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Pegylated Arg-Gly-Asp Peptide: ⁶⁴Cu Labeling and PET Imaging of Brain Tumor _vß₃-Integrin Expression

¹ PET Imaging Science Center, Keck School of Medicine, University of Southern California, Los Angeles, California
² Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California

The _v-integrins, cell adhesion molecules that are highly expressed on activated endothelial cells and tumor cells but not on dormant endothelial cells or normal cells, present an attractive target for tumor imaging and therapy. We previously coupled a cyclic Arg-Gly-Asp (RGD) peptide, c(RGDyK), with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and labeled the RGD-DOTA conjugate with ⁶⁴Cu (half-life, 12.8 h; 19% ß⁺) for solid tumor targeting, with high tumor-to-background contrast. The rapid tumor washout rate and persistent liver and kidney retention of this tracer prompted us to optimize the tracer for improved pharmacokinetic behavior. In this study, we introduced a polyethylene glycol (PEG; molecular weight, 3,400) moiety between DOTA and RGD and evaluated the ⁶⁴Cu-DOTA-PEG-RGD tracer for microPET imaging in brain tumor models. Methods: DOTA was activated in situ and conjugated with RGD-PEG-NH₂ under slightly basic conditions. _vß₃-Integrin-binding affinity was evaluated with a solid-phase receptor-binding assay in the presence of ¹²⁵I-echistatin. Female nude mice bearing subcutaneous U87MG glioblastoma xenografts were administered ⁶⁴Cu-DOTA-PEG-RGD, and the biodistributions of the radiotracer were evaluated from 30 min to 4 h after injection. microPET (20 min of static imaging at 1 h after injection) and then quantitative autoradiography were used for tumor visualization and quantification. The same tracer was also applied to an orthotopic U87MG model for tumor detection. Results: The radiotracer was synthesized with a high specific activity (14,800–29,600 GBq/mmol [400–800 Ci/mmol]). The c(RGDyK)-PEG-DOTA ligand showed intermediate binding affinity for _vß₃-integrin (50% inhibitory concentration, 67.5 ± 7.8 nmol/L [mean ± SD]). The pegylated RGD peptide demonstrated rapid blood clearance (0.57 ± 0.15 percentage injected dose [%ID]/g [mean ± SD] at 30 min after injection and 0.03 ± 0.02 %ID/g at 4 h after injection). Activity accumulation in the tumor was rapid and high at early time points (2.74 ± 0.45 %ID/g at 30 min after injection), and some activity washout was seen over time (1.62 ± 0.18 %ID/g at 4 h after injection). Compared with ⁶⁴Cu-DOTA-RGD, this tracer showed improved in vivo kinetics, with significantly reduced liver uptake (0.99 ± 0.08 %ID/g vs. 1.73 ± 0.39 %ID/g at 30 min after injection and 0.58 ± 0.07 %ID/g vs. 2.57 ± 0.49 %ID/g at 4 h after injection). The pegylated RGD peptide showed higher renal accumulation at early time points (3.51 ± 0.24 %ID/g vs. 2.18 ± 0.23 %ID/g at 30 min after infection) but more rapid clearance (1.82 ± 0.29 %ID/g vs. 2.01 ± 0.25 %ID/g at 1 h after injection) than ⁶⁴Cu-DOTA-RGD. The integrin receptor specificity of this radiotracer was demonstrated by blocking of tumor uptake by coinjection with nonradiolabeled c(RGDyK). The high tumor-to-organ ratios for the pegylated RGD peptide tracer (at 1 h after injection: tumor-to-blood ratio, 20; tumor-to-muscle ratio, 12; tumor-to-liver ratio, 2.7; and tumor-to-kidney ratio, 1.2) were confirmed by microPET and autoradiographic imaging in a subcutaneous U87MG tumor model. This tracer was also able to detect an orthotopic brain tumor in a model in which U87MG cells were implanted into the mouse forebrain. Although the magnitude of tumor uptake in the orthotopic xenograft was lower than that in the subcutaneous xenograft, the orthotopic tumor was still visualized with clear contrast from normal brain tissue. Conclusion: This study demonstrated the suitability of a PEG moiety for improving the in vivo kinetics of a ⁶⁴Cu-RGD peptide tracer without compromising the tumor-targeting ability and specificity of the peptide. Systematic investigations of the effects of the size and geometry of PEG on tumor targeting and in vivo kinetics will lead to the development of radiotracers suitable for clinical applications such as visualizing and quantifying _v-integrin expression by PET. In addition, the same ligand labeled with therapeutic radionuclides may be applicable for integrin-targeted internal radiotherapy.

Key Words: molecular imaging • PET • radiopharmaceuticals • angiogenesis • integrin • Arg-Gly-Asp • ⁶⁴Cu • pegylation

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