@article{ZhouPanZhangetal.2020, author = {Zhou, Suqiong and Pan, Yuanwei and Zhang, Jianguang and Li, Yan and Neumann, Falko and Schwerdtle, Tanja and Li, Wenzhong and Haag, Rainer}, title = {Dendritic polyglycerol-conjugated gold nanostars with different densities of functional groups to regulate osteogenesis in human mesenchymal stem cells}, series = {Nanoscale}, volume = {12}, journal = {Nanoscale}, number = {47}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {2040-3364}, doi = {10.1039/d0nr06570f}, pages = {24006 -- 24019}, year = {2020}, abstract = {Nanomaterials play an important role in mimicking the biochemical and biophysical cues of the extracellular matrix in human mesenchymal stem cells (MSCs). Increasing studies have demonstrated the crucial impact of functional groups on MSCs, while limited research is available on how the functional group's density on nanoparticles regulates MSC behavior. Herein, the effects of dendritic polyglycerol (dPG)-conjugated gold nanostars (GNSs) with different densities of functional groups on the osteogenesis of MSCs are systematically investigated. dPG@GNS nanocomposites have good biocompatibility and the uptake by MSCs is in a functional group density-dependent manner. The osteogenic differentiation of MSCs is promoted by all dPG@GNS nanocomposites, in terms of alkaline phosphatase activity, calcium deposition, and expression of osteogenic protein and genes. Interestingly, the dPGOH@GNSs exhibit a slight upregulation in the expression of osteogenic markers, while the different charged densities of sulfate and amino groups show more efficacy in the promotion of osteogenesis. Meanwhile, the sulfated nanostars dPGS20@GNSs show the highest enhancement. Furthermore, various dPG@GNS nanocomposites exerted their effects by regulating the activation of Yes-associated protein (YAP) to affect osteogenic differentiation. These results indicate that dPG@GNS nanocomposites have functional group density-dependent influence on the osteogenesis of MSCs, which may provide a new insight into regulating stem cell fate.}, language = {en} } @article{RadbruchPischonOstrowskietal.2017, author = {Radbruch, Moritz and Pischon, Hannah and Ostrowski, Anja and Volz, Pierre and Brodwolf, Robert and Neumann, Falko and Unbehauen, Michael and Kleuser, Burkhard and Haag, Rainer and Ma, Nan and Alexiev, Ulrike and Mundhenk, Lars and Gruber, Achim D.}, title = {Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin}, series = {Nanoscale Research Letters}, volume = {12}, journal = {Nanoscale Research Letters}, number = {64}, publisher = {Springer}, address = {New York}, issn = {1556-276X}, doi = {10.1186/s11671-017-1835-0}, pages = {12}, year = {2017}, abstract = {Dendritic hPG-amid-C18-mPEG core-multishell nanocarriers (CMS) represent a novel class of unimolecular micelles that hold great potential as drug transporters, e. g., to facilitate topical therapy in skin diseases. Atopic dermatitis is among the most common inflammatory skin disorders with complex barrier alterations which may affect the efficacy of topical treatment. Here, we tested the penetration behavior and identified target structures of unloaded CMS after topical administration in healthy mice and in mice with oxazolone-induced atopic dermatitis. We further examined whole body distribution and possible systemic side effects after simulating high dosage dermal penetration by subcutaneous injection. Following topical administration, CMS accumulated in the stratum corneum without penetration into deeper viable epidermal layers. The same was observed in atopic dermatitis mice, indicating that barrier alterations in atopic dermatitis had no influence on the penetration of CMS. Following subcutaneous injection, CMS were deposited in the regional lymph nodes as well as in liver, spleen, lung, and kidney. However, in vitro toxicity tests, clinical data, and morphometry-assisted histopathological analyses yielded no evidence of any toxic or otherwise adverse local or systemic effects of CMS, nor did they affect the severity or course of atopic dermatitis. Taken together, CMS accumulate in the stratum corneum in both healthy and inflammatory skin and appear to be highly biocompatible in the mouse even under conditions of atopic dermatitis and thus could potentially serve to create a depot for anti-inflammatory drugs in the skin.