Ablating CAR and integrin binding in adenovirus vectors reduces nontarget organ transduction and permits sustained bloodstream persistence following intraperitoneal administration

被引:44
作者
Akiyama, M
Thorne, SH
Kirn, D
Roelvink, PW
Einfeld, DA
King, CR
Wickham, TJ
机构
[1] GenVec Inc, Gaithersburg, MD 20878 USA
[2] Univ London Imperial Coll Sci Technol & Med, Canc Res UK, Hammersmith Hosp, London W12 ONN, England
[3] FUSO Pharmaceut Ind Ltd, Osaka 5368523, Japan
关键词
adenovirus; CAR; integrins; intraperitoneal; liver; mesothelium; cancer; ovarian; targeting; gene therapy;
D O I
10.1016/j.ymthe.2003.10.010
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
To create tumor-targeted Ad vectors, ablation of native CAR and integrin receptor binding is crucial to enhance the specificity of tumor transduction. Toward this aim, we have previously created base vectors in which binding to CAR (single-ablated) or to both CAR and integrins (double-ablated) has been ablated. In this study, the biodistribution of the conventional (CAR and integrin binding intact), single-ablated, and double-ablated vectors was evaluated following intraperitoneal administration. The mesothelial lining of the peritoneal organs was the principle site of CAR-dependent gene transfer by the conventional vector. Surprisingly, the single-ablated vector strongly transduced the liver parenchyma rather than the mesothelium, while the double-ablated vector did not significantly transduce the parenchyma or mesothelium. The high level of parenchymal transduction by the single-ablated vector suggested that it efficiently entered the bloodstream from the peritoneal cavity. Consistent with this hypothesis, a large proportion of active particles distributed and persisted in the bloodstream following intraperitoneal administration of either the single- or the double-ablated vector. The above results suggest that the double-ablated vector backbone may not only significantly improve targeting to cancers located in the peritoneal cavity, but may also significantly improve targeting to metastatic tumors located throughout the body by virtue of its enhanced bloodstream persistence.
引用
收藏
页码:218 / 230
页数:13
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