TY - JOUR
T1 - Retina-targeted delivery of 17β-estradiol by the topically applied dhed prodrug
AU - Prokai-Tatrai, Katalin
AU - Nguyen, Vien
AU - De La Cruz, Daniel L.
AU - Guerra, Rebecca
AU - Zaman, Khadiza
AU - Rahlouni, Fatima
AU - Prokai, Laszlo
N1 - Funding Information:
This work was supported in part by the National Eye Institute and the Office of Research on Women’s Health (National Institutes of Health, Bethesda, MD, USA, grant number EY027005 to K.P.-T.) and by the Robert A. Welch Foundation (endowment BK-0031 to L.P.).
Funding Information:
Funding: This work was supported in part by the National Eye Institute and the Office of Research on Women’s Health (National Institutes of Health, Bethesda, MD, USA, grant number EY027005 to K.P.-T.) and by the Robert A. Welch Foundation (endowment BK-0031 to L.P.).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
KW - 10β
KW - 17β-dihydroxyestra-1
KW - 17β-estradiol
KW - 4-dien-3-one
KW - DHED
KW - Eye drops
KW - Glaucoma
KW - Ocular neuroprotection
KW - Prodrug
KW - Rabbit
KW - Retina-targeted drug delivery
KW - Visual function
UR - http://www.scopus.com/inward/record.url?scp=85085154721&partnerID=8YFLogxK
U2 - 10.3390/pharmaceutics12050456
DO - 10.3390/pharmaceutics12050456
M3 - Article
AN - SCOPUS:85085154721
SN - 1999-4923
VL - 12
JO - Pharmaceutics
JF - Pharmaceutics
IS - 5
M1 - 456
ER -