渗透泵强化对流释放给药治疗恶性脑胶质瘤的裸小鼠模型

Convection-enhanced delivery via a mini-osmotic pump system in the mouse xenograft model

摘要:

目的 探寻渗透泵强化对流释放给药治疗脑肿瘤的祼小鼠模型，为新药的临床前期应用提供良好的实验动物模型。方法 14只祼小鼠基底节区种植4×10⁵个人胶质瘤U87细胞，并安置渗透泵强化对流释放给药系统。裸小鼠按体重和活体荧光信号强度分为二组：治疗组（n=7）的泵内注入100 μl（1 μg）的DTATEGF，对照组（n=7）泵内注入100 μl（1 μg）的无关毒素DT。观察动物的生长特征，Kaplan-Meier生存曲线分析和脑内肿瘤的病理学特征。结果 实验动物没有与渗透泵及外科手术相关的病残和病死发生。动物对渗透泵给药系统耐受好，无抓搔及渗透泵脱位，伤口无感染及裂开等情况。Kaplan-Meier生存曲线显示治疗组动物的中位生存期较对照组明显延长，差异有显著性。（治疗组126天vs.对照组68天，P=0.0002）。治疗组中有两只小鼠生存期超过180天。病理学检测祼小鼠脑内种植生长的肿瘤与人类胶质母细胞瘤的病理特征极为相似。结论 该祼小鼠实验动物模型简便、实用、可靠，适用于新的药物包括单克隆抗体、靶向小分子、肿瘤疫苗等通过强化对流投递治疗脑内恶性肿瘤的临床前期应用。

Abstract:

Objective To develop a brain tumor model in mouse where drugs could be convection-enhanced delivered via a mini-osmotic pump directly into a pre-established tumor bed. Methods Supratentorial tumors were established in 14 cases athymic nude mice which xenografts with lucifeased-modified human glioblastoma U87 cells lines and a mini-osmotic pump for convection-ehanced delivery therapeutic drugs were implanted into the body of the mice, the mice were subsequently assigned randomly to control and DTATEGF treatment groups, and the survival time were analyzed using Kaplan-Meier survival curve. Results There were no noticeable side effects of maintaining the device in place for long periods of time. The device never moved or came off the scalp, all nude mice tolerated the device well. No morbidity or mortality was observed, and no infections were seen. Survival analysis revealed that the median survival of mice treated with DTATEGF was significantly extended relative to controls (126 days vs. 68 days, P=0.0002). Histopathologic analysis revealed tumor growth within the cerebral in all mice. Conclusions This model is well suited for pre-clinical testing of the effects of various treatment strategies on established brain tumors in a mouse model which more closely simulates the clinical situation. The Results of these experiments indicate that DTATEGF can be delivered by convent-enhanced delivery (CED) via micr-osmotic pump to intracranial tumor and be successful in providing additional survival benefit.