Singh Arun D, Raval Vishal, Kumar Sandeep, Daniels Anthony
Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland, Ohio.
The Operation Eyesight Universal Institute for Eye Cancer, L V Prasad Eye Institute, Hyderabad, India.
Ophthalmol Sci. 2025 Jul 4;5(6):100875. doi: 10.1016/j.xops.2025.100875. eCollection 2025 Nov-Dec.
To assess whether levels of topotecan that are expected to be therapeutic against retinoblastoma tumors can be achieved within the retina and choroid by suprachoroidal injection (SCI) and to assess toxicity and safety in vivo.
Pharmacokinetics and dose escalation toxicity study.
New Zealand white rabbits.
In a pharmacokinetic study (N=18), aqueous, vitreous, retina, choroid, and plasma were separated and harvested serially (15, 30, 60, 120, and 360 minutes) following SCI. Topotecan (lactone) levels were measured and pharmacokinetic parameters were calculated. In the dose escalation toxicity study (N=8), toxicity was evaluated by ocular examination, fundus photography, OCT, full-field electroretinography (ffERG), and tissue histology. A single SCI of 50 μg/0.05 mL or two consecutive SCI totaling 100 μg/0.1 mL (N=4 rabbits per group) were administered.
Topotecan (lactone) tissue levels and ocular toxicity (25% reduction in ffERG).
Following a single SCI of 50 μg topotecan, high levels of topotecan were achieved rapidly in both the retina and choroid. Retinal levels peaked by 15 minutes (12400±7336 ng/gm) followed by rapid decline to 2899±1361 ng/gm by 30 minutes, and then slower progressive decline that reached lowest levels at 360 minutes (469 ng/gm). Half-life (T) in the retina was 24.8 minutes. Choroidal levels were 3.3-fold higher than retina with a similar rapid decline pattern. Vitreous level was highest at 15 min (278 ng/mL) with a slow progressive decline until 360 min (16.9 ng/ml). Plasma (mean 4.3±2.6 ng/ml) and aqueous (peak at 120 min, mean 87 ng/ml) levels remained low throughout the study. There were no signs of ocular toxicity or other adverse ocular events on either clinical examination, serial imaging studies, ffERG, or histology following sacrifice at 28 days.
A single SCI of topotecan (50 μg/0.05 ml) achieved selective tissue distribution of its lactone moiety (retina/plasma, 1377.8) that was 23-fold higher than that reported with intraarterial chemotherapy (58.9) and more than 1000-fold higher than intravenous chemotherapy (1.32). These retinal levels were nontoxic and were 885-fold higher than the known topotecan IC50 for human retinoblastoma cells (IC50 14 ng/gm). Our findings support potential benefit of SCI of topotecan for patients with retinoblastoma.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
评估通过脉络膜上腔注射（SCI）能否在视网膜和脉络膜内达到预期对视网膜母细胞瘤具有治疗作用的拓扑替康水平，并评估其体内毒性和安全性。
药代动力学和剂量递增毒性研究。
新西兰白兔。
在药代动力学研究（N = 18）中，SCI后按顺序（15、30、60、120和360分钟）分离并收集房水、玻璃体、视网膜、脉络膜和血浆。测量拓扑替康（内酯）水平并计算药代动力学参数。在剂量递增毒性研究（N = 8）中，通过眼部检查、眼底摄影、光学相干断层扫描（OCT）、全视野视网膜电图（ffERG）和组织组织学评估毒性。给予单次50μg/0.05mL的SCI或两次连续SCI，总量为100μg/0.1mL（每组4只兔子）。
拓扑替康（内酯）组织水平和眼部毒性（ffERG降低25%）。
单次注射50μg拓扑替康后，视网膜和脉络膜中均迅速达到高水平的拓扑替康。视网膜水平在15分钟时达到峰值（12400±7336ng/gm），随后迅速下降，30分钟时降至2899±1361ng/gm，并在360分钟时缓慢下降至最低水平（469ng/gm）。视网膜中的半衰期（T）为24.8分钟。脉络膜水平比视网膜高3.3倍，具有相似的快速下降模式。玻璃体水平在15分钟时最高（278ng/mL），并缓慢下降，直至360分钟（16.9ng/ml）。在整个研究过程中，血浆（平均4.3±2.6ng/ml）和房水（120分钟时达到峰值，平均87ng/ml）水平一直较低。在28天处死时，临床检查、系列影像学研究、ffERG或组织学检查均未发现眼部毒性或其他不良眼部事件的迹象。
单次注射拓扑替康（50μg/0.05ml）可实现其内酯部分的选择性组织分布（视网膜/血浆，1377.8），这比动脉内化疗报道的水平（58.9）高23倍，比静脉化疗高1000多倍（1.32）。这些视网膜水平无毒，比人视网膜母细胞瘤细胞已知的拓扑替康IC50（IC50 14ng/gm）高885倍。我们的研究结果支持拓扑替康脉络膜上腔注射对视网膜母细胞瘤患者的潜在益处。
专有或商业披露可在本文末尾的脚注和披露中找到。
