title: Direct correlation between positron emission tomographic images of two reporter genes delivered by two distinct adenoviral vectors.
abstract: Biodistribution, magnitude and duration of a therapeutic transgene's expression may be assessed by linking it to the expression of a positron emission tomography (PET) reporter gene (PRG) and then imaging the PRG's expression by a PET reporter probe (PRP) in living animals. We validate the simple approach of co-administering two distinct but otherwise identical adenoviruses, one expressing a therapeutic transgene and the other expressing the PRG, to track the therapeutic gene's expression. Two PET reporter genes, a mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk) and dopamine-2 receptor (D(2)R), each regulated by the same cytomegalovirus (CMV) promoter, have been inserted into separate adenoviral vectors (Ad). We demonstrate that cells co-infected with equivalent titers of Ad-CMV-HSV1-sr39tk and Ad-CMV-D(2)R express both reporter genes with good correlation (r(2) = 0.93). Similarly, a high correlation (r(2) = 0.97) was observed between the expression of both PRGs in the livers of mice co-infected via tail-vein injection with equivalent titers of these two adenoviruses. Finally, microPET imaging of HSV1-sr39tk and D(2)R expression with 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl) guanine ([(18)F]FHBG) and 3-(2-[(18)F]fluoroethyl)spiperone ([(18)F]FESP), utilizing several adenovirus-mediated delivery routes, illustrates the feasibility of evaluating relative levels of transgene expression in living animals, using this approach.
authors.affiliation: Department of Molecular and Medical Pharmacology, The Division of Nuclear Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1770, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Yaghoubi
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: Q
authors.initials: Q
authors.lastname: Liang
authors.forename: T
authors.initials: T
authors.lastname: Toyokuni
authors.forename: J R
authors.initials: JR
authors.lastname: Barrio
authors.forename: M
authors.initials: M
authors.lastname: Namavari
authors.forename: N
authors.initials: N
authors.lastname: Satyamurthy
authors.forename: M E
authors.initials: ME
authors.lastname: Phelps
authors.forename: H R
authors.initials: HR
authors.lastname: Herschman
authors.forename: S S
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics*; D005240:Feasibility Studies; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage; D006147:Guanine / Q000031:analogs & derivatives; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D008099:Liver / Q000000981:diagnostic imaging; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D013134:Spiperone / Q000031:analogs & derivatives; D013937:Thymidine Kinase / Q000235:genetics*; D013997:Time Factors; D014055:Tomography, Emission-Computed
chemical_list: C113308:9-(4-fluoro-3-hydroxymethylbutyl)guanine; D017448:Receptors, Dopamine D2; C051175:3-N-(2-fluoroethyl)spiperone; D013134:Spiperone; D006147:Guanine; D013937:Thymidine Kinase