TY  - JOUR
A1  - Wetzel, Alexandra Nicole
A1  - Scholtka, Bettina
A1  - Gerecke, Christian
A1  - Kleuser, Burkhard
T1  - Epigenetic histone modulation contributes to improvements in inflammatory bowel disease via EBI3
JF  - Cellular and molecular life sciences
N2  - Ulcerative colitis (UC) is characterized by relapsing-remitting inflammatory episodes paralleled by varying cytokine levels, suggesting that switching epigenetic processes might be involved. However, the epigenetic impact on cytokine levels in colitis is mostly unexplored. The heterodimeric interleukin (IL)-12 cytokine family have various functions in both pro- and anti-inflammatory processes. The family member IL-35 (EBI3/IL-12p35) was recently reported to play an anti-inflammatory role in UC. Therefore, we aimed to investigate a possible epigenetic regulation of the IL-35 subunits in vitro and in vivo, and to examine the epigenetic targeting of EBI3 expression as a therapeutic option for UC. Exposure to either the pro-inflammatory TNF alpha or to histone deacetylase inhibitors (HDACi) significantly increased EBI3 expression in Human Colon Epithelial Cells (HCEC) generated from healthy tissue. When applied in combination, a drastic upregulation of EBI3 expression occurred, suggesting a synergistic mechanism. Consequently, IL-35 was increased as well. In vivo, the intestines of HDACi-treated wild-type mice exhibited reduced pathological signs of colitis compared to non-treated colitic mice. However, the improvement by HDACi treatment was completely lost in Ebi3-deficient mice (Ebi3(-/-)). In fact, HDACi appeared to exacerbate the disease phenotype in Ebi3(-/-). In conclusion, our results reveal that under inflammatory conditions, EBI3 is upregulated by the epigenetic mechanism of histone acetylation. The in vivo data show that the deficiency of EBI3 plays a key role in colitis manifestation. Concordantly, our data suggest that conditions promoting histone acetylation, such as upon HDACi application, improve colitis by a mechanism involving the local formation of the anti-inflammatory cytokine IL-35.
KW  - Histone deacetylase inhibitor
KW  - Inhibitory cytokines
KW  - Interleukin-35
KW  - SAHA
KW  - Ulcerative colitis
Y1  - 2020
U6  - https://doi.org/10.1007/s00018-020-03451-9
SN  - 1420-682X
SN  - 1420-9071
VL  - 77
IS  - 23
SP  - 5017
EP  - 5030
PB  - Springer International Publishing AG
CY  - Cham (ZG)
ER  - 
TY  - JOUR
A1  - Gerecke, Christian
A1  - Edlich, Alexander
A1  - Giulbudagian, Michael
A1  - Schumacher, Fabian
A1  - Zhang, Nan
A1  - Said, Andre
A1  - Yealland, Guy
A1  - Lohan, Silke B.
A1  - Neumann, Falko
A1  - Meinke, Martina C.
A1  - Ma, Nan
A1  - Calderon, Marcelo
A1  - Hedtrich, Sarah
A1  - Schaefer-Korting, Monika
A1  - Kleuser, Burkhard
T1  - Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes
JF  - Nanotoxicology
N2  - Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery.
