@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} } @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{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{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{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{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{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{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{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} } @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} }