Intravascularly administered RGD-displaying measles viruses bind to and infect neovessel endothelial cells in vivo.
Systemically administered vectors must cross the endothelial lining of tumor blood vessels to access cancer cells. Vectors that interact with markers on the lumenal surface of these endothelial cells might have enhanced tumor localization. Here, we generated oncolytic measles viruses (MVs) displaying alpha(v)beta(3) integrin-binding peptides, cyclic arginine-glycine-aspartate (RGD) or echistatin, on the measles hemagglutinin protein. Both viruses had expanded tropisms, and efficiently entered target cells via binding to integrins, but also retained their native tropisms for CD46 and signaling lymphocyte activation molecule (SLAM). When fluorescently labeled and injected intravascularly into chick chorioallantoic membranes (CAMs), in contrast to unmodified viruses, the integrin-binding viral particles bound to the lumenal surface of the developing chick neovessels and infected the CAM vascular endothelial cells. In a mouse model of VEGF-induced angiogenesis in the ear pinna, the integrin-binding viruses, but not the parental virus, infected cells at sites of new blood vessel formation. When given intravenously to mice bearing tumor xenografts, the integrin-binding virus infected endothelial cells of tumor neovessels in addition to tumor parenchyma. To our knowledge, this is the first report demonstrating that oncolytic MVs can be engineered to target the lumenal endothelial surface of newly formed blood vessels when administered intravenously in living animals.
Ong
Hooi Tin
HT
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Trejo
Theodore R
TR
Pham
Linh D
LD
Oberg
Ann L
AL
Russell
Stephen J
SJ
Peng
Kah-Whye
KW
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002642:Chick Embryo; D002645:Chickens; D002522:Chlorocebus aethiops; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000821:virology; D042783:Endothelial Cells / Q000821:virology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008459:Measles virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010455:Peptides / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C057986:echistatin