Prokai-Tatrai Katalin, Nguyen Vien, De La Cruz Daniel L, Guerra Rebecca, Zaman Khadiza, Rahlouni Fatima, Prokai Laszlo
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Pharmaceutics. 2020 May 16;12(5):456. doi: 10.3390/pharmaceutics12050456.
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.
本研究的目的是在动物模型中，通过将生物前体前药10β,17β-二羟基雌-1,4-二烯-3-酮（DHED）制成眼药水滴眼，探索将强效神经保护剂17β-雌二醇（E2）靶向递送至视网膜。与母体激素相比，无论有无用作渗透增强辅料的2-羟丙基-β-环糊精存在，DHED在大鼠、兔子和猪的离体角膜通透率均有所提高。在体外，前药在视网膜中也易于生物活化生成E2，但在角膜中则不然。对大鼠和兔子进行局部给药后，雌性大鼠和兔子视网膜中源自DHED的E2峰值浓度分别达到13±5 ng/g和18±7 ng/g。然而，前药在身体其他部位保持惰性，因此不会导致循环激素浓度升高，也不会使作为E2内分泌影响典型标志物的湿子宫和垂体前叶重量增加。总之，我们在此展示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在有效且安全的眼部神经治疗方面的全部潜力提供了有力支持。