}, language = {en} } @article{EdlichVolzBrodwolfetal.2018, author = {Edlich, Alexander and Volz, Pierre and Brodwolf, Robert and Unbehauen, Michael and Mundhenk, Lars and Gruber, Achim D. and Hedtrich, Sarah and Haag, Rainer and Alexiev, Ulrike and Kleuser, Burkhard}, title = {Crosstalk between core-multishell nanocarriers for cutaneous drug delivery and antigen-presenting cells of the skin}, series = {Biomaterials : biomaterials reviews online}, volume = {162}, journal = {Biomaterials : biomaterials reviews online}, publisher = {Elsevier}, address = {Oxford}, issn = {0142-9612}, doi = {10.1016/j.biomaterials.2018.01.058}, pages = {60 -- 70}, year = {2018}, abstract = {Owing their unique chemical and physical properties core-multishell (CMS) nanocarriers are thought to underlie their exploitable biomedical use for a topical treatment of skin diseases. This highlights the need to consider not only the efficacy of CMS nanocarriers but also the potentially unpredictable and adverse consequences of their exposure thereto. As CMS nanocarriers are able to penetrate into viable layers of normal and stripped human skin ex vivo as well as in in vitro skin disease models the understanding of nanoparticle crosstalk with components of the immune system requires thorough investigation. Our studies highlight the biocompatible properties of CMS nanocarriers on Langerhans cells of the skin as they did neither induce cytotoxicity and genotoxicity nor cause reactive oxygen species (ROS) or an immunological response. Nevertheless, CMS nanocarriers were efficiently taken up by Langerhans cells via divergent endocytic pathways. Bioimaging of CMS nanocarriers by fluorescence lifetime imaging microscopy (FLIM) and flow cytometry indicated not only a localization within the lysosomes but also an energy-dependent exocytosis of unmodified CMS nanocarriers into the extracellular environment. (C) 2018 Elsevier Ltd. All rights reserved.}, language = {en} } @article{LiSchlaichKulkaetal.2019, author = {Li, Mingjun and Schlaich, Christoph and Kulka, Michael Willem and Donskyi, Ievgen S. and Schwerdtle, Tanja and Unger, Wolfgang E. S. and Haag, Rainer}, title = {Mussel-inspired coatings with tunable wettability, for enhanced antibacterial efficiency and reduced bacterial adhesion}, series = {Journal of materials chemistry : B, Materials for biology and medicine}, volume = {7}, journal = {Journal of materials chemistry : B, Materials for biology and medicine}, number = {21}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {2050-750X}, doi = {10.1039/c9tb00534j}, pages = {3438 -- 3445}, year = {2019}, abstract = {Over the last few decades, there has been a tremendous increase in research on antibacterial surface coatings as an alternative strategy against bacterial infections. Although there are several examples of effective strategies to prevent bacterial adhesion, the effect of the wetting properties on the coating was rarely considered as a crucial factor. Here we report an in-depth study on the effect of extreme wettability on the antibacterial efficiency of a silver nanoparticles ( AgNPs)-based coating. By controlling surface polymerization of mussel-inspired dendritic polyglycerol ( MI-dPG) and post-functionalization, surfaces with wetting properties ranging from superhydrophilic to superhydrophobic were fabricated. Subsequently, AgNPs were embedded into the coatings by applying in situ reduction using the free catechols-moieties present in the MI-dPG coating. The resulting polymer coatings exhibited excellent antibacterial ability against planktonic Escherichia coli ( E. coli) DH5a and Staphylococcus aureus ( S. aureus) SH1000. The antibacterial efficiency of the coatings was analyzed by using inductively coupled plasma mass spectrometry ( ICP-MS) and bacterial viability tests. Furthermore, the antifouling properties of the coatings in relation to the antibacterial properties were evaluated.