TY - JOUR
T1 - Pharmacokinetic modeling of targeted ultrasound contrast agents for quantitative assessment of anti-angiogenic therapy
T2 - a longitudinal case-control study in colon cancer
AU - Turco, Simona
AU - El Kaffas, Ahmed
AU - Zhou, Jianhua
AU - Lutz, Amelie M.
AU - Wijkstra, Hessel
AU - Willmann, Jürgen K.
AU - Mischi, Massimo
PY - 2019/9
Y1 - 2019/9
N2 - Purpose: To evaluate quantitative and semi-quantitative ultrasound molecular imaging (USMI) for antiangiogenic therapy monitoring in human colon cancer xenografts in mice. Procedures: Colon cancer was established in 17 mice by injection of LS174T (Nr = 9) or CT26 (Nn = 8) cancer cells to simulate clinical responders and non-responders, respectively. Antiangiogenic treatment (bevacizumab; Nrt = Nnt = 5) or control treatment (saline; Nrc = 4, Nnc = 3) was administered at days 0, 3, and 7. Three-dimensional USMI was performed by injection at days 0, 1, 3, 7, and 10 of microbubbles targeted to the vascular endothelial growth factor receptor 2 (VEGFR2). Microbubble binding rate (kb), estimated by first-pass binding model fitting, and semi-quantitative parameters late enhancement (LE) and differential targeted enhancement (dTE) were compared at each day to evaluate their ability to assess and predict the response to therapy. Correlation analysis with the ex-vivo immunohistological quantification of VEGFR2 expression and the percentage blood vessel area was also performed. Results: Significant changes in the USMI parameters during treatment were observed only in the responders treated with bevacizumab (p-value < 0.05). Prediction of the response to therapy as early as 1 day after treatment was achieved by the quantitative parameter kb (p-value < 0.01), earlier than possible by tumor volume quantification. USMI parameters could significantly distinguish between clinical responders and non-responders (p-value << 0.01) and correlated well with the ex-vivo quantification of VEGFR2 expression and the percentage blood vessels area (p-value << 0.01). Conclusion: USMI (semi)quantitative parameters provide earlier assessment of the response to therapy compared to tumor volume, permit early prediction of non-responders, and correlate well with ex-vivo angiogenesis biomarkers.
AB - Purpose: To evaluate quantitative and semi-quantitative ultrasound molecular imaging (USMI) for antiangiogenic therapy monitoring in human colon cancer xenografts in mice. Procedures: Colon cancer was established in 17 mice by injection of LS174T (Nr = 9) or CT26 (Nn = 8) cancer cells to simulate clinical responders and non-responders, respectively. Antiangiogenic treatment (bevacizumab; Nrt = Nnt = 5) or control treatment (saline; Nrc = 4, Nnc = 3) was administered at days 0, 3, and 7. Three-dimensional USMI was performed by injection at days 0, 1, 3, 7, and 10 of microbubbles targeted to the vascular endothelial growth factor receptor 2 (VEGFR2). Microbubble binding rate (kb), estimated by first-pass binding model fitting, and semi-quantitative parameters late enhancement (LE) and differential targeted enhancement (dTE) were compared at each day to evaluate their ability to assess and predict the response to therapy. Correlation analysis with the ex-vivo immunohistological quantification of VEGFR2 expression and the percentage blood vessel area was also performed. Results: Significant changes in the USMI parameters during treatment were observed only in the responders treated with bevacizumab (p-value < 0.05). Prediction of the response to therapy as early as 1 day after treatment was achieved by the quantitative parameter kb (p-value < 0.01), earlier than possible by tumor volume quantification. USMI parameters could significantly distinguish between clinical responders and non-responders (p-value << 0.01) and correlated well with the ex-vivo quantification of VEGFR2 expression and the percentage blood vessels area (p-value << 0.01). Conclusion: USMI (semi)quantitative parameters provide earlier assessment of the response to therapy compared to tumor volume, permit early prediction of non-responders, and correlate well with ex-vivo angiogenesis biomarkers.
KW - Antiangiogenic therapy
KW - Cancer therapy monitoring
KW - Colorectal cancer
KW - Pharmacokinetic modeling
KW - Ultrasound molecular imaging
UR - http://www.scopus.com/inward/record.url?scp=85053689971&partnerID=8YFLogxK
U2 - 10.1007/s11307-018-1274-z
DO - 10.1007/s11307-018-1274-z
M3 - Article
C2 - 30225758
AN - SCOPUS:85053689971
SN - 1536-1632
VL - 21
SP - 633
EP - 643
JO - Molecular Imaging and Biology
JF - Molecular Imaging and Biology
IS - 4
ER -
