids/chemistry; Anti-Bacterial Agents/pharmacology; Cell Line, Tumor; Chromatography, Thin Layer; Copper/chemistry; Cycloaddition Reaction; Flow Cytometry; Glycerol/*administration & dosage; Humans; Hydrogen-Ion Concentration; Metalloporphyrins/*chemistry; Microscopy, Confocal; Oxidation-Reduction; Photosensitizing Agents/*administration & dosage; Polymers/*administration & dosage; Spectrophotometry, Ultraviolet; Staphylococcus aureus/drug effects" https://doi.org/10.1021/acs.biomac.7b01485 journalArticle 1526-4602 (Electronic) 1525-7797 (Linking) An adaptable approach toward cleavable nanoparticle carrier systems for photodynamic therapy (PDT) is presented, comprising a biocompatible carrier loaded with multiple photosensitizer (PS) molecules related to the clinically employed PS Temoporfin, two linkers cleavable under different triggers and glyco-targeting with mannose. A synthetic pathway to stimuli responsive hyperbranched polyglycerol (hPG) porphyrin conjugates via the copper(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC) or the strain-promoted alkyne-azide cycloaddition (SPAAC) has been developed. The PS 10,15,20-tris(3-hydroxyphenyl)-5-(2,3,4,5,6-pentafluorophenyl)porphyrin was functionalized with disulfide containing cystamine and acid-labile benzacetal linkers. Conjugates with reductively and pH labile linkers were thus obtained. Cleavage of the active PS agents from the polymer carrier is shown in several different release studies. The uptake of the conjugates into the cells is demonstrated via confocal laser scanning microscopy (CLSM) and flow cytometry. Finally, the antitumor and antibacterial phototoxicity of selected conjugates has been assessed in four different tumor cell lines and in cultures of the bacterium Staphylococcus aureus. The conjugates exhibited phototoxicity in several tumor cell lines in which conjugates with reductively cleavable linkers were more efficient compared to conjugates with acid-cleavable linkers. For S. aureus, strong phototoxicity was observed for a combination of the reductively cleavable and the pH labile linker and likewise for the cleavable conjugate with mannose targeting groups. The results thus suggest that the conjugates have potential for antitumor as well as antibacterial PDT. KA947 Synthesis of non-ionic bolaamphiphiles and study of their self-assembly and transport behaviour for drug delivery applications "Rashmi; Singh, A. K.; Achazi, K.; Schade, B.; Bottcher, C.; Haag, R.; Sharma, S. K." Rsc Advances 2018 9 5 "aggregation behavior; amphiphilic molecules; biomedical applications; core-shell architectures; dendritic amphiphiles; liposomes; nanocarriers; nanostructures; rational design; supramolecular architectures" https://doi.org/10.1039/c8ra05921g journalArticle 2046-2069 (Electronic) 2046-2069 (Linking) A series of four bolaamphiphiles with different hydrophilic units has been synthesised. All the amphiphiles were well characterised from their physiochemical data. The aggregation tendency of newly synthesised amphiphiles was studied using fluorescence spectroscopy, dynamic light scattering (DLS), and cryogenic electron microscopy (cryo-TEM). Furthermore, their application as nanocarriers for hydrophobic guests was demonstrated by using two established standards, i.e. the dye Nile red and the drug nimodipine. A cytotoxicity and cellular uptake study has been carried out using A549 cells. Due to the presence of an ester linkage in PEG based bolaamphiphiles, a drug release study was performed in the presence of an immobilized enzyme Novozym-435 (a lipase). KA948 Synthesis of non-ionic and enzyme-responsive bolaamphiphiles for drug delivery applications "Prasad, S.; Achazi, K.; Schade, B.; Haag, R.; Sharma, S. K." European Polymer Journal 2018 12 "amphiphiles; assemblies; bolaamphiphile; cytotoxicity; encapsulation; enzyme-responsive behavior; micelles; nanocarriers; nanostructures; polymers" https://doi.org/10.1016/j.eurpolymj.2018.https://doi.org/10.007 journalArticle 0014-3057 Nanoscale drug delivery systems devised from biocompatible and biodegradable molecules with functional groups