Multimodal imaging of integrin receptor-positive tumors by bioluminescence, fluorescence, gamma scintigraphy, and single-photon emission computed tomography using a cyclic RGD peptide labeled with a near-infrared fluorescent dye and a radionuclide.
Integrins, particularly the alpha(v)beta(3) heterodimers, play important roles in tumor-induced angiogenesis and invasiveness. To image the expression pattern of the alpha(v)beta(3) integrin in tumors through a multimodality imaging paradigm, we prepared a cyclic RGDyK peptide analogue (LS308) bearing a tetraazamacrocycle 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and a lipophilic near-infrared (NIR) fluorescent dye cypate. The alpha(v)beta(3) integrin binding affinity and the internalization properties of LS308 mediated by the alpha(v)beta(3) integrin in 4t1luc cells were investigated by receptor binding assay and fluorescence microscopy, respectively. The in vivo distribution of (111)In-labeled LS308 in a 4t1luc tumor-bearing mouse model was studied by fluorescence, bioluminescence, planar gamma, and single-photon emission computed tomography (SPECT). The results show that LS308 has high affinity for alpha(v)beta(3) integrin and internalized preferentially via the alpha(v)beta(3) integrin-mediated endocytosis in 4t1luc cells. We also found that LS308 selectively accumulated in alpha(v)beta(3)-positve tumors in a receptor-specific manner and was visualized by the four imaging methods. Whereas the endogenous bioluminescence imaging identified the ensemble of the tumor tissue, the fluorescence and SPECT methods with the exogenous contrast agent LS308 reported the local expression of alpha(v)beta(3) integrin. Thus, the multimodal imaging approach could provide important complementary diagnostic information for monitoring the efficacy of new antiangiogenic drugs.
Edwards
W Barry
WB
Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Akers
Walter J
WJ
Ye
Yunpeng
Y
Cheney
Philip P
PP
Bloch
Sharon
S
Xu
Baogang
B
Laforest
Richard
R
Achilefu
Samuel
S
D000818:Animals; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging / Q000379:methods*; D006573:Heterocyclic Compounds, 1-Ring; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D049408:Luminescent Agents; D051379:Mice; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000378:metabolism*; D010456:Peptides, Cyclic; D011485:Protein Binding; D011868:Radioisotopes; D012588:Scintillation Counting; D019265:Spectroscopy, Near-Infrared; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D049408:Luminescent Agents; D010456:Peptides, Cyclic; D011868:Radioisotopes; C507169:cyclic arginine-glycine-aspartic acid peptide; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid