PET of c-Met in cancer with 64Cu-labeled hepatocyte growth factor

Haiming Luo, Hao Hong, Michael R. Slater, Stephen A. Graves, Sixiang Shi, Yunan Yang, Robert J. Nickles, Frank Fan, Weibo Cai

Research output: Journal article publicationJournal articleAcademic researchpeer-review

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)758-763
Number of pages6
JournalJournal of Nuclear Medicine
Volume56
Issue number5
Early online date3 Apr 2015
DOIs
Publication statusPublished - May 2015
Externally publishedYes

Keywords

  • cu
  • c-Met
  • Cancer
  • Hepatocyte growth factor (HGF)
  • Positron emission tomography (PET)

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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