对流投递特异性靶向毒素对裸鼠颅内人胶质母细胞瘤的影响

Intracranial elimination of human glioblastoma brain tumors in a mouse xenograft model using the bispecific targeted toxin DTATEGF and convection enhanced delivery

目的观察免疫毒素DTATEGF通过渗透泵加强对流释放（CED）给药对裸鼠颅内人胶质母细胞瘤的治疗效果。方法噻唑蓝（MTT）比色法检测DTATEGF对体外培养的Ln229细胞株的增殖抑制作用。建立裸小鼠颅内荧光素酶标记的人胶质母细胞瘤模型，将1μg的DTATEGF和对照Bickd3通过渗透泵CED投递处理颅内肿瘤。检测肿瘤的荧光信号强度，小鼠的存活时间及肿瘤标本苏木素-伊红（HE）染色形态学检测。结果DTATEGF显著抑制Ln229-luc细胞增殖，其半数抑制剂量（IC50）小于0．001nmol/L。CED投递药物实验中，小鼠很好地耐受渗透泵；DTATEGF治疗组小鼠的中位生存期85d，与对照组生存期（67d）比较差异有统计学意义（P〈0．01）。结论DTATEGF显著抑制Ln229-luc细胞株增殖，抑制裸小鼠人胶质母细胞瘤生长，延长荷瘤小鼠的生存。

Objective To investigate the anticancer effect of the bispecific immunotoxin DTATEGF in vitro and in vivo when delivered by convection-enhanced delivery （CED） via an osmotic minipump in a human glioblastoma brain tumor mouse xenograft model. Methods The effects of the immunotoxins were tested for their ability to inhibit the proliferation of Ln229-luc ceils in vitro by methyl thiazol tetrazolium （MTT） assay. On a xenograft intracranial model, 1 HUANC Jun , YUAN Dun, LI Yan, Walter A Hall, LI Bo, LONG Xiao-yan. Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha 410008, Chinag of DTATEGF or control Bickel3 was delivered intraeranially by CED via an osmotic minipump. The bioluminescent imaging （BLI） was performed and Kaplan-Meier survival curves were generated. The brain tumor samples were stained by hematoxylin and eosin for histopathological assessment. Results In vitro, DTATECF could kill Ln229-luc cells and showed an 50% inhibitory dose（ IC50 ） less than 0. 001 nmol/L. In vivo, mice with tumors were treated intracranially with drug via CED where the treatment was successful in providing a survival benefit with the median survival of mice treated with DTATECF being significantly prolonged relative to controls （85 vs. 67 days,P 〈 0. 01 ）. Conclusion DTATEGF kills the Ln229-luc cell line in vitro, and when it is delivered via CED in- tracranially, it is highly efficacious against human glioblastoma brain tumors.