TY - JOUR
T1 - Imaging of urokinase-type plasminogen activator receptor expression using a 64Cu-labeled linear peptide antagonist by microPET
AU - Li, Zi-Bo
AU - Niu, Gang
AU - Wang, Hui
AU - He, Lina
AU - Yang, Lily
AU - Ploug, Michael
AU - Chen, Xiaoyuan
PY - 2008/8/1
Y1 - 2008/8/1
N2 - PURPOSE: Malignant tumors are capable of degrading the surrounding extracellular matrix, resulting in local invasion or metastasis. Urokinase-type plasminogen activator (uPA) and its cell surface receptor (uPAR) are central molecules in one of the major protease systems involved in extracellular matrix degradation. Noninvasive imaging of this receptor in vivo with radiolabeled peptides that specifically target uPAR may therefore be useful to decipher the potential invasiveness of malignant lesions.EXPERIMENTAL DESIGN: In this study, we developed a (64)Cu-labeled uPAR-binding peptide for positron emission tomography (PET) imaging. A linear, high-affinity uPAR-binding peptide antagonist AE105 was conjugated with 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) and labeled with (64)Cu for microPET imaging of mice bearing U87MG human glioblastoma (uPAR positive) and MDA-MB-435 human breast cancer (uPAR negative).RESULTS: Surface plasmon resonance measurements show that AE105 with DOTA conjugated at the alpha-amino group (DOTA-AE105) has high affinity toward uPAR. microPET imaging reveals a rapid and high accumulation of (64)Cu-DOTA-AE105 in uPAR-positive U87MG tumors (10.8 +/- 1.5%ID/g at 4.5 hours, n = 3) but not in uPAR-negative MDA-MB-435 tumors (1.2 +/- 0.6%ID/g at 4.5 hours, n = 3). Specificity of this peptide-based imaging of uPAR was validated by further control experiments. First, a nonbinding variant of AE105 carrying a single amino acid replacement (Trp-->Glu) does not target U87MG tumors in vivo. Second, targeting of U87MG tumors by (64)Cu-DOTA-AE105 is specifically inhibited by a nonlabeled antagonist.CONCLUSION: The successful demonstration of the ability of a (64)Cu labeled uPAR-specific probe to visualize uPAR expression in vivo may allow clinical translation of this class of radiopharmaceuticals for uPAR-positive cancer detection and patient stratification for uPA/uPAR system-based cancer therapy.
AB - PURPOSE: Malignant tumors are capable of degrading the surrounding extracellular matrix, resulting in local invasion or metastasis. Urokinase-type plasminogen activator (uPA) and its cell surface receptor (uPAR) are central molecules in one of the major protease systems involved in extracellular matrix degradation. Noninvasive imaging of this receptor in vivo with radiolabeled peptides that specifically target uPAR may therefore be useful to decipher the potential invasiveness of malignant lesions.EXPERIMENTAL DESIGN: In this study, we developed a (64)Cu-labeled uPAR-binding peptide for positron emission tomography (PET) imaging. A linear, high-affinity uPAR-binding peptide antagonist AE105 was conjugated with 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) and labeled with (64)Cu for microPET imaging of mice bearing U87MG human glioblastoma (uPAR positive) and MDA-MB-435 human breast cancer (uPAR negative).RESULTS: Surface plasmon resonance measurements show that AE105 with DOTA conjugated at the alpha-amino group (DOTA-AE105) has high affinity toward uPAR. microPET imaging reveals a rapid and high accumulation of (64)Cu-DOTA-AE105 in uPAR-positive U87MG tumors (10.8 +/- 1.5%ID/g at 4.5 hours, n = 3) but not in uPAR-negative MDA-MB-435 tumors (1.2 +/- 0.6%ID/g at 4.5 hours, n = 3). Specificity of this peptide-based imaging of uPAR was validated by further control experiments. First, a nonbinding variant of AE105 carrying a single amino acid replacement (Trp-->Glu) does not target U87MG tumors in vivo. Second, targeting of U87MG tumors by (64)Cu-DOTA-AE105 is specifically inhibited by a nonlabeled antagonist.CONCLUSION: The successful demonstration of the ability of a (64)Cu labeled uPAR-specific probe to visualize uPAR expression in vivo may allow clinical translation of this class of radiopharmaceuticals for uPAR-positive cancer detection and patient stratification for uPA/uPAR system-based cancer therapy.
KW - Animals
KW - Cell Line, Tumor
KW - Copper Radioisotopes
KW - Female
KW - Heterocyclic Compounds, 1-Ring
KW - Humans
KW - Kinetics
KW - Mice
KW - Mice, Nude
KW - Neoplasm Transplantation
KW - Peptides
KW - Positron-Emission Tomography
KW - Receptors, Cell Surface
KW - Receptors, Urokinase Plasminogen Activator
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Surface Plasmon Resonance
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
KW - Research Support, U.S. Gov't, Non-P.H.S.
U2 - 10.1158/1078-0432.CCR-07-4434
DO - 10.1158/1078-0432.CCR-07-4434
M3 - Journal article
C2 - 18676745
SN - 1078-0432
VL - 14
SP - 4758
EP - 4766
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -
