Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug
The purpose of this study was to explore retina-targeted delivery of 17β-estradiol (E2), a powerful neuroprotectant, by its bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) administered as eye drops in animal models. Compared to the parent hormone, DHED displayed increased transcorn...
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doaj-556f017cb302405a9b0388009608c4da2020-11-25T03:00:54ZengMDPI AGPharmaceutics1999-49232020-05-011245645610.3390/pharmaceutics12050456Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED ProdrugKatalin Prokai-Tatrai0Vien Nguyen1Daniel L. De La Cruz2Rebecca Guerra3Khadiza Zaman4Fatima Rahlouni5Laszlo Prokai6Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USADepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USAThe purpose of this study was to explore retina-targeted delivery of 17β-estradiol (E2), a powerful neuroprotectant, by its bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) administered as eye drops in animal models. Compared to the parent hormone, DHED displayed increased transcorneal flux ex vivo both with and without the presence of 2-hydroxypropyl-β-cyclodextrin used as a penetration-enhancing excipient in rat, rabbit, and pig. In vitro, the prodrug also showed facile bioactivation to E2 in the retina but not in the cornea. After topical administration to rats and rabbits, peak DHED-derived E2 concentrations reached 13 ± 5 ng/g and 18 ± 7 ng/g in the retina of female rats and rabbits, respectively. However, the prodrug remained inert in the rest of the body and, therefore, did not cause increase in circulating hormone concentration, as well as wet uterine and anterior pituitary weights as typical markers of E2′s endocrine impact. Altogether, our studies presented here have demonstrated the premise of topical retina-selective estrogen therapy by the DHED prodrug approach for the first time and provide compelling support for further investigation into the full potential of DHED for an efficacious and safe ocular neurotherapy.https://www.mdpi.com/1999-4923/12/5/45617β-estradiol10β,17β-dihydroxyestra-1,4-dien-3-oneDHEDeye dropsglaucomaocular neuroprotection |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Katalin Prokai-Tatrai Vien Nguyen Daniel L. De La Cruz Rebecca Guerra Khadiza Zaman Fatima Rahlouni Laszlo Prokai |
spellingShingle |
Katalin Prokai-Tatrai Vien Nguyen Daniel L. De La Cruz Rebecca Guerra Khadiza Zaman Fatima Rahlouni Laszlo Prokai Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug Pharmaceutics 17β-estradiol 10β,17β-dihydroxyestra-1,4-dien-3-one DHED eye drops glaucoma ocular neuroprotection |
author_facet |
Katalin Prokai-Tatrai Vien Nguyen Daniel L. De La Cruz Rebecca Guerra Khadiza Zaman Fatima Rahlouni Laszlo Prokai |
author_sort |
Katalin Prokai-Tatrai |
title |
Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug |
title_short |
Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug |
title_full |
Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug |
title_fullStr |
Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug |
title_full_unstemmed |
Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug |
title_sort |
retina-targeted delivery of 17β-estradiol by the topically applied dhed prodrug |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2020-05-01 |
description |
The purpose of this study was to explore retina-targeted delivery of 17β-estradiol (E2), a powerful neuroprotectant, by its bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) administered as eye drops in animal models. Compared to the parent hormone, DHED displayed increased transcorneal flux ex vivo both with and without the presence of 2-hydroxypropyl-β-cyclodextrin used as a penetration-enhancing excipient in rat, rabbit, and pig. In vitro, the prodrug also showed facile bioactivation to E2 in the retina but not in the cornea. After topical administration to rats and rabbits, peak DHED-derived E2 concentrations reached 13 ± 5 ng/g and 18 ± 7 ng/g in the retina of female rats and rabbits, respectively. However, the prodrug remained inert in the rest of the body and, therefore, did not cause increase in circulating hormone concentration, as well as wet uterine and anterior pituitary weights as typical markers of E2′s endocrine impact. Altogether, our studies presented here have demonstrated the premise of topical retina-selective estrogen therapy by the DHED prodrug approach for the first time and provide compelling support for further investigation into the full potential of DHED for an efficacious and safe ocular neurotherapy. |
topic |
17β-estradiol 10β,17β-dihydroxyestra-1,4-dien-3-one DHED eye drops glaucoma ocular neuroprotection |
url |
https://www.mdpi.com/1999-4923/12/5/456 |
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