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 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.
Highlights
The beneficial effects of endogenous or exogenously applied 17β-estradiol (E2) for eye health have been shown by basic science studies [1,2,3,4,5] and epidemiological observations [6,7,8]
Along with comparative characterization of corneal permeability and in vitro metabolism in ocular tissues, we provide in vivo evidence here for the retina-selective formation of E2 from this bioprecursor prodrug when it is applied topically in eye drops to rats and rabbits
DHED, 10β,17β-dihydroxyestra-1,4-dien-3-one-16,16,17-d3 (d3-DHED) and 10β,17β-dihydroxyestra-1,4-dien-3-one-2,4,16,16,17-d5 (d5-DHED) were synthesized in our laboratory as reported before [22,30]. 17β-Estradiol-16,16,17-d3 (d3-E2) and 17β-estradiol-2,4,16,16,17-d5 (d5-E2) with 98% isotope purity were purchased from CDN Isotopes (Pointe-Claire, QC, Canada). 17β-Estradiol13,14,15,16,17,18-13C6 (13C6-E2) with 99% isotope purity was obtained from Cambridge Isotope Laboratories (Andover, MA, USA)
Summary
The beneficial effects of endogenous or exogenously applied 17β-estradiol (E2) for eye health have been shown by basic science studies [1,2,3,4,5] and epidemiological observations [6,7,8] Our interest in this regard stems from an unmet medical need for ocular neuroprotection [3,9]. The presence of the phenolic A-ring in the steroid structure makes E2 unique among neurosteroids This feature is associated with one of the best-known non-genomic effects of E2, which is its ability to act as a direct free-radical scavenging phenolic antioxidant [14,15]. This antioxidant capacity is a critical contributor to the amelioration of oxidative stress heavily implicated in the initiation and/or progression of neurodegeneration [16]
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