Ablating CAR and integrin binding in adenovirus vectors reduces nontarget organ transduction and permits sustained bloodstream persistence following intraperitoneal administration.
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.
Akiyama
Masaki
M
FUSO Pharmaceutical Industries, Ltd., 2-3-30 MorinomiyaJoto, Osaka 536-8523, Japan.
Thorne
Stephen
S
Kirn
David
D
Roelvink
Peter W
PW
Einfeld
David A
DA
King
C Richter
CR
Wickham
Thomas J
TJ
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001769:Blood / Q000821:virology; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004848:Epithelium / Q000378:metabolism / Q000821:virology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D016679:Genome, Viral; D007274:Injections, Intraperitoneal; D016023:Integrins / Q000378:metabolism*; D008099:Liver / Q000821:virology; D051379:Mice; D009928:Organ Specificity; D011991:Receptors, Virus / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods*
C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016023:Integrins; D011991:Receptors, Virus