}, language = {en} } @article{DeyAdamovskiFriebeetal.2014, author = {Dey, Pradip and Adamovski, Miriam and Friebe, Simon and Badalyan, Artavazd and Mutihac, Radu-Cristian and Paulus, Florian and Leimk{\"u}hler, Silke and Wollenberger, Ursula and Haag, Rainer}, title = {Dendritic polyglycerol-poly(ethylene glycol)-based polymer networks for biosensing application}, series = {ACS applied materials \& interfaces}, volume = {6}, journal = {ACS applied materials \& interfaces}, number = {12}, publisher = {American Chemical Society}, address = {Washington}, issn = {1944-8244}, doi = {10.1021/am502018x}, pages = {8937 -- 8941}, year = {2014}, abstract = {This work describes the formation of a new dendritic polyglycerol-poly(ethylene glycol)-based 3D polymer network as a matrix for immobilization of the redox enzyme periplasmatic aldehyde oxidoreductase to create an electrochemical biosensor. The novel network is built directly on the gold surface, where it simultaneously stabilizes the enzyme for up to 4 days. The prepared biosensors can be used for amperometric detection of benzaldehyde in the range of 0.8-400 mu M.}, language = {en} } @inproceedings{FrombachRancanFleigeetal.2015, author = {Frombach, Janna and Rancan, Fiorenza and Fleige, Emanuel and Haag, Rainer and Schumacher, Frank and Kleuser, Burkhard and Yamamoto, Kenji and R{\"u}hl, Eckart and Blume-Peytavi, Ulrike and Vogt, Annika}, title = {Skin penetration and dexamethasone release from polymer nanoparticles in ex vivo human skin}, series = {The journal of investigative dermatology}, volume = {135}, booktitle = {The journal of investigative dermatology}, publisher = {Nature Publ. Group}, address = {New York}, issn = {0022-202X}, pages = {S52 -- S52}, year = {2015}, language = {en} } @article{HoenzkeGereckeElpeltetal.2016, author = {H{\"o}nzke, Stefan and Gerecke, Christian and Elpelt, Anja and Zhang, Nan and Unbehauen, Michael and Kral, Vivian and Fleige, Emanuel and Paulus, Florian and Haag, Rainer and Sch{\"a}fer-Korting, Monika and Kleuser, Burkhard and Hedtrich, Sarah}, title = {Tailored dendritic core-multishell nanocarriers for efficient dermal drug delivery: A systematic top-down approach from synthesis to preclinical testing}, series = {Journal of controlled release}, volume = {242}, journal = {Journal of controlled release}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0168-3659}, doi = {10.1016/j.jconrel.2016.06.030}, pages = {50 -- 63}, year = {2016}, abstract = {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.}, language = {en} } @misc{RadbruchPischonOstrowskietal.2017, author = {Radbruch, Moritz and Pischon, Hannah and Ostrowski, Anja and Volz, Pierre and Brodwolf, Robert and Neumann, Falko and Unbehauen, Michael and Kleuser, Burkhard and Haag, Rainer and Ma, Nan and Alexiev, Ulrike and Mundhenk, Lars and Gruber, Achim D.}, title = {Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin}, series = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe}, number = {724}, issn = {1866-8372}, doi = {10.25932/publishup-43013}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-430136}, pages = {12}, year = {2017}, abstract = {Dendritic hPG-amid-C18-mPEG core-multishell nanocarriers (CMS) represent a novel class of unimolecular micelles that hold great potential as drug transporters, e. g., to facilitate topical therapy in skin diseases. Atopic dermatitis is among the most common inflammatory skin disorders with complex barrier alterations which may affect the efficacy of topical treatment. Here, we tested the penetration behavior and identified target structures of unloaded CMS after topical administration in healthy mice and in mice with oxazolone-induced atopic dermatitis. We further examined whole body distribution and possible systemic side effects after simulating high dosage dermal penetration by subcutaneous injection. Following topical administration, CMS accumulated in the stratum corneum without penetration into deeper viable epidermal layers. The same was observed in atopic dermatitis mice, indicating that barrier alterations in atopic dermatitis had no influence on the penetration of CMS. Following subcutaneous injection, CMS were deposited in the regional lymph nodes as well as in liver, spleen, lung, and kidney. However, in vitro toxicity tests, clinical data, and morphometry-assisted histopathological analyses yielded no evidence of any toxic or otherwise adverse local or systemic effects of CMS, nor did they affect the severity or course of atopic dermatitis. Taken together, CMS accumulate in the stratum corneum in both healthy and inflammatory skin and appear to be highly biocompatible in the mouse even under conditions of atopic dermatitis and thus could potentially serve to create a depot for anti-inflammatory drugs in the skin.