期刊
EXPERIMENTAL DERMATOLOGY
卷 22, 期 3, 页码 178-183出版社
WILEY
DOI: 10.1111/exd.12091
关键词
drug sensor; lentiviral vectors; topical drug delivery; vitamin D3 analogues; xenotransplantation model
类别
资金
- Danish National Advanced Technology Foundation
- Danish Medical Research Council
- Lundbeck Foundation
- Novo Nordisk Foundation
- Kgl. Hofbuntmager Aage Bangs Foundation
- Aase og Ejnar Danielsens Fond
- Agnes og Poul Friis Fond
Vitamin D3 analogues are widely used topical and oral remedies for various ailments such as psoriasis, osteoporosis and secondary hyperparathyroidism. In topical treatment, high skin permeability and cellular uptake are key criteria for beneficial effects due to the natural barrier properties of skin. In this study, we wish to establish an in vivo model that allows the comparison of permeability and activity of vitamin D3 analogues in human skin. We generate a bipartite, genetic sensor technology that combines efficient lentivirus-directed gene delivery to xenotransplanted human skin with vitamin D3-induced expression of a luciferase reporter gene and live imaging of animals by bioluminescence imaging. Based on the induction of a transcriptional activator consisting of the vitamin D receptor fused to the Gal4 DNA-binding domain, the vitamin D3-responsive sensor facilitates non-invasive and rapid assessment of permeability and functional properties of vitamin D3 analogues. By topical application of a panel of vitamin D3 analogues onto 'sensorized' human skin, the sensor produces a drug-induced readout with a magnitude and persistence that allow a direct comparative analysis of different analogues. This novel genetic tool has great potential as a non-invasive in vivo screening system for further development and refinement of vitamin D3 analogues.
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