title: Integrin α(v)β₃-targeted radiotracer (99m)Tc-3P-RGD₂ useful for noninvasive monitoring of breast tumor response to antiangiogenic linifanib therapy but not anti-integrin α(v)β₃ RGD₂ therapy.
abstract: OBJECTIVE
  (99m)Tc-3P-RGD2 is a (99m)Tc-labeled dimeric cyclic RGD peptide that binds to integrin α(v)β₃ with high affinity and specificity. The purpose of this study was to demonstrate the utility of (99m)Tc-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(v)β₃ 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 (99m)Tc-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 (99m)Tc-3P-RGD₂ was calculated from SPECT/CT quantification. When cyclic peptide E[c(RGDfK)]2 (RGD₂) was used as the anti-α(v)β₃ agent, SPECT/CT images were obtained only at 7 and 21 days after last RGD₂ dose.
  
  
  RESULTS
  The tumor uptake of (99m)Tc-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 (99m)Tc-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(v)β₃ 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 (99m)Tc-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(v)β₃ expression levels before linifanib therapy.
  
  
  CONCLUSIONS
  (99m)Tc-3P-RGD₂ is an excellent radiotracer for monitoring integrin α(v)β₃ expression during and after linifanib therapy. (99m)Tc-3P-RGD₂ SPECT/CT is an useful molecular imaging tool for patient selection before antiangiogenic and anti-α(v)β₃ therapy; but it would be difficult to use (99m)Tc-3P-RGD₂ for accurate and noninvasive monitoring of early tumor response to anti-α(v)β₃ therapy.
authors: 1. School of Health Sciences, Purdue University, IN 47907, USA.
authors: Shundong
authors: S
authors: Ji
authors: Yumin
authors: Y
authors: Zheng
authors: Guoqiang
authors: G
authors: Shao
authors: Yang
authors: Y
authors: Zhou
authors: Shuang
authors: S
authors: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000628:therapy*; D004195:Disease Models, Animal; D016903:Drug Monitoring / Q000379:methods*; D007191:Indazoles / Q000627:therapeutic use*; D039302:Integrin alphaVbeta3 / Q000032:analysis*; D051379:Mice; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011849:Radioactive Tracers; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D039302:Integrin alphaVbeta3; D010671:Phenylurea Compounds; D011849:Radioactive Tracers; C513486:linifanib
keywords: Linifanib; and 99mTc-3P-RGD2.; integrin αvβ3; monitoring antiangiogenic therapy