}, language = {en} } @article{LiGaoSchlaichetal.2017, author = {Li, Mingjun and Gao, Lingyan and Schlaich, Christoph and Zhang, Jianguang and Donskyi, Ievgen S. and Yu, Guozhi and Li, Wenzhong and Tu, Zhaoxu and Rolff, Jens and Schwerdtle, Tanja and Haag, Rainer and Ma, Nan}, title = {Construction of Functional Coatings with Durable and Broad-Spectrum Antibacterial Potential Based on Mussel-Inspired Dendritic Polyglycerol and in Situ-Formed Copper Nanoparticles}, series = {ACS applied materials \& interfaces}, volume = {9}, journal = {ACS applied materials \& interfaces}, publisher = {American Chemical Society}, address = {Washington}, issn = {1944-8244}, doi = {10.1021/acsami.7b10541}, pages = {35411 -- 35418}, year = {2017}, abstract = {A novel surface coating with durable broad-spectrum antibacterial ability was prepared based on mussel inspired dendritic polyglycerol (MI-dPG) embedded with copper nanoparticles (Cu NPs). The functional surface coating is fabricated via a facile dip-coating process followed by in situ reduction of copper ions with a MI-dPG coating to introduce Cu NPs into the coating matrix. This coating has been demonstrated to possess efficient long-term antibacterial properties against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and kanamycin-resistant E. coli through an "attract-kill-release" strategy. The synergistic antibacterial activity of the coating was shown by the combination of two functions of the contact killing, reactive oxygen species production and Cu ions released from the coating. Furthermore, this coating inhibited biofilm formation and showed good compatibility to eukaryotic cells. Thus, this newly developed Cu NP-incorporated MI-dPG surface coating may find potential application in the design of antimicrobial coating, such as implantable devices.}, language = {en} } @article{BastianYudeGuerenuKurganovaetal.2020, author = {Bastian, Philipp U. and Yu, Leixiao and de Guere{\~n}u Kurganova, Anna Lopez and Haag, Rainer and Kumke, Michael Uwe}, title = {Bioinspired confinement of upconversion nanoparticles for improved performance in aqueous solution}, series = {The journal of physical chemistry : C, Nanomaterials and interfaces}, volume = {124}, journal = {The journal of physical chemistry : C, Nanomaterials and interfaces}, number = {52}, publisher = {American Chemical Society}, address = {Washington, DC}, issn = {1932-7447}, doi = {10.1021/acs.jpcc.0c09798}, pages = {28623 -- 28635}, year = {2020}, abstract = {The resonance energy transfer (RET) from NaYF4:Yb,Er upconverting nanoparticles (UNCPs) to a dye (5-carboxytetramethylrhodamine (TAMRA)) was investigated by photoluminescence experiments and microscale thermophoresis (MST). The dye was excited via RET from the UCNPs which was excited in the near-infrared (NIR). The change of the dye diffusion speed (free vs coupled) was investigated by MST. RET shows significant changes in the decay times of the dye as well as of the UCNPs. MST reveals significant changes in the diffusion speed. A unique amphiphilic coating polymer (customized mussel protein (CMP) polymer) for UCNP surface coating was used, which mimics blood protein adsorption and mussel food protein adhesion to transfer the UCNP into the aqueous phase and to allow surface functionalization. The CMP provides very good water dispersibility to the UCNPs and minimizes ligand exchange and subsequent UCNP aging reactions because of the interlinkage of the CMP on the UCNP surface. Moreover, CMP provides N-3-functional groups for dick chemistry-based functionalization demonstrated with the dye 5-carboxytetramethylrhodamine (TAMRA). This establishes the