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  • Elsevier (CrossRef)  (49)
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  • 1
    Language: English
    In: Toxicology in Vitro, December 2011, Vol.25(8), pp.1557-1567
    Description: ► We compared the cytotoxicity of TP and TP-PM on Jurkat and HT29 cells. ► TP and TP-PM could induce an inhibition of cell growth and proliferation in both tumor cell lines. ► TP and TP-PM induced apoptosis and caused activation of caspase 3/7. ► TP-PM induced in tested cell lines stronger effects than TP. Triptolide (TP), a diterpenoid triepoxide purified from the Chinese herb Hook F is characterized by strong anti-tumor effects on various cancer cells. Except its anti-tumor effects, TP also shows multiple pharmacological side activities, such as anti-inflammatory, immune-suppressive and male anti-fertility. In order to reduce these side effects, especially the immuno-suppressive activity when used to cure cancer, a novel polymeric micelle system containing TP (TP-PM) was constructed. The immune-modulation effects of TP-PM have been evaluated by previous studies. In this study, we compared the cytotoxicity of TP and TP-PM on Jurkat and HT29 cells. Therefore, we determined the cell viability, membrane integrity, cell proliferation, apoptosis, and caspase 3/7 activity after exposure to TP and TP-PM. The results demonstrated that actually low concentrated TP and TP-PM could induce an inhibition of cell growth and proliferation as well as membrane damage in both tumor cell lines. TP and TP-PM induced apoptosis and caused activation of caspase 3/7 even at low concentrations. Both formulations destroyed the membrane of Jurkat cells, nevertheless, TP-PM showed stronger pernicious effects. In general, TP-PM induced in both tested cell lines stronger effects than TP. Therefore, polymeric micelles can be considered as promising carriers for TP in cancer therapy.
    Keywords: Cytotoxicity ; Triptolide ; Polymeric Micelles ; In Vitro ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry ; Public Health
    ISSN: 0887-2333
    E-ISSN: 1879-3177
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  • 2
    Language: English
    In: Analytica Chimica Acta, 28 September 2016, Vol.938, pp.106-113
    Description: Limited drug penetration into tumor tissue is a significant factor to the effectiveness of cancer therapy. Tumor spheroids, a 3D cell culture model system, can be used to study drug penetration for pharmaceutical development. In this study, a method for quantitative bioimaging of platinum group elements by laser ablation (LA) coupled to inductively coupled plasma mass spectrometry (ICP-MS) is presented. Different matrix-matched standards were used to develop a quantitative LA-ICP-MS method with high spatial resolution. To investigate drug penetration, tumor spheroids were incubated with platinum complexes (Pt(II)acetylacetonate, cisplatin) and the palladium tagged photosensitizer 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin ( THPP). Distribution and accumulation of the pharmaceuticals were determined with the developed method.
    Keywords: La-Icp-MS ; Quantification ; Tumor Spheroids ; Pt Cytostatics ; Photosensitizer ; Chemistry
    ISSN: 0003-2670
    E-ISSN: 1873-4324
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  • 3
    Language: English
    In: Biomaterials, 2010, Vol.31(8), pp.2388-2398
    Description: Specific transport of anti-cancer drugs into tumor cells may result in increased therapeutic efficacy and decreased adverse events. Expression of αvβ3 integrin is enhanced in various types of cancer and monoclonal antibodies (mAbs) directed against αvβ3 integrins hold promise for anti-cancer therapy. DI17E6 is a monoclonal antibody directed against αv integrins that inhibits growth of melanomas and and inhibits angiogenesis due to interference with αvβ3 integrins. Here, DI17E6 was covalently coupled to human serum albumin nanoparticles. Resulting nanoparticles specifically targeted αvβ3 integrin positive melanoma cells. Moreover, doxorubicin loaded DI17E6 nanoparticles showed increased cytotoxic activity in αvβ3-positive melanoma cells than the free drug. Therefore, DI17E6-coupled human serum albumin nanoparticles represent a potential delivery system for targeted drug transport into αvβ3-positive cells.
