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  • 1
    Language: English
    In: Pharmaceutical Research, 2015, Vol.32(12), pp.3986-3998
    Description: Byline: Susanne Beyer (1), Aline Moosmann (2), Astrid S. Kahnt (3), Thomas Ulshofer (4), Michael J. Parnham (4), Nerea Ferreiros (5), Sylvia Wagner (2), Matthias G. Wacker (1) Keywords: biorelevant release; Eudragit[R] RS 100; nanoparticles; peroral drug delivery; Ussing chamber Abstract: Purpose The contribution of permeability and drug release to drug targeting were investigated in the course of development of a nanosized formulation of the anti-inflammatory compound TMP-001, for the local treatment in the gastrointestinal tract. Methods TMP-001 was encapsulated by nanoprecipitation into Eudragit[R] RS 100. The permeability of these carriers was investigated in an Ussing chamber model and the release rate was determined under biorelevant conditions. Formulation toxicity and particle-cell-interaction were investigated by flow cytometry, fluorescence and electron microscopy. Furthermore, spray drying was performed. Results Effective internalization of Eudragit[R]-nanoparticles into cancer cells was demonstrated. A burst release of the nanoparticles implied poor interaction of TMP-001 with Eudragit[R]. A sustained release (70.5% release after 30 min compared to 98.0% for the API) was accomplished after spray drying yielded an increased particle size. Recovery rate of TMP-001 after spray drying was 94.2[+ or -]5.9%. Conclusion The release of API from polymeric nanoparticles contributes profoundly to the in vivo-performance of drug delivery devices in the gastrointestinal tract. The impact of drug-polymer interaction and particle size was analyzed. Sustained release of TMP-001 could only be achieved by increasing particle size. Therefore, biorelevant release testing has been demonstrated to be a valid tool for nanoformulation design. Author Affiliation: (1) Institute of Pharmaceutical Technology, Goethe University, Max-von-Laue-Str. 9, 60438, Frankfurt (Main), Germany (2) Department of Bioprocess Technologies & Nanotechnology, Fraunhofer Institute for Biomedical Engineering, Ensheimer Stra[sz]e 48, 66386, St. Ingbert, Germany (3) Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt (Main), Germany (4) Fraunhofer Institute of Molecular Biology and Applied Ecology, Project Group for Translational Medicine and Pharmacology, Theodor-Stern-Kai 7, 60596, Frankfurt (Main), Germany (5) Institute of Clinical Pharmacology, Goethe University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany Article History: Registration Date: 15/07/2015 Received Date: 30/04/2015 Accepted Date: 15/07/2015 Online Date: 28/07/2015
    Keywords: biorelevant release ; Eudragit® RS 100 ; nanoparticles ; peroral drug delivery ; Ussing chamber
    ISSN: 0724-8741
    E-ISSN: 1573-904X
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  • 2
    Language: English
    In: Nanotechnology, 2011, Vol.22(24), p.245102 (12pp)
    Description: The second generation photosensitizer m THPC was approved by the European Medicines Agency (EMA) for the palliative treatment of advanced head and neck cancer in October 2001. It is known that m THPC possesses a significant phototoxicity against a variety of human cancer cells in vitro but also exhibits dark toxicity and can cause adverse effects (especially skin photosensitization). Due to its poor water solubility, the administration of hydrophobic photosensitizer still presents several difficulties. To overcome the administration problems, the use of nanoparticles as drug carrier systems is much investigated. Nanoparticles based on poly(lactic-co-glycolic acid) (PLGA) have been extensively studied as delivery systems into tumours due to their biocompatibility and biodegradability. The goal of this study was the comparison of free m THPC and m THPC-loaded PLGA nanoparticles concerning cytotoxicity and intracellular accumulation in human colon carcinoma cells (HT29). The nanoparticles delivered the photosensitizer to the colon carcinoma cells and enabled drug release without losing its activity. The cytotoxicity assays showed a time- and concentration-dependent decrease in cell proliferation and viability after illumination. However, first and foremost m THPC lost its dark toxic effects using the PLGA nanoparticles as a drug carrier system. Therefore, PLGA nanoparticles are a promising drug carrier system for the hydrophobic photosensitizer m THPC.
    Keywords: Colonic Neoplasms -- Metabolism ; Intracellular Space -- Metabolism ; Lactic Acid -- Toxicity ; Mesoporphyrins -- Toxicity ; Nanoparticles -- Toxicity ; Polyglycolic Acid -- Toxicity;
    ISSN: 0957-4484
    E-ISSN: 1361-6528
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  • 3
    Language: English
    In: PLoS ONE, 2012, Vol.7(3), p.e32568
    Description: The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. ; In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different co-incubation experiments were performed with competing ligands of the respective receptor. ; This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier.
    Keywords: Research Article ; Biology ; Materials Science ; Medicine ; Biotechnology ; Pharmacology ; Biochemistry
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, 2010, Vol.5(12), p.e14213
    Description: Due to the use of organophosphates (OP) as pesticides and the availability of OP-type nerve agents, an effective medical treatment for OP poisonings is still a challenging problem. The acute toxicity of an OP poisoning is mainly due to the inhibition of acetylcholinesterase (AChE) in the peripheral and central nervous systems (CNS). This results in an increase in the synaptic concentration of the neurotransmitter acetylcholine, overstimulation of cholinergic receptors and disorder of numerous body functions up to death. The standard treatment of OP poisoning includes a combination of a muscarinic antagonist and an AChE reactivator (oxime). However, these oximes can not cross the blood-brain barrier (BBB) sufficiently. Therefore, new strategies are needed to transport oximes over the BBB. ; In this study, we combined different oximes (obidoxime dichloride and two different HI 6 salts, HI 6 dichloride monohydrate and HI 6 dimethanesulfonate) with human serum albumin nanoparticles and could show an oxime transport over an BBB model. In general, the nanoparticulate transported oximes achieved a better reactivation of OP-inhibited AChE than free oximes. ; With these nanoparticles, for the first time, a tool exists that could enable a transport of oximes over the BBB. This is very important for survival after severe OP intoxication. Therefore, these nanoparticulate formulations are promising formulations for the treatment of the peripheral and the CNS after OP poisoning.
