PET imaging of tumor neovascularization in a transgenic mouse model with a novel 64Cu-DOTA-knottin peptide

TY - JOUR

T1 - PET imaging of tumor neovascularization in a transgenic mouse model with a novel 64Cu-DOTA-knottin peptide

AU - Nielsen, Carsten Haagen

AU - Kimura, Richard H

AU - Withofs, Nadia

AU - Tran, Phuoc T

AU - Miao, Zheng

AU - Cochran, Jennifer R

AU - Cheng, Zhen

AU - Felsher, Dean

AU - Kjær, Andreas

AU - Willmann, Juergen K

AU - Gambhir, Sanjiv S

N1 - Copyright © 2010 AACR.

PY - 2010/11/15

Y1 - 2010/11/15

N2 - Due to the high mortality of lung cancer, there is a critical need to develop diagnostic procedures enabling early detection of the disease while at a curable stage. Targeted molecular imaging builds on the positive attributes of positron emission tomography/computed tomography (PET/CT) to allow for a noninvasive detection and characterization of smaller lung nodules, thus increasing the chances of positive treatment outcome. In this study, we investigate the ability to characterize lung tumors that spontaneously arise in a transgenic mouse model. The tumors are first identified with small animal CT followed by characterization with the use of small animal PET with a novel 64Cu-1,4,7,10-tetra-azacylododecane-N,N′,N″, N‴-tetraacetic acid (DOTA)-knottin peptide that targets integrins upregulated during angiogenesis on the tumor associated neovasculature. The imaging results obtained with the knottin peptide are compared with standard 18F-fluorodeoxyglucose (FDG) PET small animal imaging. Lung nodules as small as 3 mm in diameter were successfully identified in the transgenic mice by small animal CT, and both 64Cu-DOTA-knottin 2.5F and FDG were able to differentiate lung nodules from the surrounding tissues. Uptake and retention of the 64Cu-DOTA-knottin 2.5F tracer in the lung tumors combined with a low background in the thorax resulted in a statistically higher tumor to background (normal lung) ratio compared with FDG (6.01 ± 0.61 versus 4.36 ± 0.68; P < 0.05). Ex vivo biodistribution showed 64Cu-DOTA-knottin 2.5F to have a fast renal clearance combined with low nonspecific accumulation in the thorax. Collectively, these results show 64Cu-DOTA-knottin 2.5F to be a promising candidate for clinical translation for earlier detection and improved characterization of lung cancer.

AB - Due to the high mortality of lung cancer, there is a critical need to develop diagnostic procedures enabling early detection of the disease while at a curable stage. Targeted molecular imaging builds on the positive attributes of positron emission tomography/computed tomography (PET/CT) to allow for a noninvasive detection and characterization of smaller lung nodules, thus increasing the chances of positive treatment outcome. In this study, we investigate the ability to characterize lung tumors that spontaneously arise in a transgenic mouse model. The tumors are first identified with small animal CT followed by characterization with the use of small animal PET with a novel 64Cu-1,4,7,10-tetra-azacylododecane-N,N′,N″, N‴-tetraacetic acid (DOTA)-knottin peptide that targets integrins upregulated during angiogenesis on the tumor associated neovasculature. The imaging results obtained with the knottin peptide are compared with standard 18F-fluorodeoxyglucose (FDG) PET small animal imaging. Lung nodules as small as 3 mm in diameter were successfully identified in the transgenic mice by small animal CT, and both 64Cu-DOTA-knottin 2.5F and FDG were able to differentiate lung nodules from the surrounding tissues. Uptake and retention of the 64Cu-DOTA-knottin 2.5F tracer in the lung tumors combined with a low background in the thorax resulted in a statistically higher tumor to background (normal lung) ratio compared with FDG (6.01 ± 0.61 versus 4.36 ± 0.68; P < 0.05). Ex vivo biodistribution showed 64Cu-DOTA-knottin 2.5F to have a fast renal clearance combined with low nonspecific accumulation in the thorax. Collectively, these results show 64Cu-DOTA-knottin 2.5F to be a promising candidate for clinical translation for earlier detection and improved characterization of lung cancer.

KW - Animals

KW - Antigens, CD31

KW - Copper Radioisotopes

KW - Cystine-Knot Miniproteins

KW - Fluorescent Antibody Technique

KW - Integrins

KW - Mice

KW - Mice, Transgenic

KW - Mutation

KW - Neoplasms

KW - Neovascularization, Pathologic

KW - Positron-Emission Tomography

KW - Proto-Oncogene Proteins c-myc

KW - Proto-Oncogene Proteins p21(ras)

KW - Radiopharmaceuticals

KW - Sensitivity and Specificity

KW - Tissue Distribution

KW - Tomography, X-Ray Computed

U2 - 10.1158/0008-5472.CAN-10-1338

DO - 10.1158/0008-5472.CAN-10-1338

M3 - Journal article

C2 - 21062977

SN - 0008-5472

VL - 70

SP - 9022

EP - 9030

JO - Cancer Research

JF - Cancer Research

IS - 22

ER -