Improved positron emission tomography imaging of glioblastoma cancer using novel68Ga-labeled peptides targeting the urokinase-type plasminogen activator receptor (uPAR).
The urokinase-type plasminogen activator receptor (uPAR) is overexpressed in several cancers including glioblastoma (GBM) and is an established biomarker for metastatic potential. The uPAR-targeting peptide AE105-NH2(Ac-Asp-Cha-Phe-(D)Ser-(D)Arg-Tyr-Leu-Trp-Ser-CONH2) is a promising candidate for non-invasive positron emission tomography (PET) imaging of uPAR. Despite the optimal physical properties of68Ga for peptide-based PET imaging, low tumor uptakes have previously been reported using68Ga-labeled AE105-NH2-based tracers. In an attempt to optimize the tumor uptake, we developed three novel tracers with alkane (AOC) and polyethylene glycol (PEG) spacers inserted between AE105-NH2and the radio metal chelator 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA). The resulting tracers NODAGA-AOC-AE105-NH2, NODAGA-PEG3-AE105-NH2and NODAGA-PEG8-AE105-NH2were compared to the non-spacer version, NODAGA-AE105-NH2. Following radiolabeling with68Ga, we evaluated the in vitro and in vivo performance in mice bearing subcutaneous tumors derived from the uPAR-expressing human GBM cell line U87MG. In vivo PET/CT imaging showed that introduction of PEG spacers more than doubled the in vivo tumor uptake after 1 h compared with the non-spacer version:68Ga-NODAGA-PEG3-AE105-NH2(2.08 ± 0.37%ID/g) and68Ga-NODAGA-PEG8-AE105-NH2(2.01 ± 0.22%ID/g) vs.68Ga-NODAGA-AE105-NH2(0.70 ± 0.40%ID/g), p < 0.05. In addition,68Ga-NODAGA-PEG8-AE105-NH2showed significantly higher (p < 0.05) tumor-to-background contrast (3.68 ± 0.23) than the other tracers. The specific tumor-targeting property of68Ga-NODAGA-PEG8-AE105-NH2was established by effectively blocking the tumor uptake with co-injection of unlabeled AE105-NH2(1 h: unblocked 2.01 ± 0.22%ID/g vs. blocked 1.24 ± 0.09%ID/g, p < 0.05). Ex vivo biodistribution confirmed the improved tumor uptakes of the PEG-modified tracers.68Ga-NODAGA-PEG8-AE105-NH2is thus a promising candidate for human translation for PET imaging of GBM.
Department of Radiology, School of Medicine, Stanford University, 1201 Welch Road, Lucas Center, P095, Mail Code 5484, Stanford, CA, 94305, USA.|Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, KF-4012, Blegdamsvej 9, 2100, Copenhagen, Denmark.|Cluster for Molecular Imaging, University of Copenhagen, Panum Institute bldg. 12.3, Blegdamsvej 3, 2200, Copenhagen, Denmark.
Mathias Dyrberg
MD
Loft
Department of Radiology, School of Medicine, Stanford University, 1201 Welch Road, Lucas Center, P095, Mail Code 5484, Stanford, CA, 94305, USA.
Yao
Y
Sun
Department of Radiology, School of Medicine, Stanford University, 1201 Welch Road, Lucas Center, P095, Mail Code 5484, Stanford, CA, 94305, USA.
Changhao
C
Liu
Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, KF-4012, Blegdamsvej 9, 2100, Copenhagen, Denmark.|Cluster for Molecular Imaging, University of Copenhagen, Panum Institute bldg. 12.3, Blegdamsvej 3, 2200, Copenhagen, Denmark.
Camilla
C
Christensen
Department of Radiology, School of Medicine, Stanford University, 1201 Welch Road, Lucas Center, P095, Mail Code 5484, Stanford, CA, 94305, USA.
Daijuan
D
Huang
Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, KF-4012, Blegdamsvej 9, 2100, Copenhagen, Denmark. akjaer@sund.ku.dk.|Cluster for Molecular Imaging, University of Copenhagen, Panum Institute bldg. 12.3, Blegdamsvej 3, 2200, Copenhagen, Denmark. akjaer@sund.ku.dk.
Andreas
A
Kjaer
Department of Radiology, School of Medicine, Stanford University, 1201 Welch Road, Lucas Center, P095, Mail Code 5484, Stanford, CA, 94305, USA. zcheng@stanford.edu.
Zhen
Z
Cheng
D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry / Q000494:pharmacology; D005708:Gallium / Q000737:chemistry / Q000494:pharmacology; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D049268:Positron-Emission Tomography; D055293:Receptors, Urokinase Plasminogen Activator / Q000819:agonists*
D003287:Contrast Media; D010455:Peptides; D055293:Receptors, Urokinase Plasminogen Activator; D005708:Gallium
Glioblastoma; PET; PET/CT; Radiotracer; uPAR