principle coupling scheme for suitable biomarkers such as antibodies. The CMP provides very stable aqueous UCNP dispersions that are storable up to 3 years in a fridge at 5 degrees C without dissolution or coagulation. The outstanding properties of CMP in shielding the UCNP from unwanted solvent effects is reflected in the distinct increase of the photoluminescence decay times after UCNP functionalization. The UCNP-to-TAMRA energy transfer is also spectroscopically investigated at low temperatures (4-200 K), revealing that one of the two green Er(III) emission bands contributes the major part to the energy transfer. The TAMRA fluorescence decay time increases by a factor of 9500 from 2.28 ns up to 22 mu s due to radiationless energy transfer from the UCNP after NIR excitation of the latter. This underlines the unique properties of CMP as a versatile capping ligand for distinctly improving the UCNPs' performance in aqueous solutions, for coupling of biomolecules, and for applications for in vitro and in vivo experiments using UCNPs as optical probes in life science applications.}, language = {en} } @article{LuoUtechtDokicetal.2011, author = {Luo, Ying and Utecht, Manuel Martin and Dokic, Jadranka and Korchak, Sergey and Vieth, Hans-Martin and Haag, Rainer and Saalfrank, Peter}, title = {Cis-trans isomerisation of substituted aromatic imines a comparative experimental and theoretical study}, series = {ChemPhysChem : a European journal of chemical physics and physical chemistry}, volume = {12}, journal = {ChemPhysChem : a European journal of chemical physics and physical chemistry}, number = {12}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1439-4235}, doi = {10.1002/cphc.201100179}, pages = {2311 -- 2321}, year = {2011}, abstract = {The cis-trans isomerisation of N-benzylideneaniline (NBA) and derivatives containing a central C=N bond has been investigated experimentally and theoretically. Eight different NBA molecules in three different solvents were irradiated to enforce a photochemical trans (hv) -> cis isomerisation and the kinetics of the thermal backreaction cis (Delta)-> trans were determined by NMR spectroscopy measurements in the temperature range between 193 and 288 K. Theoretical calculations using density functional theory and Eyring transition-state theory were carried out for 12 different NBA species in the gas phase and three different solvents to compute thermal isomerisation rates of the thermal back reaction. While the computed absolute rates are too large, they reveal and explain experimental trends. Time-dependent density functional theory provides optical spectra for vertical transitions and excitation energy differences between trans and cis forms. Together with isomerisation rates, the latter can be used to identify "optimal switches" with good photochromicity and reasonable thermal stability.}, language = {en} } @article{DeyBergmannCuellarCamachoetal.2018, author = {Dey, Pradip and Bergmann, Tobias and Cuellar-Camacho, Jose Luis and Ehrmann, Svenja and Chowdhury, Mohammad Suman and Zhang, Minze and Dahmani, Ismail and Haag, Rainer and Azad, Walid}, title = {Multivalent flexible nanogels exhibit broad-spectrum antiviral activity by blocking virus entry}, series = {ACS nano}, volume = {12}, journal = {ACS nano}, number = {7}, publisher = {American Chemical Society}, address = {Washington}, issn = {1936-0851}, doi = {10.1021/acsnano.8b01616}, pages = {6429 -- 6442}, year = {2018}, abstract = {The entry process of viruses into host cells is complex and involves stable but transient multivalent interactions with different cell surface receptors. The initial contact of several viruses begins with attachment to heparan sulfate (HS) proteoglycans on the cell surface, which results in a cascade of events that end up with virus entry. The development of antiviral agents based on multivalent interactions to shield virus particles and block initial interactions with cellular receptors has attracted attention in antiviral research. Here, we designed nanogels with different degrees of flexibility based on dendritic polyglycerol sulfate to mimic cellular HS. The designed nanogels are nontoxic and broad-spectrum, can multivalently interact with viral glycoproteins, shield virus surfaces, and efficiently block infection. We also visualized virus-nanogel interactions as well as the uptake of nanogels by the cells through clathrin-mediated endocytosis using confocal microscopy. As many human viruses attach to the cells through HS moieties, we introduce our flexible nanogels as robust inhibitors for these viruses.