KW  - Drug delivery
KW  - nanoparticles
KW  - particle characterization
KW  - keratinocytes
KW  - nanotoxicology
Y1  - 2017
U6  - https://doi.org/10.1080/17435390.2017.1292371
SN  - 1743-5390
SN  - 1743-5404
VL  - 11
SP  - 267
EP  - 277
PB  - Routledge, Taylor & Francis Group
CY  - Abingdon
ER  - 
TY  - JOUR
A1  - Sahle, Fitsum Feleke
A1  - Gerecke, Christian
A1  - Kleuser, Burkhard
A1  - Bodmeier, Roland
T1  - Formulation and comparative in vitro evaluation of various dexamethasone-loaded pH-sensitive polymeric nanoparticles intended for dermal applications
JF  - International Journal of Pharmaceutics
N2  - pH-sensitive nanoparticles have a great potential for dermal and transfollicular drug delivery. In this study, pH-sensitive, dexamethasone-loaded Eudragit (R) L 100, Eudragit (R) L 100-55, Eudragit (R) S 100, HPMCP-50, HPMCP-55 and cellulose acetate phthalate nanoparticles were prepared by nanoprecipitation and characterized. The pH-dependent swelling, erosion, dissolution and drug release kinetics were investigated in vitro using dynamic light scattering and Franz diffusion cells, respectively. Their toxicity potential was assessed by the ROS and MTT assays. 100-700 nm nanoparticles with high drug loading and entrapment efficiency were obtained. The nanoparticles bear no toxicity potential. Cellulose phthalates nanoparticles were more sensitive to pH than acrylates nanoparticles. They dissolved in 10 mM pH 7.5 buffer and released > 80% of the drug within 7 h. The acrylate nanoparticles dissolved in 40 mM pH 7.5 buffer and released 65-70% of the drug within 7 h. The nanoparticles remained intact in 10 and 40 mM pH 6.0 buffers (HPMCP nanoparticles dissolved in 40 mM pH 6.0 buffer) and released slowly. The nanoparticles properties could be modulated by blending the different polymers. In conclusion, various pH-sensitive nanoparticles that could release differently on the skin surface and dissolve and release in the hair follicles were obtained.
KW  - Cellulose acetate phthalate
KW  - Dexamethasone
KW  - Eudragit (R)
KW  - HPMCP
KW  - pH-sensitive nanoparticle
KW  - Skin nanocarrier
Y1  - 2016
U6  - https://doi.org/10.1016/j.ijpharm.2016.11.029
SN  - 0378-5173
SN  - 1873-3476
VL  - 516
IS  - 1-2
SP  - 21
EP  - 31
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Balzus, Benjamin
A1  - Sahle, Fitsum Feleke
A1  - Hönzke, Stefan
A1  - Gerecke, Christian
A1  - Schumacher, Fabian
A1  - Hedtrich, Sarah
A1  - Kleuser, Burkhard
A1  - Bodmeier, Roland
T1  - Formulation and ex vivo evaluation of polymeric nanoparticles for controlled delivery of corticosteroids to the skin and the corneal epithelium
JF  - European journal of pharmaceutics and biopharmaceutics : EJPB ; official journal of the International Association for Pharmaceutical Technology
N2  - Controlled delivery of corticosteroids using nanoparticles to the skin and corneal epithelium may reduce their side effects and maximize treatment effectiveness. Dexamethasone-loaded ethyl cellulose, Eudragit® RS and ethyl cellulose/Eudragit® RS nanoparticles were prepared by the solvent evaporation method. Dexamethasone release from the polymeric nanoparticles was investigated in vitro using Franz diffusion cells. Drug penetration was also assessed ex vivo using excised human skin. Nanoparticle toxicity was determined by MTT and H2DCFDA assays. Eudragit® RS nanoparticles were smaller and positively charged but had a lower dexamethasone loading capacity (0.3–0.7%) than ethyl cellulose nanoparticles (1.4–2.2%). By blending the two polymers (1:1), small (105 nm), positively charged (+37 mV) nanoparticles with sufficient dexamethasone loading (1.3%) were obtained. Dexamethasone release and penetration significantly decreased with decreasing drug to polymer ratio and increased when Eudragit® RS was blended with ethyl cellulose. Ex vivo, drug release and penetration from the nanoparticles was slower than a conventional cream. The nanoparticles bear no toxicity potentials except ethyl cellulose nanoparticles had ROS generation potential at high concentration. In conclusion, the nanoparticles showed great potential to control the release and penetration of corticosteroids on the skin and mucus membrane and maximize treatment effectiveness.
