In vivo imaging of tumour angiogenesis in mice with the alpha(v)beta (3) integrin-targeted tracer 99mTc-RAFT-RGD.
OBJECTIVE
The molecular imaging of tumour neoangiogenesis currently represents a major field of research for the diagnostic and treatment strategy of solid tumours. Endothelial cells from tumour neovessels overexpress the alpha(v)beta(3) integrin, which selectively binds to Arg-Gly-Asp (RGD)-containing peptides. We evaluated the potential of the novel radiotracer (99m)Tc-RAFT-RGD for the non-invasive molecular imaging of alpha(v)beta(3) integrin expression in mice models of tumour development.


METHODS
(99m)Tc-RAFT-RGD, (99m)Tc-cRGD (specific control) and (99m)Tc-RAFT-RAD (non-specific control) were injected intravenously to mice bearing B16F0 or TS/A-pc tumours. In vivo whole-body tomographic imaging and post-mortem biodistribution studies were performed 60 min following tracer injection. Adjacent tumour slices were used to compare the localisation of neovessels from immunostaining and the pattern of (99m)Tc-RAFT-RGD uptake from autoradiographic ex vivo imaging.


RESULTS
Biodistribution studies indicated that (99m)Tc-RAFT-RGD tumour uptake was significantly higher than that of (99m)Tc-RAFT-RAD in B16F0 (2.4+/-0.5 vs 1.0+/-0.1%ID/g, respectively) and in TS/A-pc tumours (2.7+/-0.8 vs 0.7+/-0.1%ID/g, respectively). Immunohistochemical and autoradiographic studies indicated that (99m)Tc-RAFT-RGD intratumoural uptake preferentially occurred in angiogenic areas. Tomographic imaging allowed tumour visualisation following injection of (99m)Tc-RAFT-RGD and (99m)Tc-cRGD with similar tumour-to-contralateral muscle (T/CM) ratios in B16F0 and in TS/A-pc tumours whereas (99m)Tc-RAFT-RAD T/CM ratios did not allow tumour imaging. In accordance with the higher level of alpha(v)beta(3) integrin expression on TS/A-pc tumours than on B16F0 tumours as determined from western blot and immunoprecipitation analyses, the (99m)Tc-RAFT-RGD T/CM ratio was significantly higher in TS/A-pc than in B16F0 tumours.


CONCLUSIONS
(99m)Tc-RAFT-RGD allowed the in vivo imaging of alpha(v)beta(3) integrin tumour expression.
INSERM U877, Radiopharmaceutiques Biocliniques, Faculté de Medecine, Université de Grenoble, La Tronche, France.
Lucie
L
Sancey
Valérie
V
Ardisson
Laurent M
LM
Riou
Mitra
M
Ahmadi
Danièle
D
Marti-Batlle
Didier
D
Boturyn
Pascal
P
Dumy
Daniel
D
Fagret
Catherine
C
Ghezzi
Jean-Philippe
JP
Vuillez
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008545:Melanoma / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009928:Organ Specificity; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution
D039302:Integrin alphaVbeta3; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; C529229:technetium 99m RAFT-RGD