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  - Radbruch, Moritz Jan Florian
A1  - Pischon, Jeanette Hannah Charlotte
A1  - Du, Fang
A1  - Haag, Rainer
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Mundhenk, Lars
A1  - Gruber, Achim
T1  - Biodegradable core-multishell nanocarrier: topical tacrolimus delivery for treatment of dermatitis
JF  - Journal of controlled release : official journal of the Controlled Release Society and of the Japanese Society of Drug Delivery Systems
N2  - Two challenges in topical drug delivery to the skin include solubilizing hydrophobic drugs in water-based formulations and increasing drug penetration into the skin. Polymeric core-multishell nanocarrier (CMS), particularly the novel biodegradable CMS (bCMS = hPG-PCL1.1K-mPEG(2k)-CMS) have shown both advantages on excised skin ex vivo. 
Here, we investigated topical delivery of tacrolimus (TAC; > 500 g/mol) by bCMS in a hydrogel on an oxazolone-induced model of dermatitis in vivo. As expected, bCMS successfully delivered TAC into the skin. 
However, in vivo they did not increase, but decrease TAC penetration through the stratum corneum compared to ointment. 
Differences in the resulting mean concentrations were mostly non-significant in the skin (epidermis: 35.7 +/- 20.9 ng/cm(2) for bCMS vs. 92.6 +/- 62.7 ng/cm(2) for ointment; dermis: 76.8 +/- 26.8 ng/cm(2) vs 118.2 +/- 50.4 ng/cm(2)), but highly significant in blood (plasma: 1.1 +/- 0.4 ng/ml vs 11.3 +/- 9.3 ng/ml; erythrocytes: 0.5 +/- 0.2 ng/ml vs 3.4 +/- 2.4 ng/ml) and liver (0.01 +/- 0.01 ng/mg vs 0.03 +/- 0.01 ng/mg). bCMS were detected in the stratum corneum but not in viable skin or beyond. 
The therapeutic efficacy of TAC delivered by bCMS was equivalent to that of standard TAC ointment. 
Our results suggest that bCMS may be a promising carrier for the topical delivery of TAC. The quantitative difference to previous results should be interpreted in light of structural differences between murine and human skin, but highlights the need as well as potential methods to develop more a complex ex vivo analysis on human skin to ensure quantitative predictive value.
KW  - drug delivery systems
KW  - core-multishell (CMS) nanocarriers
KW  - tacrolimus
KW  - topical drug delivery
KW  - dermal drug administration
KW  - penetration enhancement
Y1  - 2022
U6  - https://doi.org/10.1016/j.jconrel.2022.07.025
SN  - 0168-3659
SN  - 1873-4995
VL  - 349
SP  - 917
EP  - 928
PB  - Elsevier
CY  - New York, NY [u.a.]
ER  -