TY  - JOUR
A1  - Giulbudagian, Michael
A1  - Yealland, Guy
A1  - Hönzke, S.
A1  - Edlich, A.
A1  - Geisendörfer, Birte
A1  - Kleuser, Burkhard
A1  - Hedtrich, Sarah
A1  - Calderon, Marcelo
T1  - Breaking the Barrier
BT  - potent anti-inflammatory activity following efficient topical delivery of etanercept using thermoresponsive nanogels
JF  - Theranostics
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.
KW  - thermoresponsive-nanogel
KW  - topical
KW  - anti-inflammatory therapy
KW  - etanercept
KW  - skin equivalents
Y1  - 2018
U6  - https://doi.org/10.7150/thno.21668
SN  - 1838-7640
VL  - 8
IS  - 2
SP  - 450
EP  - 463
PB  - Ivyspring International Publisher
CY  - Lake haven
ER  -