    Keywords: Albumin ; Chemotherapy ; Drug Delivery ; Ecm (Extracellular Matrix) ; Integrin ; Nanoparticles ; Medicine ; Engineering
    ISSN: 0142-9612
    E-ISSN: 1878-5905
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  • 4
    Language: English
    In: Toxicology Letters, 2011, Vol.206(1), pp.60-66
    Description: • We loaded the oxime HI 6 on human serum albumin nanoparticles. • We investigated the physico-chemical properties of the HI 6-loaded nanoparticles. • The transfer through an blood–brain barrier model was increased with HI 6-loaded nanoparticles. The standard treatment of intoxication with organophosphorus (OP) compounds includes the administration of oximes acting as acetylcholinesterase (AChE) reactivating antidotes. However, the blood–brain barrier (BBB) restricts the rapid transport of these drugs from the blood into the brain in therapeutically relevant concentrations. Since human serum albumin (HSA) nanoparticles enable the delivery of a variety of drugs across the BBB into the brain, HI 6 dimethanesulfonate and HI 6 dichloride monohydrate were bound to these nanoparticles in the present study. The resulting sorption isotherms showed a better fit to Freundlich's empirical adsorption isotherm than to Langmuir's adsorption isotherm. At the pH of 8.3 maximum drug binding capacities of 344.8 μg and 322.6 μg per mg of nanoparticles were calculated for HI 6 dimethanesulfonate and HI 6 dichloride monohydrate, respectively. These calculated values are higher than the adsorption capacity of 93.5 μg/mg for obidoxime onto HSA nanoparticles determined in a previous study. testing of the nanoparticulate oxime formulations in primary porcine brain capillary endothelial cells (pBCEC) demonstrated an up to two times higher reactivation of OP-inhibited AChE than the free oximes. These findings show that nanoparticles made of HSA may enable a sufficient antidote OP-poisoning therapy with HI 6 derivatives even within the central nervous system (CNS).
    Keywords: Nanoparticles ; Human Serum Albumin ; Hi 6 ; Adsorption Isotherm ; In Vitro Blood–Brain Barrier Model ; Drug Delivery ; Pharmacy, Therapeutics, & Pharmacology ; Public Health
    ISSN: 0378-4274
    E-ISSN: 1879-3169
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  • 5
    Language: English
    In: Nanomedicine: Nanotechnology, Biology, and Medicine, 2011, Vol.7(4), pp.454-463
    Description: The specific application and transport of drugs into malignant tissue is a critical point during diagnosis and therapy. Nanoparticles are known as excellent drug carrier systems and offer the possibility of surface modification with targeting ligands, leading to a specific accumulation in the targeted tissue. First, the specificity of such a carrier system has to be proven. In this study, cetuximab-modified nanoparticles based on biodegradable human serum albumin (HSA) are investigated regarding their cellular binding and intracellular accumulation. Different EGFR-expressing colon carcinoma cells were used to test possible cytotoxic potential, specific binding and intracellular accumulation. A specific accumulation targeting the EGFR could be shown. These results emphasize that cetuximab-modified HSA-nanoparticles are a promising carrier system for later drug transport. To our knowledge, this is the first study investigating the specific accumulation of HSA nanoparticles into different EGFR-expressing colon carcinoma cells. In this study, cetuximab-modified nanoparticles based on human serum albumin (HSA) are investigated regarding their cellular binding and intracellular accumulation. The results suggest that these nanoparticles are a promising carrier system for EGFR overexpressing colon carcinoma cells. Specific cellular accumulation of cetuximab-modified nanoparticles based on human serum albumin in different EGFR-expressing colon carcinoma cell lines. HSA-cetuximab nanoparticles show a cell specific accumulation depending the cellular EGFR-expression.
