Methods for delivery of adenoviral vectors to tumor vasculature.
The discovery that the luminal membrane of tumor vascular endothelial cells contains antigens different from those on the luminal membrane of endothelial cells in the vessels of normal tissues has opened the door to the use of adenoviral vectors for tumor vascular targeting as a form of cancer treatment. Other laboratories have shown that introduction of the RGD peptide increases binding of the adenoviral vector to dividing endothelial cells and to tumor cells. The major obstacle to achieving delivery of intravenously administered adenoviral vectors to tumor vascular endothelial cells and tumor cells is the nonspecific uptake of adenoviral vectors in the liver and other organs. Another obstacle is the low level of the coxsackievirus-adenovirus receptor, to which the adenoviral fiber protein binds, on tumor vascular endothelial cells and tumor cells. We therefore introduced the RGD peptide into the adenoviral vector fiber protein and then tested the effect of intravenous 6% hetastarch on the delivery to adenoviral vector to tumor tissue. Our results show that pretreatment with hetastarch increases the delivery of the adenoviral vector to tumor cells and their vasculature, reduces up-take by normal tissues, reduces vector-mediated toxicity to the liver, and intensifies vector-induced suppression of tumor cell growth.
Liu
Yanzheng
Y
Sidney Kimmel Cancer Center, San Diego, CA 92121, USA.
Koziol
James
J
Deisseroth
Albert
A
Borgstrom
Per
P
D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D041702:BALB 3T3 Cells; D005437:Flucytosine / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D006895:Hydroxyethyl Starch Derivatives / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008099:Liver / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply*; D009842:Oligopeptides / Q000378:metabolism; D012867:Skin / Q000166:cytology; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
D006895:Hydroxyethyl Starch Derivatives; D009842:Oligopeptides; D049452:Green Fluorescent Proteins; C047981:arginyl-glycyl-aspartic acid; D005437:Flucytosine; D008156:Luciferases