}, language = {en} } @article{NeffevonRuestenLangeBrauneetal.2014, author = {Neffe, Axel T. and von R{\"u}sten-Lange, Maik and Braune, Steffen and L{\"u}tzow, Karola and Roch, Toralf and Richau, Klaus and Kr{\"u}ger, Anne and Becherer, Tobias and Th{\"u}nemann, Andreas F. and Jung, Friedrich and Haag, Rainer and Lendlein, Andreas}, title = {Multivalent grafting of hyperbranched oligo- and polyglycerols shielding rough membranes to mediate hemocompatibility}, series = {Journal of materials chemistry : B, Materials for biology and medicine}, volume = {2}, journal = {Journal of materials chemistry : B, Materials for biology and medicine}, number = {23}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {2050-750X}, doi = {10.1039/c4tb00184b}, pages = {3626 -- 3635}, year = {2014}, abstract = {Hemocompatible materials are needed for internal and extracorporeal biomedical applications, which should be realizable by reducing protein and thrombocyte adhesion to such materials. Polyethers have been demonstrated to be highly efficient in this respect on smooth surfaces. Here, we investigate the grafting of oligo- and polyglycerols to rough poly(ether imide) membranes as a polymer relevant to biomedical applications and show the reduction of protein and thrombocyte adhesion as well as thrombocyte activation. It could be demonstrated that, by performing surface grafting with oligo-and polyglycerols of relatively high polydispersity (>1.5) and several reactive groups for surface anchoring, full surface shielding can be reached, which leads to reduced protein adsorption of albumin and fibrinogen. In addition, adherent thrombocytes were not activated. This could be clearly shown by immunostaining adherent proteins and analyzing the thrombocyte covered area. The presented work provides an important strategy for the development of application relevant hemocompatible 3D structured materials.}, language = {en} } @article{LangeBrauneLuetzowetal.2012, author = {Lange, Maik and Braune, Steffen and Luetzow, Karola and Richau, Klaus and Scharnagl, Nico and Weinhart, Marie and Neffe, Axel T. and Jung, Friedrich and Haag, Rainer and Lendlein, Andreas}, title = {Surface functionalization of poly(ether imide) membranes with linear, methylated oligoglycerols for reducing thrombogenicity}, series = {Macromolecular rapid communications}, volume = {33}, journal = {Macromolecular rapid communications}, number = {17}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1022-1336}, doi = {10.1002/marc.201200426}, pages = {1487 -- 1492}, year = {2012}, abstract = {Materials for biomedical applications are often chosen for their bulk properties. Other requirements such as a hemocompatible surface shall be fulfilled by suitable chemical functionalization. Here we show, that linear, side-chain methylated oligoglycerols (OGMe) are more stable to oxidation than oligo(ethylene glycol) (OEG). Poly(ether imide) (PEI) membranes functionalized with OGMes perform at least as good as, and partially better than, OEG functionalized PEI membranes in view of protein resistance as well as thrombocyte adhesion and activation. Therefore, OGMes are highly potent surface functionalizing molecules for improving the hemocompatibility of polymers.