TY - JOUR A1 - Radbruch, Moritz A1 - Pischon, Hannah A1 - Ostrowski, Anja A1 - Volz, Pierre A1 - Brodwolf, Robert A1 - Neumann, Falko A1 - Unbehauen, Michael A1 - Kleuser, Burkhard A1 - Haag, Rainer A1 - Ma, Nan A1 - Alexiev, Ulrike A1 - Mundhenk, Lars A1 - Gruber, Achim D. T1 - Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin JF - Nanoscale Research Letters N2 - 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. KW - CMS KW - Skin KW - Topical treatment KW - Dermal delivery KW - Atopic dermatitis KW - Oxazolone KW - Fluorescence lifetime imaging microscopy KW - Nanomaterials KW - Multi-domain nanoparticles KW - Penetration enhancement Y1 - 2017 U6 - https://doi.org/10.1186/s11671-017-1835-0 SN - 1556-276X VL - 12 IS - 64 PB - Springer CY - New York ER - TY - JOUR A1 - Edlich, Alexander A1 - Volz, Pierre A1 - Brodwolf, Robert A1 - Unbehauen, Michael A1 - Mundhenk, Lars A1 - Gruber, Achim D. A1 - Hedtrich, Sarah A1 - Haag, Rainer A1 - Alexiev, Ulrike A1 - Kleuser, Burkhard T1 - Crosstalk between core-multishell nanocarriers for cutaneous drug delivery and antigen-presenting cells of the skin JF - Biomaterials : biomaterials reviews online N2 - 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. KW - Core-multishell nanocarriers KW - Fluorescence lifetime imaging microscopy KW - Langerhans cells KW - Nanoparticle uptake KW - Nanotoxicology Y1 - 2018 U6 - https://doi.org/10.1016/j.biomaterials.2018.01.058 SN - 0142-9612 SN - 1878-5905 VL - 162 SP - 60 EP - 70 PB - Elsevier CY - Oxford ER - TY - GEN A1 - Radbruch, Moritz A1 - Pischon, Hannah A1 - Ostrowski, Anja A1 - Volz, Pierre A1 - Brodwolf, Robert A1 - Neumann, Falko A1 - Unbehauen, Michael A1 - Kleuser, Burkhard A1 - Haag, Rainer A1 - Ma, Nan A1 - Alexiev, Ulrike A1 - Mundhenk, Lars A1 - Gruber, Achim D. T1 - Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin T2 - Postprints der Universität Potsdam Mathematisch-Naturwissenschaftliche Reihe N2 - 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. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 724 KW - CMS KW - skin KW - topical treatment KW - dermal delivery KW - atopic dermatitis KW - oxazolone KW - fluorescence lifetime imaging microscopy KW - nanomaterials KW - multi-domain nanoparticles KW - penetration enhancement Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-430136 SN - 1866-8372 IS - 724 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 - Frombach, Janna A1 - Unbehauen, Michael A1 - Kurniasih, Indah N. A1 - Schumacher, Fabian A1 - Volz, Pierre A1 - Hadam, Sabrina A1 - Rancan, Fiorenza A1 - Blume-Peytavi, Ulrike A1 - Kleuser, Burkhard A1 - Haag, Rainer A1 - Alexiev, Ulrike A1 - Vogt, Annika T1 - Core-multishell nanocarriers enhance drug penetration and reach keratinocytes and antigen-presenting cells in intact human skin JF - Journal of controlled release N2 - 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. KW - Drug delivery KW - Skin penetration KW - Cellular uptake KW - Nanoparticles KW - Dendritic cells KW - High resolution microscopy Y1 - 2019 U6 - https://doi.org/10.1016/j.jconrel.2019.02.028 SN - 0168-3659 SN - 1873-4995 VL - 299 SP - 138 EP - 148 PB - Elsevier CY - Amsterdam ER -