脉络膜上注射拓扑替康治疗视网膜母细胞瘤的临床前研究

IF 4.6 Q1 OPHTHALMOLOGY

Ophthalmology science Pub Date : 2025-07-04 DOI:10.1016/j.xops.2025.100875

Arun D. Singh MD , Vishal Raval MD , Sandeep Kumar PhD , Anthony Daniels MD

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引用次数: 0

摘要

目的评价在视网膜和脉络膜上注射拓扑替康能否达到预期的治疗视网膜母细胞瘤肿瘤的水平，并评价其在体内的毒性和安全性。设计药代动力学和剂量递增毒性研究。实验对象：新西兰大白兔。方法在一项药物动力学研究中（N=18），在脊髓损伤后（15、30、60、120和360分钟），分别分离水、玻璃体、视网膜、脉络膜和血浆。测定拓扑替康（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、OCT、全视场视网膜电图（ffERG）和组织组织学评估毒性。单次脊髓损伤50 μg/0.05 mL或连续两次脊髓损伤100 μg/0.1 mL（每组N=4只）。主要观察指标替康（内酯）组织水平和眼毒性（ffERG降低25%）。结果单次注射50 μg拓扑替康后，视网膜和脉络膜均迅速出现高水平拓扑替康。视网膜水平在15分钟达到峰值（12400±7336 ng/gm），随后在30分钟迅速下降到2899±1361 ng/gm，然后缓慢渐进下降，在360分钟达到最低水平（469 ng/gm）。视网膜半衰期（T1/2）为24.8分钟。脉络膜水平比视网膜高3.3倍，呈相似的快速下降模式。玻璃体水平在15 min时最高（278 ng/mL），随后缓慢下降至360 min （16.9 ng/mL）。血浆（平均4.3±2.6 ng/ml）和水溶液（在120分钟达到峰值，平均87 ng/ml）水平在整个研究过程中保持较低水平。临床检查、系列影像学检查、ffERG或28天后的组织学检查均未发现眼毒性或其他眼部不良事件的迹象。结论topotecan单次SCI （50 μg/0.05 ml）可实现其内酯部分（视网膜/血浆，1377.8）的选择性组织分布，比动脉化疗（58.9）高23倍，比静脉化疗（1.32）高1000多倍。这些视网膜水平是无毒的，比已知的拓扑替康对人视网膜母细胞瘤细胞的IC50 （IC50 14 ng/gm）高885倍。我们的研究结果支持拓扑替康治疗视网膜母细胞瘤患者的潜在益处。财务披露专有或商业披露可在本文末尾的脚注和披露中找到。

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Suprachoroidal Injection of Topotecan for Retinoblastoma: A Preclinical Study

Purpose

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.

Design

Pharmacokinetics and dose escalation toxicity study.

Subjects

New Zealand white rabbits.

Methods

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.

Main Outcome Measures

Topotecan (lactone) tissue levels and ocular toxicity (25% reduction in ffERG).

Results

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_1/2) 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.

Conclusions

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.