Imaging the spatial distribution of transgene expression in the lungs with positron emission tomography.
This study was designed to evaluate the utility of positron emission tomography (PET) to quantify the magnitude and spatial distribution of transgene expression after different methods of adenoviral vector delivery (with surfactant- and saline-based vehicles) within rat lungs. In all, 17 animals (eight in the surfactant group, nine in the saline group) were studied 3 days after intratracheal administration of a replication-incompetent adenovirus encoding a mutant Herpes simplex virus-1 thymidine kinase (mHSV1-TK)-enhanced green fluorescent protein fusion gene driven by a Cytomegalovirus promoter (Ad-CMV-mNLS-HSV1sr39tk-egfp). PET images were obtained 1 h after i.v. administration of 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine ([(18)F]-FHBG), an imaging substrate for mHSV1-TK. Overall, the average lung concentration of [(18)F]-FHBG was significantly greater in the surfactant group than in the saline group (0.24+/-0.06 versus 0.17+/-0.03% injected dose/ml lung, P< or =0.05). Lung [(18)F]-FHBG distribution was more peripheral and more homogeneous in the surfactant group than in the saline group (mean coefficient of variation=31+/-4 versus 36+/-3%, respectively, P< or =0.05). Regions of increased tracer concentration in the surfactant group compared to the saline group were evenly distributed throughout the lungs. We conclude that PET imaging provides useful and meaningful information about the effectiveness of different gene transfer delivery strategies within the lungs, and that surfactant-based vehicles may be a superior strategy for pulmonary gene transfer.
Richard
J-C
JC
Washington University School of Medicine, St Louis, MO 63110, USA.
Factor
P
P
Welch
L C
LC
Schuster
D P
DP
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D049452:Green Fluorescent Proteins; D006147:Guanine / Q000031:analogs & derivatives*; D018259:Herpesvirus 1, Human / Q000201:enzymology; D007322:Instillation, Drug; D008164:Luminescent Proteins / Q000235:genetics; D008168:Lung / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009154:Mutation; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D013501:Surface-Active Agents / Q000008:administration & dosage; D013937:Thymidine Kinase / Q000235:genetics; D014055:Tomography, Emission-Computed; D019076:Transgenes
C113308:9-(4-fluoro-3-hydroxymethylbutyl)guanine; D008164:Luminescent Proteins; D019275:Radiopharmaceuticals; D013501:Surface-Active Agents; D049452:Green Fluorescent Proteins; D006147:Guanine; D013937:Thymidine Kinase