Episcleral Implants for Topotecan Delivery to the Posterior Segment of the Eye
Episcleral Implants for Topotecan Delivery to the Posterior Segment of the Eye
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DOI：
10.1167/iovs.09-4050
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Chantada, Guillermo L.
中科院分区：
文献类型：
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作者：
Carcaboso, Angel M.;Chiappetta, Diego A.;Chantada, Guillermo L.
目的.静脉注射或眼周注射拓扑替康已被提议作为晚期眼内视网膜母细胞瘤患者的新治疗方式，但这两种方法诱导的全身拓扑替康内酯暴露可能导致毒性。本研究的目的是开发一种载托泊替康的眼部给药系统，以尽量减少全身暴露，并实现选择性的经巩膜渗透。生产含有低（0.3 mg）或高（2.3 mg）托泊替康负载的生物相容性聚合物植入物，并在体外进行表征。肾上腺素（500 μ g）被染色以在4个动物组中的2个中诱导体内局部血管收缩。将植入物插入兔的巩膜外层，并在48小时内测定眼组织和血浆中的托泊替康（内酯和总）浓度。在体外，植入物在48小时内释放30%至50%的负载药物，到第10天释放45%至70%。在体内，研究的所有制剂在48小时内局部暴露的眼组织中高度蓄积托泊替康内酯（巩膜和脉络膜中的范围为10（5）-10（6）ng/g，视网膜中为10（2）-10（3）ng/g）。在同时接受局部血管收缩和高负荷植入的动物中发现玻璃体托泊替康内酯水平较低（约5 ng/mL）。血浆和对侧眼中的托泊替康内酯浓度极低或无法检测到，作为所提出策略的组织选择性标志物。这些研究可能有助于提高视网膜母细胞瘤化疗治疗的疗效和安全性，并可能支持经巩膜给药期间局部血管和组织促进药物清除和局部蓄积的作用。（Invest Ophthalmol维斯科学。2010; 51：2126-2134）DOI：10.1167/iovs.09-4050
PURPOSE. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration.METHODS. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mu g) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours.RESULTS. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to 10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy.CONCLUSIONS. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery. (Invest Ophthalmol Vis Sci. 2010; 51: 2126-2134) DOI:10.1167/iovs.09-4050