Non-invasive longitudinal imaging of tumor progression using an (111)indium labeled CXCR4 peptide antagonist.

Buckle, Tessa; van Berg, Nynke S; Kuil, Joeri; Bunschoten, Anton; Oldenburg, Joppe; Borowsky, Alexander D; Wesseling, Jelle; Masada, Ryo; Oishi, Shinya; Fujii, Nobutaka; van Leeuwen, Fijs Wb

The chemokine receptor 4 (CXCR4) is a biomarker that is over-expressed in ductal carcinoma in situ (DCIS). Hence, CXCR4-targeted (molecular) imaging approaches may have diagnostic value in such a challenging, premalignant lesion. The indium labeled CXCR4 peptide-antagonist, (111)In-DTPA-Ac-TZ14011, was used to visualize CXCR4-expression in a mammary intraepithelial neoplastic outgrowth (MIN-O) mouse tumor model resembling human DCIS. MIN-O lesion development was longitudinally monitored using SPET/CT and tracer uptake was compared to uptake in control lesions. Expression of CXCR4 was validated using immunohistochemistry and flow cytometric analysis. The uptake of (111)In-DTPA-Ac-TZ14011 was related to tumor angiogenesis using (111)In-cDTPA-[RGDfK]. Twenty-four hours after tracer injection, MIN-O lesions could be discriminated from low CXCR4-expressing control tumors, while the degree of angiogenesis based on the α(v)β(3) integrin expression in both tumor types was similar. The uptake of (111)In-DTPA-Ac-TZ14011 in early MIN-O lesions was significantly lower than in larger intermediate and late-stage lesions, two-and-a-half-times (p=0.03) and seven-times (p=0.002), respectively. Intermediate and late stage lesions show a higher degree of membranous CXCR4-staining at immunohistochemistry and flow cytometric analysis. From this study we can conclude that (111)In-DTPA-Ac-TZ14011 can be used to visualize the CXCR4-expression in MIN-O lesions longitudinally.