Molecular Imaging of Very Late Antigen–4 (α4β1 Integrin) in the Premetastatic Niche

• DOI: 10.2967/jnumed.111.100073
• Publication Date: 2012-04-11T02:31:25Z
• Authors: Monica Shokeen; Alexander Zheleznyak; Jessica M. Wilson; Majiong Jiang; Ruiwu Liu; Riccardo Ferdani; Kit S. Lam; Julie K. Schwarz; Carolyn J. Anderson
• Keywords: Bioluminescence imaging; CD31

Despite advances in cancer treatment over the past few decades, metastatic disease remains primary cause of morbidity and mortality. Recent reports suggest formation a "premetastatic niche" before cascade, where <i>niche</i> is defined as microenvironment for tumor cells to be able engraft proliferate at secondary sites. Bone marrow–derived (BMD) that express vascular endothelial growth factor receptor–1 very late antigen–4 (VLA-4) have been shown arrive sites metastasis form receptive environment cells. Here we describe experiments toward imaging VLA-4–positive BMD using high-affinity PET probe, ⁶⁴Cu-labeled 11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] hexadecane (CB-TE2A)-LLP2A. <b>Methods:</b> VLA-4–negative MDA-MB-231/firefly luciferase (<i>fluc</i>) human breast were injected intraarterially left ventricle nude mice. Tumor mice was monitored 30 d by bioluminescence small-animal PET/CT. Small-animal images collected 2 h after tail vein with ⁶⁴Cu-CB-TE2A-LLP2A (5.6–11.1 MBq [150–300 μCi; specific activity, 400 μCi/μg]). Cellular uptake determined B16F10 mouse melanoma MDA-MB-231/<i>fluc</i> Biodistribution bearing subcutaneous tumors flank conducted validate targeting vivo. <b>Results:</b> Uptake higher than MDA-MB-231 (<i>P</i> &lt; 0.05). In tumor–bearing mice, had high VLA-4–rich organs marrow, spleen, (11.26% ± 2.59%, 8.36% 2.15%, 3.09% 0.58% dose/g, respectively). Cumulative standardized value data from independent studies (<i>n</i> = 7 8 mice) on implanted suggested an influx corresponded Immunohistochemical analysis flow cytometry also showed upregulation cell clusters sites, providing evidence noninvasive premetastatic niche. <b>Conclusion:</b> The results study demonstrated potential VLA-4–targeted visualize reorganization expansion noninvasively