TY  - JOUR
A1  - Hönzke, Stefan
A1  - Gerecke, Christian
A1  - Elpelt, Anja
A1  - Zhang, Nan
A1  - Unbehauen, Michael
A1  - Kral, Vivian
A1  - Fleige, Emanuel
A1  - Paulus, Florian
A1  - Haag, Rainer
A1  - Schäfer-Korting, Monika
A1  - Kleuser, Burkhard
A1  - Hedtrich, Sarah
T1  - Tailored dendritic core-multishell nanocarriers for efficient dermal drug delivery: A systematic top-down approach from synthesis to preclinical testing
JF  - Journal of controlled release
N2  - 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.
KW  - Dendritic core-multishell nanocarriers
KW  - Biocompatibility
KW  - Dexamethasone
KW  - Inflammatory skin disease
KW  - Dermal drug delivery
KW  - Skin model
Y1  - 2016
U6  - https://doi.org/10.1016/j.jconrel.2016.06.030
SN  - 0168-3659
SN  - 1873-4995
VL  - 242
SP  - 50
EP  - 63
PB  - Elsevier
CY  - Amsterdam
ER  -