SFB 1112 Publication Highlight: Giulbudagian et al., Theranostics: Breaking the barrier ...

News vom 30.11.2017


Giulbudagian M, Yealland G, Hönzke S, Edlich A, Geisendörfer B, Kleuser B, Hedtrich S, Calderón M:



Breaking the barrier - Potent anti-inflammatory activity following efficient topical delivery of etanercept using thermoresponsive nanogels


Theranostics 2018; 8(2):450-463 DOI 10.7150/thno.21668

Frontcover-Highlight Theranostics 2018:8(2)

Abstract

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; TNFα 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-TNFα fusion protein etanercept (ETR) (~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.


Conclusions

This proof-of-concept study holds major implications for tNG production as well as high throughput protein encapsulation strategies. Potentially, the herein presented methodology could be adapted for the fabrication of tNGs from a library of various thermoresponsive polymers. To the best of our knowledge, it is also the first strategy to show local anti-inflammatory activity within skin following topical protein application. Compared to systemic routes, topical administration of proteinaceous biologicals could prove advantageous in several regards: improved therapeutic targeting against dermatological conditions, reductions in off target effects and reductions in the therapeutic doses required of these costly therapies.

Source: http://www.thno.org/v08p0450.htm (30.11.2017)

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