新型溶瘤腺病毒经由静脉输注后的生物学分布和动力学.docVIP

  新型溶瘤腺病毒经由静脉输注后的生物学 分布和动力学# 黄晓园1，曹阳2，庄亮3** 5 10 15 （1. 华中科技大学同济医学院附属同济医院妇产科； 2. 华中科技大学同济医学院附属同济医院血液内科； 3. 华中科技大学同济医学院附属同济医院肿瘤科） 摘要：【目的】 评价新型溶瘤腺病毒 M1 由静脉途径进入体内后的病毒分布、复制和代谢 清除动力学，以及 M1 单独使用的抗肿瘤效应。【方法】 建立具有高频转移特性的人胃癌 裸鼠原位移植瘤动物模型；观察各处理组模型鼠的生存时间；在指定时间点处死动物，分离 原发瘤及转移瘤进行病毒滴度测定；采用免疫组化和原位杂交来检测病毒的分布和活性复 制；采用 Western blot 检测 M1 的靶点封闭效应。【结果】 在人胃癌裸鼠原位模型上，M1 经静脉输注后不仅分布于胃原发瘤，而且存在于转移灶；M1 在肿瘤细胞中活性复制导致肿 瘤细胞坏死和靶基因 plk1 表达降低。【结论】 溶瘤腺病毒 M1 的静脉内输注可以发挥溶 瘤和靶向灭活 plk1 的双重效应，因此其单独应用时能够在原发瘤和远处转移灶有效感染复 制，最终清除肿瘤病灶。 关键词：溶瘤腺病毒；静脉输注；分布；动力学 中图分类号：R730.23 20 Biodistribution and kinetics of novel selective oncolytic adenovirus M1 via systemic administration HUANG Xiaoyuan1, CAO Yang2, ZHUANG Liang3 (1. Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, 25 30 35 40 Huazhong University of Science and Technology, Wuhan 430030, China; 2. Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; 3. Department of Tumor, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China) Abstract: Oncolytic adenoviruses represent a promising novel therapeutic option for the treatment of cancer. Despite rapid translation into human clinical trials and demonstrated safety, the fundamental properties of oncolytic adenovirus biodistribution, spread, viral persistence and replication in vivo have not been completely elucidated. The aim of this study was to evaluate the kinetics of viral distribution, spread, replication and anti-tumoral efficacy as a single agent after intravenous administration of a novel oncolytic mutant M1, the E1A CR2-deleted Adv5 with a fragment of antisense plk1 cDNA inserted into the deleted 6.7K/gp19K region, which combine oncolytic properties with efficient plk1 silencing in our previous reports. In the present study, we established a new human orthotopic gastric carcinoma with high frequency metastasis mouse model and demonstrated