Improved positron emission tomography imaging of glioblastoma cancer using novel 68Ga-labeled peptides targeting the urokinase-type plasminogen activator receptor (uPAR)

Mathias Dyrberg Loft; Yao Sun; Changhao Liu; Camilla Christensen; Daijuan Huang; Andreas Kjaer; Zhen Cheng

doi:10.1007/s00726-017-2407-4

Improved positron emission tomography imaging of glioblastoma cancer using novel ⁶⁸Ga-labeled peptides targeting the urokinase-type plasminogen activator receptor (uPAR)

Mathias Dyrberg Loft, Yao Sun, Changhao Liu, Camilla Christensen, Daijuan Huang, Andreas Kjaer, Zhen Cheng

5 Citations (Scopus)

Abstract

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 of ⁶⁸Ga for peptide-based PET imaging, low tumor uptakes have previously been reported using ⁶⁸Ga-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-NH₂ and 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-NH₂ and NODAGA-PEG₈-AE105-NH₂ were compared to the non-spacer version, NODAGA-AE105-NH₂. Following radiolabeling with ⁶⁸Ga, 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) and ⁶⁸Ga-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-NH₂ showed significantly higher (p < 0.05) tumor-to-background contrast (3.68 ± 0.23) than the other tracers. The specific tumor-targeting property of ⁶⁸Ga-NODAGA-PEG₈-AE105-NH₂ was 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-NH₂ is thus a promising candidate for human translation for PET imaging of GBM.

Original language	English
Journal	Amino Acids
Volume	49
Issue number	6
Pages (from-to)	1089-1100
Number of pages	12
ISSN	0939-4451
DOIs	https://doi.org/10.1007/s00726-017-2407-4
Publication status	Published - 1 Jun 2017

Keywords

Cell Line, Tumor
Contrast Media/chemistry
Gallium/chemistry
Glioblastoma/diagnostic imaging
Humans
Peptides/chemistry
Positron-Emission Tomography
Receptors, Urokinase Plasminogen Activator/agonists

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00726-017-2407-4

Cite this

Improved positron emission tomography imaging of glioblastoma cancer using novel ⁶⁸Ga-labeled peptides targeting the urokinase-type plasminogen activator receptor (uPAR). / Loft, Mathias Dyrberg; Sun, Yao; Liu, Changhao et al.

In: Amino Acids, Vol. 49, No. 6, 01.06.2017, p. 1089-1100.

Research output: Contribution to journal › Journal article › Research › peer-review

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title = "Improved positron emission tomography imaging of glioblastoma cancer using novel 68Ga-labeled peptides targeting the urokinase-type plasminogen activator receptor (uPAR)",

abstract = "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 of 68Ga for peptide-based PET imaging, low tumor uptakes have previously been reported using 68Ga-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-NH2 and 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-NH2 and NODAGA-PEG8-AE105-NH2 were compared to the non-spacer version, NODAGA-AE105-NH2. Following radiolabeling with 68Ga, 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) and 68Ga-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-NH2 showed significantly higher (p < 0.05) tumor-to-background contrast (3.68 ± 0.23) than the other tracers. The specific tumor-targeting property of 68Ga-NODAGA-PEG8-AE105-NH2 was 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-NH2 is thus a promising candidate for human translation for PET imaging of GBM.",

keywords = "Cell Line, Tumor, Contrast Media/chemistry, Gallium/chemistry, Glioblastoma/diagnostic imaging, Humans, Peptides/chemistry, Positron-Emission Tomography, Receptors, Urokinase Plasminogen Activator/agonists",

author = "Loft, {Mathias Dyrberg} and Yao Sun and Changhao Liu and Camilla Christensen and Daijuan Huang and Andreas Kjaer and Zhen Cheng",

year = "2017",

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T1 - Improved positron emission tomography imaging of glioblastoma cancer using novel 68Ga-labeled peptides targeting the urokinase-type plasminogen activator receptor (uPAR)

AU - Loft, Mathias Dyrberg

AU - Sun, Yao

AU - Liu, Changhao

AU - Christensen, Camilla

AU - Huang, Daijuan

AU - Kjaer, Andreas

AU - Cheng, Zhen

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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 of 68Ga for peptide-based PET imaging, low tumor uptakes have previously been reported using 68Ga-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-NH2 and 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-NH2 and NODAGA-PEG8-AE105-NH2 were compared to the non-spacer version, NODAGA-AE105-NH2. Following radiolabeling with 68Ga, 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) and 68Ga-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-NH2 showed significantly higher (p < 0.05) tumor-to-background contrast (3.68 ± 0.23) than the other tracers. The specific tumor-targeting property of 68Ga-NODAGA-PEG8-AE105-NH2 was 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-NH2 is thus a promising candidate for human translation for PET imaging of GBM.

AB - 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 of 68Ga for peptide-based PET imaging, low tumor uptakes have previously been reported using 68Ga-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-NH2 and 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-NH2 and NODAGA-PEG8-AE105-NH2 were compared to the non-spacer version, NODAGA-AE105-NH2. Following radiolabeling with 68Ga, 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) and 68Ga-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-NH2 showed significantly higher (p < 0.05) tumor-to-background contrast (3.68 ± 0.23) than the other tracers. The specific tumor-targeting property of 68Ga-NODAGA-PEG8-AE105-NH2 was 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-NH2 is thus a promising candidate for human translation for PET imaging of GBM.

KW - Cell Line, Tumor

KW - Contrast Media/chemistry

KW - Gallium/chemistry

KW - Glioblastoma/diagnostic imaging

KW - Humans

KW - Peptides/chemistry

KW - Positron-Emission Tomography

KW - Receptors, Urokinase Plasminogen Activator/agonists

U2 - 10.1007/s00726-017-2407-4

DO - 10.1007/s00726-017-2407-4

M3 - Journal article

C2 - 28316028

SN - 0939-4451

VL - 49

SP - 1089

EP - 1100

JO - Amino Acids

JF - Amino Acids

IS - 6

ER -