Integrin αvβ3-Targeted Radiotracer 99mTc-3P-RGD2 Useful for Noninvasive Monitoring of Breast Tumor Response to Antiangiogenic Linifanib Therapy but not Anti-Integrin αvβ3 RGD2 Therapy

摘要

Purpose: 99mTc-3P-RGD₂ is a 99mTc-labeled dimeric cyclic RGD peptide that binds to integrin α_vβ₃ with high affinity and specificity. The purpose of this study was to demonstrate the utility of 99mTc-3P-RGD₂ SPECT/CT (single photon emission computed tomography/computed tomography) as a molecular imaging tool for noninvasive monitoring breast tumor early response to antiangiogenesis therapy with linifanib, and to illustrate its limitations in monitoring the efficacy of anti-α_vβ₃ treatment. Methods: To support SPECT/CT imaging, biodistribution and therapy studies, the xenografted breast cancer model was established by subcutaneous injection of 5 × 106 MDA-MB-435 cells into the fat pad of each athymic nude mouse. Linifanib (ABT-869) was used as antiangiogenesis agent. The tumor volume was 180 ± 90 mm3 on the day (-1 day) before baseline SPECT/CT. Each animal was treated twice daily with vehicle or 12.5 mg/kg linifanib. Longitudinal 99mTc-3P-RGD₂ SPECT/CT imaging was performed on days -1, 1, 4 and 11. Tumors were harvested at each time point for pathological analysis of hematoxylin and eosin (H&E) and immunohistochemistry (IHC). Tumor uptake of 99mTc-3P-RGD₂ was calculated from SPECT/CT quantification. When cyclic peptide E[c(RGDfK)]₂ (RGD₂) was used as the anti-α_vβ₃ agent, SPECT/CT images were obtained only at 7 and 21 days after last RGD₂ dose. Results: The tumor uptake of 99mTc-3P-RGD₂ from SPECT/CT quantification was almost identical to that from biodistribution. There was a dramatic reduction in both %ID and %ID/cm3 tumor uptake of 99mTc-3P-RGD₂ during the first 24 hours of linifanib therapy. The therapeutic effect of linifanib was on both tumor cells and vasculature, as determined by IHC analysis of integrin α_vβ₃ and CD31. Changes in tumor vasculature were further confirmed by pathological H&E analysis of tumor tissues. While its %ID tumor uptake increased steadily in vehicle-treated group, the %ID tumor uptake of 99mTc-3P-RGD₂ decreased in linifanib-treated group slowly over the 11-day study period. The degree of tumor response to linifanib therapy correlated well to the integrin α_vβ₃ expression levels before linifanib therapy. Conclusion: 99mTc-3P-RGD₂ is an excellent radiotracer for monitoring integrin α_vβ₃ expression during and after linifanib therapy. 99mTc-3P-RGD₂ SPECT/CT is an useful molecular imaging tool for patient selection before antiangiogenic and anti-α_vβ₃ therapy; but it would be difficult to use 99mTc-3P-RGD₂ for accurate and noninvasive monitoring of early tumor response to anti-α_vβ₃ therapy.