}, language = {en} } @misc{NeffevonRuestenLangeBrauneetal.2014, author = {Neffe, Axel T. and von R{\"u}sten-Lange, Maik and Braune, Steffen and L{\"u}tzow, Karola and Roch, Toralf and Richau, Klaus and Kr{\"u}ger, Anne and Becherer, Tobias and Th{\"u}nemann, Andreas F. and Jung, Friedrich and Haag, Rainer and Lendlein, Andreas}, title = {Multivalent grafting of hyperbranched oligo- and polyglycerols shielding rough membranes to mediate hemocompatibility}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-99444}, year = {2014}, abstract = {Hemocompatible materials are needed for internal and extracorporeal biomedical applications, which should be realizable by reducing protein and thrombocyte adhesion to such materials. Polyethers have been demonstrated to be highly efficient in this respect on smooth surfaces. Here, we investigate the grafting of oligo- and polyglycerols to rough poly(ether imide) membranes as a polymer relevant to biomedical applications and show the reduction of protein and thrombocyte adhesion as well as thrombocyte activation. It could be demonstrated that, by performing surface grafting with oligo- and polyglycerols of relatively high polydispersity (>1.5) and several reactive groups for surface anchoring, full surface shielding can be reached, which leads to reduced protein adsorption of albumin and fibrinogen. In addition, adherent thrombocytes were not activated. This could be clearly shown by immunostaining adherent proteins and analyzing the thrombocyte covered area. The presented work provides an important strategy for the development of application relevant hemocompatible 3D structured materials.}, language = {en} } @article{ZabihiGraffSchumacheretal.2018, author = {Zabihi, Fatemeh and Graff, Patrick and Schumacher, Fabian and Kleuser, Burkhard and Hedtrich, Sarah and Haag, Rainer}, title = {Synthesis of poly(lactide-co-glycerol) as a biodegradable and biocompatible polymer with high loading capacity for dermal drug delivery}, series = {Nanoscale}, volume = {10}, journal = {Nanoscale}, number = {35}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {2040-3364}, doi = {10.1039/c8nr05536j}, pages = {16848 -- 16856}, year = {2018}, abstract = {Due to the low cutaneous bioavailability of tacrolimus (TAC), penetration enhancers are used to improve its penetration into the skin. However, poor loading capacity, non-biodegradability, toxicity, and in some cases inefficient skin penetration are challenging issues that hamper their applications for the dermal TAC delivery. Here we present poly(lactide-co-glycerol) (PLG) as a water soluble, biodegradable, and biocompatible TAC-carrier with high loading capacity (14.5\% w/w for TAC) and high drug delivery efficiencies into the skin. PLG was synthesized by cationic ring-opening copolymerization of a mixture of glycidol and lactide and showed 35 nm and 300 nm average sizes in aqueous solutions before and after loading of TAC, respectively. Delivery experiments on human skin, quantified by fluorescence microscopy and LC-MS/MS, showed a high ability for PLG to deposit Nile red and TAC into the stratum corneum and viable epidermis of skin in comparison with Protopic (R) (0.03\% w/w, TAC ointment). The cutaneous distribution profile of delivered TAC proved that 80\%, 16\%, and 4\% of the cutaneous drug level was deposited in the stratum corneum, viable epidermis, and upper dermis, respectively. TAC delivered by PLG was able to efficiently decrease the IL-2 and TSLP expressions in human skin models. Taking advantage of the excellent physicochemical and biological properties of PLG, it can be used for efficient dermal TAC delivery and potential treatment of inflammatory skin diseases.}, language = {en} } @article{FrombachUnbehauenKurniasihetal.2019, author = {Frombach, Janna and Unbehauen, Michael and Kurniasih, Indah N. and Schumacher, Fabian and Volz, Pierre and Hadam, Sabrina and Rancan, Fiorenza and Blume-Peytavi, Ulrike and Kleuser, Burkhard and Haag, Rainer and Alexiev, Ulrike and Vogt, Annika}, title = {Core-multishell nanocarriers enhance drug penetration and reach keratinocytes and antigen-presenting cells in intact human skin}, series = {Journal of controlled release}, volume = {299}, journal = {Journal of controlled release}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0168-3659}, doi = {10.1016/j.jconrel.2019.02.028}, pages = {138 -- 148}, year = {2019}, abstract = {In reconstructed skin and diffusion cell studies, core-multishell nanocarriers (CMS-NC) showed great potential for drug delivery across the skin barrier. Herein, we investigated penetration, release of dexamethasone (DXM), in excised full-thickness human skin with special focus on hair follicles (HF). Four hours