which are readily amenable to external stimuli, have become a promising approach to circumvent the pitfalls associated with the hydrophobic drugs concomitant with the amplification of drugs' action. Taking the cognizance of advantages offered by nanostructures and also in search of amphiphiles with intended biomedical applications, a novel and elite family of amphiphilic system that can self-assemble into enzyme-responsive supramolecular architectures has been synthesized via a chemo-enzymatic approach using an immobilized enzyme (lipase) from Candida antarctica (Novozym 435) and employing biocompatible starting materials, i.e. p-hydroxybenzoic acid, monomethoxypolyethyleneglycol (mPEG), and glycerol. The aggregation behavior of the resulting bolaamphiphiles have been studied using critical aggregation concentration and dynamic light scattering measurements, further supplemented by cryogenic transmission electron microscopic studies. The developed amphiphiles render efficient solubilization of model hydrophobic drugs and dyes, e.g. Nile red, nimodipine, and curcumin in aqueous solution. Moreover, the results demonstrate that a subtle structural modulation of the amphiphilic system alters the transportation behavior of the guest molecule. The investigation of the enzyme-responsive behavior of the synthesized bolaamphiphiles using a hydrolase enzyme, Candida antarctica lipase reveals that amide based nanocarriers disassemble and release the encapsulated cargo on incubation with the enzyme. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay unravels negligible cytotoxicity of the bolaamphiphiles at the tested concentrations, indicating their relevance in the development of nanocarriers for biomedical applications. KA949 Nonionic Dendritic and Carbohydrate Based Amphiphiles: Self-Assembly and Transport Behavior "Prasad, S.; Achazi, K.; Schade, B.; Haag, R.; Sharma, S. K." Macromol Biosci 2018 7 "A549 Cells; amphiphiles; Anilino Naphthalenesulfonates/chemistry; Antineoplastic Agents, Phytogenic/chemistry/*pharmacology; Benzoates/*chemistry; binding studies; Biocompatible Materials/*chemical synthesis/metabolism; Biological Transport; Cell Survival/drug effects; Curcumin/chemistry/*pharmacology; cytotoxicity; Drug Carriers/*chemical synthesis/metabolism; Drug Compounding/methods; encapsulation; Ethylamines/chemistry; Fluorescent Dyes/chemistry; Glycerol/*chemistry; Humans; Hydrophobic and Hydrophilic Interactions; Microscopy, Electron, Transmission; Polymers/*chemistry; self-assembly" https://doi.org/10.1002/mabi.201800019 journalArticle 1616-5195 (Electronic) 1616-5187 (Linking) Herein, a new series of non-ionic dendritic and carbohydrate based amphiphiles is synthesized employing biocompatible starting materials and studied for supramolecular aggregate formation in aqueous solution. The dendritic amphiphiles 12 and 13 possessing poly(glycerol) [G2.0] as hydrophilic unit and C-10 and C-18 hydrophobic alkyl chains, respectively, exhibit low critical aggregation concentration (CAC) in the order of 10(-5) m and hydrodynamic diameters in the 8-10 nm range and supplemented by cryogenic transmission electron microscopy. Ultraviolet-visible (UV-Vis) and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests by the self-assembled architectures, with the nanotransporters 12 and 13 possessing the highest encapsulation efficiency of 80.74 and 98.03% for curcumin. Efficient uptake of encapsulated curcumin in adenocarcinomic human alveolar basal epithelial (A549) cells is observed by confocal laser scanning microscopy. Amphiphiles 12 and 13 are non-cytotoxic at the concentrations studied, however, curcumin encapsulated samples efficiently reduce the viability of A549 cells in vitro. Experimental studies indicate the ability of amphiphile 13 to encapsulate 1-anilinonaphthalene-8-sulfonic acid (ANS) and curcumin with binding constant of 1.16 x 105(5) m(-1) and 1.43 x 10(6) m(-1) , respectively. Overall, our findings demonstrate the potential of these dendritic amphiphiles for the development of prospective nanocarriers for the solubilization of hydrophobic drugs.