Oncolytic vaccinia virus expressing the human somatostatin receptor SSTR2: molecular imaging after systemic delivery using 111In-pentetreotide.
Oncolytic vaccinia viruses (VV) have demonstrated tumor specificity, high levels of transgene expression, and anti-tumor effects. The ability to visualize vector biodistribution noninvasively will be necessary as gene therapy vectors come to clinical trials, and the creation of a VV that can both treat tumors and permit noninvasive imaging after systemic delivery is therefore an exciting concept. To facilitate imaging, a VV expressing the human somatostatin receptor type 2 (SSTR2) was created. Cells infected with the SSTR2-expressing VV or controls were incubated with the somatostatin analog 111In-pentetreotide with or without an excess of nonradiolabeled pentetreotide. The SSTR2-infected cells bound 111In-pentetreotide sixfold more efficiently than control virus-infected cells and this binding was specifically blocked by nonradiolabeled pentetreotide. Nude mice bearing subcutaneous murine colon CA xenografts were injected intraperitoneally with the SSTR2-expressing VV or control VV. After 6 days, mice were injected with 111In-pentetreotide and imaged. Mice were sacrificed and organs collected and counted in a gamma counter. The uptake of radioactivity in tumors and normal tissues (percentage injected dose per gram) and tumor-to-normal tissue ratios were determined. Tumors infected with the SSTR2-expressing VV accumulated significantly higher concentrations of radioactivity compared to tumors in animals receiving the control virus. SSTR2-infected tumors were visible on imaging 6 days after VV injection and could be visualized for up to 3 weeks post-viral injection using repeat injections of 111In-pentetreotide. This reporter gene imaging strategy could be a very effective method to visualize vector distribution, expression, and persistence over time and enhances the potential of VV as a novel anti-cancer therapeutic.
McCart
J Andrea
JA
Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, ON, Canada. amccart@uhnres.utoronto.ca
Mehta
Navneet
N
Scollard
Deborah
D
Reilly
Raymond M
RM
Carrasquillo
Jorge A
JA
Tang
Nan
N
Deng
Hui
H
Miller
Marshall
M
Xu
Hui
H
Libutti
Steven K
SK
Alexander
H Richard
HR
Bartlett
David L
DL
D000818:Animals; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000493:pharmacokinetics; D000882:Haplorhini; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008819:Mice, Nude; D011877:Radionuclide Imaging; D017481:Receptors, Somatostatin / Q000096:biosynthesis / Q000235:genetics*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D007205:Indium Radioisotopes; D017481:Receptors, Somatostatin; D013004:Somatostatin; C093733:somatostatin receptor 2; C081788:pentetreotide