Abstract
BackgroundHybrid PET/optical imaging provides quantitative and complementary information for diagnosis of tumors. Herein, we developed a 64Cu-labeled AlexaFluor 680-streptavidin ((AF)SAv)/biotin-based dimeric cyclic RGD peptide (RGD2) for hybrid PET/optical imaging of integrin αVβ3 expression.Methods64Cu-1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA)-(AF)SAv/biotin-PEG-RGD2 was prepared by formation of a complex comprising DOTA-(AF)SAv and biotin-PEG-RGD2, followed by radiolabeling with 64Cu. Receptor binding studies of DOTA-(AF)SAv/biotin-PEG-RGD2 were performed using U87MG cells and 125I-RGDyK as the radioligand, and cellular uptake studies of 64Cu-DOTA-(AF)SAv/biotin-PEG-RGD2 were also performed. MicroPET imaging followed by optical imaging of U87MG tumor-bearing mice was acquired after injection of the hybrid probe, and region of interest (ROI) analysis of tumors was performed. Ex vivo PET/optical imaging and biodistribution studies of the major tissues were performed after the in vivo imaging, and immunofluorescence staining of the tumor tissue sections was carried out.Results64Cu-DOTA-(AF)SAv/biotin-PEG-RGD2 was prepared in 52.1 ± 5.4 % radiochemical yield and with specific activity of 1.0 ± 0.1 GBq/mg. Receptor binding studies showed that DOTA-(AF)SAv/biotin-PEG-RGD2 had higher binding affinity for integrin αVβ3 than RGD2, reflecting a possible polyvalency effect. Moreover, the hybrid probe revealed time-dependent uptake by U87MG cells. In a microPET/optical imaging study, the hybrid probe demonstrated high accumulation in tumors; ROI analysis revealed 2.7 ± 0.2 % ID/g at 1 h and 4.7 ± 0.2 % ID/g at 21 h after injection, and subsequently acquired optical images showed tumors with strong fluorescence intensity. Ex vivo PET/optical images of the major tissues confirmed the in vivo imaging data, and biodistribution studies demonstrated high and specific uptake in tumors (4.8 ± 0.1 % ID/g). Immunofluorescence staining showed the formation of new blood vessels in tumor tissues, suggesting that the tumor uptake was due to specific binding of the hybrid probe to integrin αVβ3 expressed on tumor cells.ConclusionsThese results indicate that a 64Cu-DOTA-(AF)SAv/biotin-PEG-RGD2 is able to provide quantitative information on hybrid PET/optical imaging of integrin αVβ3 expression.
Highlights
Hybrid PET/optical imaging provides quantitative and complementary information for diagnosis of tumors
RGD2 was purchased from Peptide International (Louisville, KY, USA), biotin-PEG(3400)-NHS ester was from Nanocs (New York, NY, USA), (AF)SAv was from Life Technologies (Carlsbad, CA, USA), and DOTA-NHS ester was from Macrocyclics (Dallas, TX, USA). 64CuCl2 was kindly provided by KIRAMS (Seoul, Korea)
This imaging probe design may be suitable for hybrid imaging of tumor angiogenesis, because RGD2 can be used for αVβ3 receptor binding while the radioisotope and fluorescent dye can be used for PET and optical imaging, respectively
Summary
Hybrid PET/optical imaging provides quantitative and complementary information for diagnosis of tumors. PET provides sensitive and quantitative information, and PET probes are translated for clinical use compared with probes used for other modalities [2]. MRI offers the highest spatial resolution but has low sensitivity [2]. Hybrid imaging, by compensating for the drawbacks of single imaging modalities, is more accurate and allows for earlier diagnosis of diseases. This has spurred the development of hybrid imaging probes containing diverse functionalities for application in hybrid PET/optical, PET/MR, and other combinations of imaging modalities
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