and 16 h after topical application of clinically relevant dosages of 10 mu g DXM/cm(2) skin encapsulated in CMS-NC (12 nm diameter, 5.8\% loading), presence of DXM in the tissue as assessed by fluorescence microscopy of anti-DXM-stained tissue sections as well as ELISA and HPLC-MS/MS in tissue extracts was enhanced compared to standard LAW-creme but lower compared to DXM aqueous/alcoholic solution. Such enhanced penetration compared to conventional cremes offers high potential for topical therapies, as recurrent applications of corticosteroid solutions face limitations with regard to tolerability and fast drainage. The findings encourage more detailed investigations on where and how the nanocarrier and drug dissociate within the skin and what other factors, e.g. thermodynamic activity, influence the penetration of this formulations. Microscopic studies on the spatial distribution within the skin revealed accumulation in HF and furrows accompanied by limited cellular uptake assessed by flow cytometry (up to 9\% of total epidermal cells). FLIM clearly visualized the presence of CMS-NC in the viable epidermis and dermis. When exposed in situ a fraction of up to 25\% CD1a(+) cells were found within the epidermal CMS-NC+ population compared to approximately 3\% CD1a(+)/CMS-NC+ cells after in vitro exposure in short-term cultures of epidermal cell suspensions. The latter reflects the natural percentage of Langerhans cells (LC) in epidermis suspensions and indicated that CMS-NC were not preferentially internalized by one cell type. The increased CMS-NC+ LC proportion after exposure within the tissue is in accordance with the strategic suprabasal LC-localization. More specifically we postulate that the extensive dendrite meshwork, their position around HF orifices and their capacity to modulate tight junctions facilitated a preferential uptake of CMS-NC by LC within the skin. This newly identified aspect of CMS-NC penetration underlines the potential of CMS-NC for dermatotherapy and encourages further investigations of CMS-NC for the delivery of other molecule classes for which intracellular delivery is even more crucial.}, language = {en} } @article{PanMaLiuetal.2021, author = {Pan, Yuanwei and Ma, Xuehua and Liu, Chuang and Xing, Jie and Zhou, Suqiong and Parshad, Badri and Schwerdtle, Tanja and Li, Wenzhong and Wu, Aiguo and Haag, Rainer}, title = {Retinoic acid-loaded dendritic polyglycerol-conjugated gold nanostars for targeted photothermal therapy in breast cancer stem cells}, series = {ACS nano}, volume = {15}, journal = {ACS nano}, number = {9}, publisher = {American Chemical Society}, address = {Washington}, issn = {1936-0851}, doi = {10.1021/acsnano.1c05452}, pages = {15069 -- 15084}, year = {2021}, abstract = {The existence of cancer stem cells (CSCs) poses a major obstacle for the success of current cancer therapies, especially the fact that non-CSCs can spontaneously turn into CSCs, which lead to the failure of the treatment and tumor relapse. Therefore, it is very important to develop effective strategies for the eradication of the CSCs. In this work, we have developed a CSCs-specific targeted, retinoic acid (RA)-loaded gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatform for the efficient eradication of CSCs. The nanocomposites possess good biocompatibility and exhibit effective CSCs-specific multivalent targeted capability due to hyaluronic acid (HA) decorated on the multiple attachment sites of the bioinert dendritic polyglycerol (dPG). With the help of CSCs differentiation induced by RA, the self-renewal of breast CSCs and tumor growth were suppressed by the high therapeutic efficacy of photothermal therapy (PTT) in a synergistic inhibitory manner. Moreover, the stemness gene expression and CSC-driven tumorsphere formation were significantly diminished. In addition, the in vivo tumor growth and CSCs were also effectively eliminated, which indicated superior anticancer activity, effective CSCs suppression, and prevention of relapse. Taken together, we developed a CSCs-specific targeted, RA-loaded GNSs-dPG nanoplatform for the targeted eradication of CSCs and for preventing the relapse.}, language = {en} }