TY - GEN A1 - Giulbudagian, Michael A1 - Yealland, Guy A1 - Hönzke, Stefan A1 - Edlich, Alexander A1 - Geisendörfer, Birte A1 - Kleuser, Burkhard A1 - Hedtrich, Sarah A1 - Calderón, Marcelo T1 - Breaking the barrier BT - potent anti-inflammatory activity following efficient topical delivery of etanercept using thermoresponsive nanogels T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Topical administration permits targeted, sustained delivery of therapeutics to human skin. Delivery to the skin, however, is typically limited to lipophilic molecules with molecular weight of < 500 Da, capable of crossing the stratum corneum. Nevertheless, there are indications protein delivery may be possible in barrier deficient skin, a condition found in several inflammatory skin diseases such as psoriasis, using novel nanocarrier systems. Methods: Water in water thermo-nanoprecipitation; dynamic light scattering; zeta potential measurement; nanoparticle tracking analysis; atomic force microscopy; cryogenic transmission electron microscopy; UV absorption; centrifugal separation membranes; bicinchoninic acid assay; circular dichroism; TNF alpha binding ELISA; inflammatory skin equivalent construction; human skin biopsies; immunohistochemistry; fluorescence microscopy; western blot; monocyte derived Langerhans cells; ELISA Results: Here, we report the novel synthesis of thermoresponsive nanogels (tNG) and the stable encapsulation of the anti-TNFa fusion protein etanercept (ETR) (similar to 150 kDa) without alteration to its structure, as well as temperature triggered release from the tNGs. Novel tNG synthesis without the use of organic solvents was conducted, permitting in situ encapsulation of protein during assembly, something that holds great promise for easy manufacture and storage. Topical application of ETR loaded tNGs to inflammatory skin equivalents or tape striped human skin resulted in efficient ETR delivery throughout the SC and into the viable epidermis that correlated with clear anti-inflammatory effects. Notably, effective ETR delivery depended on temperature triggered release following topical application. Conclusion: Together these results indicate tNGs hold promise as a biocompatible and easy to manufacture vehicle for stable protein encapsulation and topical delivery into barrier-deficient skin. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1030 KW - thermoresponsive-nanogel KW - topical KW - anti-inflammatory therapy KW - etanercept KW - skin equivalents Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-459301 SN - 1866-8372 IS - 1030 SP - 450 EP - 463 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 - THES A1 - Edlich, Alexander T1 - Interaktionen zwischen Nanotransportern und antigenpräsentierenden Zellen der Haut Y1 - 2018 ER -