    Keywords: Research Article ; Biotechnology ; Neurological Disorders ; Pharmacology -- Drug Development
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(3), p.e92068
    Description: This study was performed to explore the feasibility of tracing nanoparticles for drug transport in the healthy rat brain with a clinical MRI scanner. Phantom studies were performed to assess the R1 ( =  1/T1) relaxivity of different magnetically labeled nanoparticle (MLNP) formulations that were based on biodegradable human serum albumin and that were labeled with magnetite of different size. In vivo MRI measurements in 26 rats were done at 3T to study the effect and dynamics of MLNP uptake in the rat brain and body. In the brain, MLNPs induced T1 changes were quantitatively assessed by T1 relaxation time mapping in vivo and compared to post-mortem results from fluorescence imaging. Following intravenous injection of MLNPs, a visible MLNP uptake was seen in the liver and spleen while no visual effect was seen in the brain. However a histogram analysis of T1 changes in the brain demonstrated global and diffuse presence of MLNPs. The magnitude of these T1 changes scaled with post-mortem fluorescence intensity. This study demonstrates the feasibility of tracking even small amounts of magnetite labeled NPs with a sensitive histogram technique in the brain of a living rodent.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: PloS one, 2018, Vol.13(9), pp.e0204318
    Description: Microneedling therapy is a widely used technique in dermatology. However, little is known about the underlying molecular effects of this therapy on extracellular matrix remodeling, wound healing, and inflammation. The aim of this study was to examine morphological and molecular changes caused by microneedling treatment in a standardized in vitro full-thickness 3D model of human skin. A microneedling device was used to treat full-thickness 3D skin models. Specimens were harvested at specified time points and qRT-PCR and microarray studies were performed. Frozen sections were examined histologically. Microneedling treatment caused morphological changes in the skin model resulting in an almost complete recovery of the epidermis five days after treatment. Microarray analysis identified an upregulation of genes that are associated with tissue remodeling and wound healing (e.g. COL3A1, COL8A1, TIMP3), epithelial proliferation and differentiation (KRT13, IGF1), immune cell recruitment (CCL11), and a member of the heat shock protein family (HSPB6). On the other hand, we detected a downregulation of pro-inflammatory cytokines (e.g. IL1α, IL1β, IL24, IL36γ, IL36RN), and antimicrobial peptides (e.g. S100A7A, DEFB4). These data were confirmed by independent RT-PCR analyses. We present for the first time the direct molecular effects of microneedling therapy on epidermal keratinocytes and dermal fibroblasts using a standardized 3D skin model. Treatment resulted in histological alterations and changed the expression of various genes related to epidermal differentiation, inflammation, and dermal remodeling. This data suggests that skin microneedling plays a role in dermal remodeling, increases epidermal differentiation, and might also have a direct effect on collagen synthesis. These findings may increase our understanding of the molecular mechanisms of human skin repair induced by microneedling therapy and will allow comparisons with competing applications, such as ablative laser therapies.
    Keywords: Research Article ; Biology And Life Sciences ; Medicine And Health Sciences ; Biology And Life Sciences ; Medicine And Health Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Medicine And Health Sciences ; Medicine And Health Sciences ; Medicine And Health Sciences ; Engineering And Technology ; Biology And Life Sciences ; Biology And Life Sciences ; Medicine And Health Sciences ; Biology And Life Sciences ; Biology And Life Sciences ; Medicine And Health Sciences;
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(1), p.e0146378
    Description: Delayed graft function is a prevalent clinical problem in renal transplantation for which there is no objective system to predict occurrence in advance. It can result in a significant increase in the necessity for hospitalisation post-transplant and is a significant risk factor for other post-transplant complications.The importance of microRNAs (miRNAs), a specific subclass of small RNA, have been clearly demonstrated to influence many pathways in health and disease. To investigate the influence of miRNAs on renal allograft performance post-transplant, the expression of a panel of miRNAs in pre-transplant renal biopsies was measured using qPCR. Expression was then related to clinical parameters and outcomes in two independent renal transplant cohorts.Here we demonstrate, in two independent cohorts of pre-implantation human renal allograft biopsies, that a novel pre-transplant renal performance scoring system (GRPSS), can determine the occurrence of DGF with a high sensitivity (〉90%) and specificity (〉60%) for donor allografts pre-transplant, using just three senescence associated microRNAs combined with donor age and type of organ donation.These results demonstrate a relationship between pre-transplant microRNA expression levels, cellular biological ageing pathways and clinical outcomes for renal transplantation. They provide for a simple, rapid quantitative molecular pre-transplant assay to determine post-transplant allograft function and scope for future intervention. Furthermore, these results demonstrate the involvement of senescence pathways in ischaemic injury during the organ transplantation process and an indication of accelerated bio-ageing as a consequence of both warm and cold ischaemia.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    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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  • 9
    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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  • 10
    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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