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首页> 外文期刊>Journal of mass spectrometry: JMS >Fast and sensitive liquid chromatography/electrospray spectrometry mass method to study ocular penetration of EDL-155, a novel antitumor agent for retinoblastoma in rats
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Fast and sensitive liquid chromatography/electrospray spectrometry mass method to study ocular penetration of EDL-155, a novel antitumor agent for retinoblastoma in rats

机译：快速灵敏的液相色谱/电喷雾质谱方法研究大鼠视网膜母细胞瘤新型抗肿瘤药EDL-155的眼部渗透

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Our group has used the tetra hydroisoquinoline derivative EDL-155 to treat glioblastoma in animal models and it is currently being evaluated in the treatment of ocular cancers. The purpose of this study was to develop a rapid and sensitive liquid chromatography and tandem mass spectrometry (LC-MS/MS) method to study the plasma and vitreous humor disposition of EDL-155 in rats. Animals received a single periocular injection of EDL-155 (20 mg/kg). Animals were sacrificed at specified times (5, 60, 120, 240 and 360 min) and plasma and vitreous humor samples were obtained. EDL-155 was isolated by protein precipitation and the extracts were analyzed by reversed-phase high-pressure liquid chromatography (HPLC) with MS/MS detection. A structurally similar analog was used as internal standard (IS). The chromatographic run time was 3.5 min per injection. The mass spectrometer was operated in positive-ion, multiple reaction monitoring (MRM) mode. The mass transitions monitored were m/z 332.2 -> 167.2 (EDL-155) and m/z 391.2 -> 200.2 (IS). The lower limit of quantification (LLOQ) was 0.1 ng/ml in both vitreous humor and plasma. The method was validated for selectivity, linearity, accuracy and precision in rat vitreous humor and partially validated for accuracy and precision in rat plasma. The ion suppression, recovery and stability of the analyte in the biological matrix were also tested. The assay was rapid, sensitive and robust enough to support EDL-155 ocular penetration studies in a rodent model of intraocular cancer. Application of this method revealed that EDL-155 was rapidly passed into the vitreous humor following periocular administration. Further, vitreous humor exposure exceeded systemic exposure by approximately sevenfold. High local concentrations coupled with minimal systemic exposure supports further testing of EDL-155 as localized therapy for intraocular cancers.
机译：我们的小组已使用四氢异喹啉衍生物EDL-155来治疗动物模型中的胶质母细胞瘤，目前正在对眼癌进行评估。这项研究的目的是开发一种快速灵敏的液相色谱和串联质谱（LC-MS / MS）方法，以研究大鼠EDL-155的血浆和玻璃体液处置。动物接受一次眼周注射的EDL-155（20 mg / kg）。在指定的时间（5、60、120、240和360分钟）处死动物，获得血浆和玻璃体液样本。通过蛋白质沉淀分离EDL-155，并通过反相高压液相色谱（HPLC）和MS / MS检测对提取物进行分析。结构相似的类似物用作内标（IS）。每次进样的色谱运行时间为3.5分钟。质谱仪以阳离子，多反应监测（MRM）模式运行。监测的质量转变为m / z 332.2-> 167.2（EDL-155）和m / z 391.2-> 200.2（IS）。玻璃体液和血浆的定量下限（LLOQ）均为0.1 ng / ml。该方法在大鼠玻璃体液中的选择性，线性，准确度和精密度得到验证，在大鼠血浆中的准确性和精密度得到部分验证。还测试了生物基质中分析物的离子抑制，回收率和稳定性。该测定法快速，灵敏且稳健，足以支持在眼内啮齿动物模型中进行EDL-155眼部渗透研究。该方法的应用表明，眼周给药后，EDL-155迅速进入玻璃体液。此外，玻璃体液暴露超过全身暴露约七倍。高局部浓度加上最小的全身暴露量支持进一步测试EDL-155作为眼内癌的局部治疗方法。

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