TY - JOUR
T1 - 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of αvβ3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer
AU - Kazmierczak, Philipp M.
AU - Todica, Andrei
AU - Gildehaus, Franz Josef
AU - Hirner-Eppeneder, Heidrun
AU - Brendel, Matthias
AU - Eschbach, Ralf S.
AU - Hellmann, Magdalena
AU - Nikolaou, Konstantin
AU - Reiser, Maximilian F.
AU - Wester, Hans Jurgen
AU - Kropf, Saskia
AU - Rominger, Axel
AU - Cyran, Clemens C.
N1 - Publisher Copyright:
© 2016 Kazmierczak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/12
Y1 - 2016/12
N2 - To investigate 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of αvβ3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer. Materials and Methods Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq 68Ga-TRAP-(RGD)3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImaxtumor/VOImeanmuscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (αvβ3-integrin, microvascular density±CD31, proliferation±Ki-67, apoptosis± TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12). Results 68Ga-TRAP-(RGD)3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (?TBRfollow-up/baseline: therapy -1.07±0.83, control +0.32±1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (Δvolumetherapy 134±77 μL, Δvolumecontrol 132±56 μL, p = 1.000). Immunohistochemistry revealed a significant reduction of αvβ3-integrin expression (308±135 vs. 635±325, p = 0.03), microvascular density (CD31, 168±108 vs. 432±70, p = 0.002), proliferation (Ki-67, 5,195±1,002 vs. 7,574±418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432±1,974 vs. 3,776±1,378, p = 0.002) in the therapy compared to the control group. Conclusions 68Ga-TRAP-(RGD)3 hybrid imaging allows for the in vivo assessment of αvβ3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.
AB - To investigate 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of αvβ3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer. Materials and Methods Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq 68Ga-TRAP-(RGD)3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImaxtumor/VOImeanmuscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (αvβ3-integrin, microvascular density±CD31, proliferation±Ki-67, apoptosis± TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12). Results 68Ga-TRAP-(RGD)3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (?TBRfollow-up/baseline: therapy -1.07±0.83, control +0.32±1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (Δvolumetherapy 134±77 μL, Δvolumecontrol 132±56 μL, p = 1.000). Immunohistochemistry revealed a significant reduction of αvβ3-integrin expression (308±135 vs. 635±325, p = 0.03), microvascular density (CD31, 168±108 vs. 432±70, p = 0.002), proliferation (Ki-67, 5,195±1,002 vs. 7,574±418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432±1,974 vs. 3,776±1,378, p = 0.002) in the therapy compared to the control group. Conclusions 68Ga-TRAP-(RGD)3 hybrid imaging allows for the in vivo assessment of αvβ3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=85006851356&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0168248
DO - 10.1371/journal.pone.0168248
M3 - Article
C2 - 27992512
AN - SCOPUS:85006851356
SN - 1932-6203
VL - 11
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - e0168248
ER -
