Integrin α_vβ₃-Targeted Radiotracer ^99mTc-3P-RGD₂ Useful for Noninvasive Monitoring of Breast Tumor Response to Antiangiogenic Linifanib Therapy but not Anti-Integrin α_vβ₃ RGD₂ Therapy

Abstract

Purpose: 99mTc-3P-RGD2 is a 99mTc-labeled dimeric cyclic RGD peptide that binds to integrin αvβ3 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-αvβ3 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-αvβ3 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 αvβ3 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 αvβ3 expression levels before linifanib therapy.Conclusion: 99mTc-3P-RGD2 is an excellent radiotracer for monitoring integrin αvβ3 expression during and after linifanib therapy. 99mTc-3P-RGD2 SPECT/CT is an useful molecular imaging tool for patient selection before antiangiogenic and anti-αvβ3 therapy; but it would be difficult to use 99mTc-3P-RGD2 for accurate and noninvasive monitoring of early tumor response to anti-αvβ3 therapy.

Radiolabeled Cyclic RGD Peptide Bioconjugates as Radiotracers Targeting Multiple Integrins

“…199,200 Linifanib a multi-targeted receptor tyrosine kinase inhibitor targeting VEGF and PDGF receptors. 201–206 It was found that there was a significant decrease in its tumor uptake and T/M ratios in the xenografted U87MG model while no significant changes in tumor uptake of 99m Tc-3P-RGD 2 were seen in the PC-3 model after linifanib therapy.…”

99mTc-3PRGD2 SPECT to monitor early response to neoadjuvant chemotherapy in stage II and III breast cancer

“…Previous studies have shown that 99m Tc-3PRGD 2 SPECT provides images of impressive quality and has high sensitivity in detecting lung and breast lesions in humans [14][15][16][17]. 99m Tc-3PRGD 2 SPECT has also been found to be useful in monitoring early tumor response to antiangiogenesis therapy in breast cancer xenografts [18,19].…”

“…For example, 18 F-FDG PET enables visualization and quantification of tumor glucose metabolism and has been found to be able to document the response to NCT in breast cancer [4][5][6][7]. Functional MRI techniques including dynamic contrast-enhanced MRI, diffusion-weighted imaging and magnetic resonance spectroscopy, provide surrogate markers of response to NCT [8][9][10].…”

Can 111In-RGD2 Monitor Response to Therapy in Head and Neck Tumor Xenografts?

“…The HNSCC xenografts used in these studies express only integrin a v b 3 on angiogenic blood vessels, making them an ideal model for studies involving RGD tracers and angiogenesis. Some studies also suggested that these tracers could monitor response to antiangiogenic therapy in integrin a v b 3 -overexpressing tumor models, which corresponds with monitoring viable tumor mass (16,19); we therefore also studied integrin a v b 3 -overexpressing tumors.…”

“…More recently, it was also found that monomeric RGD tracers can monitor response to treatment with either antiangiogenic or antimigratory and antiproliferative therapy (16)(17)(18). So far, only one publication suggests that dimeric RGD peptide tracers can monitor response to therapy, here the antiangiogenic linifanib (19).…”