KW  - Dermal delivery
KW  - Dexamethasone
KW  - Ethyl cellulose
KW  - Eudragit (R) RS
KW  - Ocular delivery
KW  - Polymeric nanoparticle
Y1  - 2017
U6  - https://doi.org/10.1016/j.ejpb.2017.02.001
SN  - 0939-6411
SN  - 1873-3441
VL  - 115
SP  - 122
EP  - 130
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Edlich, Alexander
A1  - Gerecke, Christian
A1  - Giulbudagian, Michael
A1  - Neumann, Falko
A1  - Hedtrich, Sarah
A1  - Schaefer-Korting, Monika
A1  - Ma, Nan
A1  - Calderon, Marcelo
A1  - Kleuser, Burkhard
T1  - Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin
JF  - European Journal of Pharmaceutics and Biopharmaceutics
N2  - Engineered nanogels are of high value for a targeted and controlled transport of compounds due to the ability to change their chemical properties by external stimuli. As it has been indicated that nanogels possess a high ability to penetrate the stratum corneum, it cannot be excluded that nanogels interact with dermal dendritic cells, especially in diseased skin. In this study the potential crosstalk of the thermore-sponsive nanogels (tNGs) with the dendritic cells of the skin was investigated with the aim to determine the immunotoxicological properties of the nanogels. The investigated tNGs were made of dendritic polyglycerol (dPG) and poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)), as polymer conferring thermoresponsive properties. Although the tNGs were taken up, they displayed neither cytotoxic and genotoxic effects nor any induction of reactive oxygen species in the tested cells. Interestingly, specific uptake mechanisms of the tNGs by the dendritic cells were depending on the nanogels cloud point temperature (Tcp), which determines the phase transition of the nanoparticle. The study points to caveolae-mediated endocytosis as being the major tNGs uptake mechanism at 37 degrees C, which is above the Tcp of the tNGs. Remarkably, an additional uptake mechanism, beside caveolae-mediated endocytosis, was observed at 29 degrees C, which is the Tcp of the tNGs. At this temperature, which is characterized by two different states of the tNGs, macropinocytosis was involved as well. In summary, our study highlights the impact of thermoresponsivity on the cellular uptake mechanisms which has to be taken into account if the tNGs are used as a drug delivery system.
KW  - Dendritic cells
KW  - Drug delivery systems
KW  - Nanogel
KW  - Nanoparticle
KW  - Nanoparticle uptake
KW  - Nanotoxicology
Y1  - 2017
U6  - https://doi.org/10.1016/j.ejpb.2016.12.016
SN  - 0939-6411
SN  - 1873-3441
VL  - 116
SP  - 155
EP  - 163
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Zhang, Nan
A1  - Said, Andre
A1  - Wischke, Christian
A1  - Kral, Vivian
A1  - Brodwolf, Robert
A1  - Volz, Pierre
A1  - Boreham, Alexander
A1  - Gerecke, Christian
A1  - Li, Wenzhong
A1  - Neffe, Axel T.
A1  - Kleuser, Burkhard
A1  - Alexiev, Ulrike
A1  - Lendlein, Andreas
A1  - Schäfer-Korting, Monika
T1  - Poly[acrylonitrile-co-(N-vinyl pyrrolidone)] nanoparticles - Composition-dependent skin penetration enhancement of a dye probe and biocompatibility
JF  - European Journal of Pharmaceutics and Biopharmaceutics
N2  - Nanoparticles can improve topical drug delivery: size, surface properties and flexibility of polymer nanoparticles are defining its interaction with the skin. Only few studies have explored skin penetration for one series of structurally related polymer particles with systematic alteration of material composition. Here, a series of rigid poly[acrylonitrile-co-(N-vinyl pyrrolidone)] model nanoparticles stably loaded with Nile Red or Rhodamin B, respectively, was comprehensively studied for biocompatibility and functionality. Surface properties were altered by varying the molar content of hydrophilic NVP from 0 to 24.1% and particle size ranged from 35 to 244 nm. Whereas irritancy and genotoxicity were not revealed, lipophilic and hydrophilic nanoparticles taken up by keratinocytes affected cell viability. Skin absorption of the particles into viable skin ex vivo was studied using Nile Red as fluorescent probe. Whilst an intact stratum corneum efficiently prevented penetration, almost complete removal of the horny layer allowed nanoparticles of smaller size and hydrophilic particles to penetrate into viable epidermis and dermis. Hence, systematic variations of nanoparticle properties allows gaining insights into critical criteria for biocompatibility and functionality of novel nanocarriers for topical drug delivery and risks associated with environmental exposure.
