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Adaption of nanocarrier-based drug delivery systems to the redox-state and thiol gradients of healthy and diseased skin

Subject Area Biological and Biomimetic Chemistry
Dermatology
Organic Molecular Chemistry - Synthesis and Characterisation
Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
Term from 2018 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 407272851
 
Final Report Year 2022

Final Report Abstract

In conclusion, we addressed all objectives and scientific questions outlined in the proposal. The results in Subproject 1 have all been published and the new redox-sensitive nanocarriers are now available for further biological studies. In Subproject 2 we established an inflammatory experimental model based on excised human skin exposed to pro-inflammatory and pro-oxidative stimuli capable of inducing features also found in inflamed skin. The stimuli effectively altered the thiol content and distributions that are relevant for the investigation of penetration and drug-release by nanocarriers with reduction or oxidation-sensitive drug release properties. Among the candidate nanocarriers provided, oxidation-sensitive nanocarriers were found to exhibit superior penetration and drug delivery in inflamed skin. The biological efficacy of the loaded drug rapamycin was investigated on keratinocytes, fibroblasts, dendritic cells and co-cultured T cells. Because anti-proliferative effects on T cell populations provided the strongest readout, co-cultures with IL-2 as well as IL17A-producing T cell lines help generate highly sensitive quantitative read-outs both on the cytokine levels as well as with regard to inhibitory effects on the mTOR signaling pathway, one of the target signaling pathway of rapamycin. Despite inter-individual variability of the biological read-outs, the work demonstrates that the use of oxidation-sensitive nanocarriers provide superior drug delivery properties which correlate with superior biological effects. Specifically, osCMS2b nanocarrier formulations improved rapamycin retention in the skin with higher local concentrations resulting in a selective downregulation of the mTOR activity. Overall, we addressed all objectives of the proposal. The data show, that nanocarriers addressing the oxidative changes in inflamed skin display superior drug delivery properties. The ex vivo model will be of wider use for the investigation of immunomodulatory compounds and novel drug classes. RNA sequencing analyses are ongoing, so that we expect to get more results on the mechanisms detectable using the developed ex vivo skin inflammatory model and deeper insights on the biological effects of the newly developed redox-sensitive rapamycin formulations. In Subproject 3 the technical and scientific goals were exceeded by exploiting hyperspectral imaging and gaining further insights beyond previous state-of-the-art. The results were to date partially published, where more publications will result from the research performed. Furthermore, the results were presented at several national and international conferences and presentations given at research institutions. Once the results are fully evaluated, it is expected that the architecture of redox-triggered nanocarriers for transporting difficult to formulate drugs will have substantially improved, allowing for advanced drug delivery and therapeutic concepts.

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