Retina-targeted delivery of 17β-estradiol by the topically applied dhed prodrug

Katalin Prokai-Tatrai, Vien Nguyen, Daniel L. De La Cruz, Rebecca Guerra, Khadiza Zaman, Fatima Rahlouni, Laszlo Prokai

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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 E2s 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.

Original languageEnglish
Article number456
JournalPharmaceutics
Volume12
Issue number5
DOIs
StatePublished - May 2020

Keywords

  • 10β
  • 17β-dihydroxyestra-1
  • 17β-estradiol
  • 4-dien-3-one
  • DHED
  • Eye drops
  • Glaucoma
  • Ocular neuroprotection
  • Prodrug
  • Rabbit
  • Retina-targeted drug delivery
  • Visual function

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