    Keywords: Nanoparticles ; Human Serum Albumin ; Colon Carcinoma ; Egfr ; Cetuximab ; Medicine
    ISSN: 1549-9634
    E-ISSN: 1549-9642
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  • 6
    Language: English
    In: European Journal of Pharmaceutics and Biopharmaceutics, October 2014, Vol.88(2), pp.510-517
    Description: Severe intoxications with organophosphates require the immediate administration of atropine in combination with acetyl cholinesterase (AChE) reactivators such as HI-6. Although this therapy regimen enables the treatment of peripheral symptoms, the blood–brain barrier (BBB) restricts the access of the hydrophilic antidotes to the central nervous system which could lead to a fatal respiratory arrest. Therefore, HI-6-loaded albumin nanoparticles were previously developed to enhance the transport across this barrier and were able to reactivate organophosphate-(OP)-inhibited AChE in an BBB model. Since HI-6 is known to be moisture-sensitive, the feasibility of freeze-drying of the HI-6-loaded nanoparticles was investigated in the present study using different cryo- and lyoprotectants at different concentrations. Trehalose and sucrose (3%, w/v)-containing formulations were superior to mannitol concerning the physicochemical parameters of the nanoparticles whereas trehalose-containing samples were subject of a prolonged storage stability study at temperatures between −20 °C and +40 °C for predetermined time intervals. Shelf-life computations of the freeze-dried HI-6 nanoparticle formulations revealed a shelf-life time of 18 months when stored at −20 °C. The formulations’ efficacy was proven by reactivation of OP-inhibited AChE after transport over a porcine brain capillary endothelial cell layer model.
    Keywords: Nanoparticles ; Recombinant Human Serum Albumin ; Hi-6 ; Drug Delivery ; Freeze-Drying ; Storage Stability ; Organophosphate Intoxication ; Oximes ; Blood–Brain Barrier (BBB) ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0939-6411
    E-ISSN: 1873-3441
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  • 7
    Language: English
    In: Journal of Controlled Release, 2009, Vol.137(1), pp.78-86
    Description: The blood–brain barrier (BBB) represents a considerable obstacle to brain entry of the majority of drugs and thus severely restricts the therapy of many serious CNS diseases including brain tumours, brain HIV, Alzheimer and other neurodegenerative diseases. The use of nanoparticles coated with polysorbate 80 or with attached apolipoprotein E has enabled the delivery of drugs across the BBB. However, the mechanism of this enhanced transport is still not fully understood. In this present study, human serum albumin nanoparticles, with covalently bound apolipoprotein E (Apo E) as a targetor as well as without apolipoprotein E, were manufactured and injected intravenously into SV 129 mice. The animals were sacrificed after 15 and 30 min, and their brains were examined by transmission electron microscopy. Only the nanoparticles with covalently bound apolipoprotein E were detected in brain capillary endothelial cells and neurones, whereas no uptake into the brain was detectable with nanoparticles without apolipoprotein E. We have also demonstrated uptake of the albumin/ApoE nanoparticles into mouse endothelial (b.End3) cells in vitro and their intracellular localisation. These findings indicate that nanoparticles with covalently bound apolipoprotein E are taken up into the cerebral endothelium by an endocytic mechanism followed by transcytosis into brain parenchyma. Electron-microscopy of mouse brain tissue shows that nanoparticles with covalently bound apolipoprotein E are endocytosed after intravenous injection by brain endothelial cells and transported into the surrounding tissue by transcytosis.
