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
T2  - 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
UR  - https://publishup.uni-potsdam.de/frontdoor/index/index/docId/49733
SN  - 0168-3659
SN  - 1873-4995
VL  - 299
SP  - 138
EP  - 148
PB  - Elsevier
CY  - Amsterdam
ER  -