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

摘要

Integrins, particularly the α_vβ_3 heterodimers, play important roles in tumor-induced angiogenesis and invasiveness. To image the expression pattern of the α_vβ_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 α_vβ_3 integrin binding affinity and the internal-ization properties of LS308 mediated by the α_vβ_3 integrin in 4t1 luc cells were investigated by receptor binding assay and fluorescence microscopy, respectively. The in vivo distribution of ~(111)In-labeled LS308 in a 4t1 luc 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 α_vβ_3 integrin and internalized preferentially via the α_vβ_3 integrin-mediated endocytosis in 4t1 luc cells. We also found that LS308 selectively accumulated in α_vβ_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 α_vβ_3 integrin. Thus, the multimodal imaging approach could provide important complementary diagnostic information for monitoring the efficacy of new antiangiogenic drugs.