KW  - Biocompatibility testing
KW  - Drug delivery systems
KW  - Nanoparticle
KW  - Poly[acrylonitrile-co-(N-vinyl pyrrolidone)]
KW  - Polymers
KW  - Skin absorption
Y1  - 2017
U6  - https://doi.org/10.1016/j.ejpb.2016.10.019
SN  - 0939-6411
SN  - 1873-3441
VL  - 116
SP  - 66
EP  - 75
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Gerecke, Christian
A1  - Schumacher, Fabian
A1  - Berndzen, Alide
A1  - Homann, Thomas
A1  - Kleuser, Burkhard
T1  - Vitamin C in combination with inhibition of mutant IDH1 synergistically activates TET enzymes and epigenetically modulates gene silencing in colon cancer cells
JF  - Epigenetics : the official journal of the DNA Methylation Society
N2  - Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) lead to metabolic alterations and a sustained formation of 2-hydroxyglutarate (2-HG). 2-HG is an oncometabolite as it inhibits the activity of alpha-ketoglutarate-dependent dioxygenases such as ten-eleven translocation (TET) enzymes. Inhibitors of mutant IDH enzymes, like ML309, are currently tested in order to lower the levels of 2-HG. Vitamin C (VC) is an inducer of TET enzymes. To test a new therapeutic avenue of synergistic effects, the anti-neoplastic activity of inhibition of mutant IDH1 via ML309 in the presence of VC was investigated in the colon cancer cell line HCT116 IDH1(R132H/+) (harbouring a mutated IDH1 allele) and the parental cells HCT116 IDH1(+/+) (wild type IDH1). Measurement of the oncometabolite indicated a 56-fold higher content of 2-HG in mutated cells compared to wild type cells. A significant reduction of 2-HG was observed in mutated cells after treatment with ML 309, whereas VC produced only minimally changes of the oncometabolite. However, combinatorial treatment with both, ML309 and VC, in mutated cells induced pronounced reduction of 2-HG leading to levels comparable to those in wild type cells. The decreased level of 2-HG in mutated cells after combinatorial treatment was accompanied by an enhanced global DNA hydroxymethylation and an increased gene expression of certain tumour suppressors. Moreover, mutated cells showed an increased percentage of apoptotic cells after treatment with non-cytotoxic concentrations of ML309 and VC. These results suggest that combinatorial therapy is of interest for further investigation to rescue TET activity and treatment of IDH1/2 mutated cancers.
KW  - Vitamin C
KW  - epigenetics
KW  - IDH1
KW  - TET
KW  - cancer cells
Y1  - 2019
U6  - https://doi.org/10.1080/15592294.2019.1666652
SN  - 1559-2294
SN  - 1559-2308
VL  - 15
IS  - 3
SP  - 307
EP  - 322
PB  - Taylor & Francis Group
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Sahle, Fitsum Feleke
A1  - Balzus, Benjamin
A1  - Gerecke, Christian
A1  - Kleuser, Burkhard
A1  - Bodmeier, Roland
T1  - Formulation and in vitro evaluation of polymeric enteric nanoparticles as dermal carriers with pH-dependent targeting potential
JF  - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, EUFEPS
N2  - pH-sensitive nanoparticles which release in a controlled fashion on the skin or dissolve in the hair follicle could significantly improve treatment effectiveness and make transfollicular drug delivery a success. Dexamethasone-loaded Eudragit L 100 nanoparticles were prepared by nanoprecipitation from an organic drug-polymer solution. Their toxicity potential was assessed using isolated human fibroblasts. pH-dependent swelling and erosion kinetics of the nanoparticles were investigated by dynamic light scattering and viscosity measurements and its effect on drug release was assessed in vitro with Franz diffusion cells. Stable, 100-550 nm-sized dexamethasone-loaded Eudragit L 100 nanoparticles with drug loading capacity and entrapment efficiency as high as 83% and 85%, respectively, were obtained by using polyvinyl alcohol as a stabilizer and ethanol as organic solvent The nanoparticles showed little or no toxicity on isolated normal human fibroblasts. Dexamethasone existed in the nanoparticles as solid solution or in amorphous form. The nanoparticles underwent extensive swelling and slow drug release in media with a low buffer capacity (as low as 10 mM) and a higher pH or at a pH close to the dissolution pH of the polymer (pH 6) and a higher buffer capacity. In 40 mM buffer and above pH 6.8, the nanoparticles eroded fast or dissolved completely and thus released the drug rapidly. pH-sensitive nanoparticles which potentially release in a controlled manner on the stratum corneum but dissolve in the hair follicle could be prepared. (C) 2016 Elsevier B.V. All rights reserved.
KW  - Dexamethasone
KW  - Enteric polymer
KW  - Eudragit L 100
KW  - pH-sensitive nanoparticles
KW  - Skin nanocarrier
KW  - Erosion kinetics
Y1  - 2016
U6  - https://doi.org/10.1016/j.ejps.2016.07.004
SN  - 0928-0987
SN  - 1879-0720
VL  - 92
SP  - 98
EP  - 109
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Ahlberg, Sebastian
A1  - Rancan, Fiorenza
A1  - Epple, Matthias
A1  - Loza, Kateryna
A1  - Höppe, David
A1  - Lademann, Jürgen
A1  - Vogt, Annika
A1  - Kleuser, Burkhard
A1  - Gerecke, Christian
A1  - Meinke, Martina C.
T1  - Comparison of different methods to study effects of silver nanoparticles on the pro- and antioxidant status of human keratinocytes and fibroblasts
JF  - Methods : focusing on rapidly developing techniques
KW  - Oxidative stress
KW  - Dichlorofluorescein assay
KW  - Electron paramagnetic resonance spectroscopy
KW  - HaCaT cells
KW  - Glutathione
KW  - Free radicals
Y1  - 2016
U6  - https://doi.org/10.1016/j.ymeth.2016.05.015
SN  - 1046-2023
SN  - 1095-9130
VL  - 109
SP  - 55
EP  - 63
PB  - Elsevier
CY  - San Diego
ER  - 
TY  - JOUR
A1  - Hönzke, Stefan
A1  - Gerecke, Christian
A1  - Elpelt, Anja
A1  - Zhang, Nan
A1  - Unbehauen, Michael
A1  - Kral, Vivian
A1  - Fleige, Emanuel
A1  - Paulus, Florian
A1  - Haag, Rainer
A1  - Schäfer-Korting, Monika
A1  - Kleuser, Burkhard
A1  - Hedtrich, Sarah
T1  - Tailored dendritic core-multishell nanocarriers for efficient dermal drug delivery: A systematic top-down approach from synthesis to preclinical testing
JF  - Journal of controlled release
N2  - Drug loaded dendritic core-multishell (CMS) nanocarriers are of especial interest for the treatment of skin diseases, owing to their striking dermal delivery efficiencies following topical applications. CMS nanocarriers are composed of a polyglycerol core, connected by amide-bonds to an inner alkyl shell and an outer methoxy poly(ethylene glycol) shell. Since topically applied nanocarriers are subjected to biodegradation, the application of conventional amide-based CMS nanocarriers (10-A-18-350) has been limited by the potential production of toxic polyglycerol amines. To circumvent this issue, three tailored ester-based CMS nanocarriers (10-E-12-350, 10-E-15-350, 10-E-18-350) of varying inner alkyl chain length were synthesized and comprehensively characterized in terms of particle size, drug loading, biodegradation and dermal drug delivery efficiency. Dexamethasone (DXM), a potent drug widely used for the treatment of inflammatory skin diseases, was chosen as a therapeutically relevant test compound for the present study. Ester-and amide-based CMS nanocarriers delivered DXM more efficiently into human skin than a commercially available DXM cream. Subsequent in vitro and in vivo toxicity studies identified CMS (10-E-15-350) as the most biocompatible carrier system. The anti-inflammatory potency of DXM-loaded CMS (10-E-15-350) nanocarriers was assessed in TNF alpha supplemented skin models, where a significant reduction of the pro-inflammatory cytokine IL-8 was seen, with markedly greater efficacy than commercial DXM cream. In summary, we report the rational design and characterization of tailored, biodegradable, ester-based CMS nanocarriers, and their subsequent stepwise screening for biocompatibility, dermal delivery efficiency and therapeutic efficacy in a top-down approach yielding the best carrier system for topical applications. (C) 2016 Elsevier B.V. All rights reserved.
KW  - Dendritic core-multishell nanocarriers
KW  - Biocompatibility
KW  - Dexamethasone
KW  - Inflammatory skin disease
KW  - Dermal drug delivery
KW  - Skin model
Y1  - 2016
U6  - https://doi.org/10.1016/j.jconrel.2016.06.030
SN  - 0168-3659
SN  - 1873-4995
VL  - 242
SP  - 50
EP  - 63
PB  - Elsevier
CY  - Amsterdam
ER  -