    Keywords: Apolipoprotein E ; Blood–Brain Barrier ; Brain Targeting ; Nanoparticles ; Transcytosis ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0168-3659
    E-ISSN: 1873-4995
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  • 8
    Language: English
    In: Nanomedicine: Nanotechnology, Biology, and Medicine, February 2015, Vol.11(2), pp.275-282
    Description: The cytokine secretion of primary cells of human macrophages during the interaction of TiO nanoparticles (with an average primary size of 100-120 nm) is investigated down to concentration levels suggested to be relevant for conditions. We find that high TiO concentrations induce the cytokines Interleukin IL-1β, IL-6, and IL-10 secretion, while at low concentrations only IL-6 secretion is observed. To obtain further evidence on conditions we investigated the development and structure of the protein corona of the nanoparticles. We demonstrated that the surface of TiO particles attract preferably secondary modified proteins which then induce cytokine secretion of macrophages. Our results indicate that concentration of corona covered TiO particles below 1 μg/ml induce IL-6 secretion which is reported to be responsible for the development of autoimmune diseases as well as for the secretion of acute phase proteins. This study investigates the effects of protein corona covered titanium dioxide nanoparticles on human macrophages, concluding that concentration of such particles below 1 μg/ml induces IL-6 secretion, which may be responsible for the development of autoimmune diseases as well as for the secretion of acute phase proteins. This finding has important implications on future applications of such nanoparticles. Macrophage interaction with protein corona covered TiO nanoparticles. The reaction of the immune cells to low concentration of TiO nanoparticles despite the intense use of this material is not well investigated. We have shown that the protein corona developed on the surface of this particle agglomerate secondary modified proteins. Using primary cells of macrophages, we demonstrated that this corona induced at low particle concentrations the secretion of interleukin-6 which mediates, among others, autoimmune diseases.
    Keywords: Titanium Dioxide ; Nanoparticles ; Human Macrophage ; Protein Corona ; Immunology ; Nanotoxicology ; Interleukin-6 ; Medicine
    ISSN: 1549-9634
    E-ISSN: 1549-9642
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  • 9
    Language: English
    In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis
    Description: In accordance with the 3 Rs to reduce testing, more advanced models, moving from 2D monolayer to 3D cultures, should be developed for prediction of human toxicity of industrial chemicals and environmental pollutants. In this study we compared cytotoxic and genotoxic responses induced by chemicals in 2D and 3D spheroidal cultures of the human liver cancer cell line HepG2. HepG2 spheroids were prepared by hanging drop technology. Both 3D spheroids and 2D monolayer cultures were exposed to different chemicals (colchicine, chlorpromazine hydrochloride or methyl methanesulfonate) for geno- and cytotoxicity studies. Cytotoxicity was investigated by alamarBlue assay, flow cytometry and confocal imaging. DNA damage was investigated by the comet assay with and without Fpg enzyme for detection of DNA strand breaks and oxidized or alkylated base lesions. The results from the cyto- and genotoxicity tests showed differences in sensitivity comparing the 2D and 3D HepG2 models. This study shows that human 3D spheroidal hepatocellular cultures can be successfully applied for genotoxicity testing by the comet assay and represent a promising advanced model for toxicity testing.
    Keywords: Liver Spheroids ; Advanced in Vitro Model ; Genotoxicity ; Comet Assay ; 2d and 3d Culture ; Biology ; Public Health
    ISSN: 1383-5718
    E-ISSN: 1879-3592
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  • 10
    Language: English
    In: Virology, 2006, Vol.352(2), pp.295-305
    Description: We have previously shown that Rev-dependent expression of HIV-1 Gag from CMV immediate early promoter critically depends on the AU-rich codon bias of the gag gene. Here, we demonstrate that adaptation of the green fluorescent protein (GFP) reporter gene to HIV codon bias is sufficient to turn this hivGFP RNA into a quasi-lentiviral message following the rules of late lentiviral gene expression. Accordingly, GFP expression was significantly decreased in transfected cells strictly correlating with reduced RNA levels. In the presence of the HIV 5′ major splice donor, the hivGFP RNAs were stabilized in the nucleus and efficiently exported to the cytoplasm following fusion of the 3′ Rev-responsive element (RRE) and coexpression of HIV-1 Rev. This Rev-dependent translocation was specifically inhibited by leptomycin B suggesting export via the CRM1-dependent pathway used by late lentiviral transcripts. In conclusion, this quasi-lentiviral reporter system may provide a new platform for developing sensitive Rev screening assays.
    Keywords: HIV-1 ; Gfp ; Codon Usage ; Rev ; Rre ; RNA Export ; Cte ; Crm1 ; Biology
    ISSN: 0042-6822
    E-ISSN: 1096-0341
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