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.

中文翻译：

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通过局部应用的DHED前药在视网膜上递送17β-雌二醇。

这项研究的目的是探索通过以眼药水形式使用其生物前体前体药物10β，17β-dihydroxyestra-1,4-dien-3-one（DHED）来靶向视网膜靶向递送17β-雌二醇（E2）（一种强大的神经保护剂）的方法。在动物模型中。与母体激素相比，DHED在有和没有2-羟丙基-β-环糊精存在下（在大鼠，兔子和猪中均用作渗透增强赋形剂）均显示出更高的离体角膜通量。在体外，前药在视网膜中也显示出对E2的生物激活作用，而在角膜中则没有。对大鼠和兔子局部给药后，雌性大鼠和兔子视网膜中DHED衍生的E2峰值浓度分别达到13±5 ng / g和18±7 ng / g。但是，前药在身体的其余部分保持惰性，因此，不会导致循环激素浓度增加，子宫和垂体湿重也没有增加，这是E2内分泌影响的典型标志。总之，我们在这里提出的研究首次证明了通过DHED前药方法进行局部视网膜选择性雌激素治疗的前提，并为进一步研究DHED在有效而安全的眼神经疗法中的全部潜力提供了有力的支持。