TY - JOUR
T1 - PET of c-Met in cancer with 64Cu-labeled hepatocyte growth factor
AU - Luo, Haiming
AU - Hong, Hao
AU - Slater, Michael R.
AU - Graves, Stephen A.
AU - Shi, Sixiang
AU - Yang, Yunan
AU - Nickles, Robert J.
AU - Fan, Frank
AU - Cai, Weibo
N1 - Publisher Copyright:
COPYRIGHT © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2015/5
Y1 - 2015/5
N2 - The hepatocyte growth factor (HGF) and its receptor, c-Met, are actively involved in tumor progression and metastasis and are closely associated with a poor prognostic outcome for cancer patients. Thus, the development of PET agents that can assess c-Met expression would be extremely useful for diagnosing cancer and subsequently monitoring response to c-Met-targeted therapies. Here, we report the characterization of recombinant human HGF (rh-HGF) as a PET tracer for detection of c-Met expression in vivo. Methods: rh-HGF was expressed in human embryonic kidney 293 cells and purified by nickel-nitrilotriacetic acid affinity chromatography. The concentrated rh-HGF was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid and labeled with 64Cu. c-Met binding evaluation by flow cytometry was performed on both U87MG and MDA-MB-231 cell lines, which have a high level and a low level, respectively, of c-Met. PET imaging and biodistribution studies were performed on nude mice bearing U87MG and MDA-MB-231 xenografted tumors. Results: The rh-HGF expression yield was 150-200 μg of protein per 5 × 106 cells after a 48-h transfection, with purity of approximately 85%-90%. Flow cytometry examination confirmed that rh-HGF had a strong and specific capacity to bind to c-Met. After 64Cu labeling, PET imaging revealed specific and prominent uptake of 64Cu-NOTA-rh-HGF in c-Met-positive U87MG tumors (percentage injected dose per gram, 6.8 ± 1.8 at 9 h after injection) and significantly lower uptake in c-Met-negative MDA-MB-231 tumors (percentage injected dose per gram, 1.8 ± 0.6 at 9 h after injection). The fact that sonication-denatured rh-HGF had significantly lower uptake in U87MG tumors, along with histology analysis, confirmed the c-Met specificity of 64Cu-NOTA-rh-HGF. Conclusion: This study provided initial evidence that 64Cu-NOTA-rh-HGF visualizes c-Met expression in vivo, an appli that may prove useful for c-Met-targeted cancer therapy.
AB - The hepatocyte growth factor (HGF) and its receptor, c-Met, are actively involved in tumor progression and metastasis and are closely associated with a poor prognostic outcome for cancer patients. Thus, the development of PET agents that can assess c-Met expression would be extremely useful for diagnosing cancer and subsequently monitoring response to c-Met-targeted therapies. Here, we report the characterization of recombinant human HGF (rh-HGF) as a PET tracer for detection of c-Met expression in vivo. Methods: rh-HGF was expressed in human embryonic kidney 293 cells and purified by nickel-nitrilotriacetic acid affinity chromatography. The concentrated rh-HGF was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid and labeled with 64Cu. c-Met binding evaluation by flow cytometry was performed on both U87MG and MDA-MB-231 cell lines, which have a high level and a low level, respectively, of c-Met. PET imaging and biodistribution studies were performed on nude mice bearing U87MG and MDA-MB-231 xenografted tumors. Results: The rh-HGF expression yield was 150-200 μg of protein per 5 × 106 cells after a 48-h transfection, with purity of approximately 85%-90%. Flow cytometry examination confirmed that rh-HGF had a strong and specific capacity to bind to c-Met. After 64Cu labeling, PET imaging revealed specific and prominent uptake of 64Cu-NOTA-rh-HGF in c-Met-positive U87MG tumors (percentage injected dose per gram, 6.8 ± 1.8 at 9 h after injection) and significantly lower uptake in c-Met-negative MDA-MB-231 tumors (percentage injected dose per gram, 1.8 ± 0.6 at 9 h after injection). The fact that sonication-denatured rh-HGF had significantly lower uptake in U87MG tumors, along with histology analysis, confirmed the c-Met specificity of 64Cu-NOTA-rh-HGF. Conclusion: This study provided initial evidence that 64Cu-NOTA-rh-HGF visualizes c-Met expression in vivo, an appli that may prove useful for c-Met-targeted cancer therapy.
KW - cu
KW - c-Met
KW - Cancer
KW - Hepatocyte growth factor (HGF)
KW - Positron emission tomography (PET)
UR - http://www.scopus.com/inward/record.url?scp=84929493068&partnerID=8YFLogxK
U2 - 10.2967/jnumed.115.154690
DO - 10.2967/jnumed.115.154690
M3 - Journal article
C2 - 25840981
AN - SCOPUS:84929493068
SN - 0161-5505
VL - 56
SP - 758
EP - 763
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 5
ER -