18F, 64Cu, and 68Ga Labeled RGD-Bombesin Heterodimeric Peptides for PET Imaging of Breast Cancer

Liu, Zhaofei; Yan, Yongjun; Liu, Shuanglong; Wang, Fan; Chen, Xiaoyuan

doi:10.1021/bc9000245

Cited by 134 publications

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“…One major advantage of heterodimer over the corresponding monomers is the multivalency effect, resulting in improved binding affinity and increased number of effective receptors (20,(22)(23)(24). Consistently, both 68 Ga-BBN-RGD and 68 Ga-BBN showed uptake in the primary prostate tumors that were either GPRR-positive or integrin a v b 3 -positive.…”

Section: Discussionmentioning

confidence: 72%

“…In a PC3 xenograft model, 18 F-FB-BBN-RGD had significantly higher tumor uptake than monomeric RGD and monomeric BBN peptide tracer analogs at all time points examined (20). A series of preclinical studies using the same strategy have confirmed several advantages of heterodimers including increased number of effective receptors, improved binding affinity, and pharmacokinetics (20,(22)(23)(24).…”

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confidence: 86%

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Clinical Translation of a Dual Integrin α_vβ₃– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, ⁶⁸Ga-BBN-RGD

et al. 2016

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This study aimed to document the first-in-human application of a 68 Ga-labeled heterodimeric peptide BBN-RGD (bombesin-RGD) that targets both integrin a v b 3 and gastrin-releasing peptide receptor (GRPR). We evaluated the safety and assessed the clinical diagnostic value of 68 Ga-BBN-RGD PET/CT in prostate cancer patients in comparison with 68 Ga-BBN. Methods: Five healthy volunteers (4 men and 1 woman; age range, 28-53 y) were enrolled to validate the safety of 68 Ga-BBN-RGD. Dosimetry was calculated using the OLINDA/EXM software. Thirteen patients with prostate cancer (4 newly diagnosed and 9 posttherapy) were enrolled. All the patients underwent PET/CT scans 15-30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68 Ga-BBN-RGD and also accepted 68 Ga-BBN PET/CT within 2 wk for comparison. Results: With a mean injected dose of 107.3 6 14.8 MBq per patient, no side effect was found during the whole procedure and 2 wk follow-up, demonstrating the safety of 68 Ga-BBN-RGD. A patient would be exposed to a radiation dose of 2.90 mSv with an injected dose of 129.5 MBq (3.5 mCi), which is much lower than the dose limit set by the Food and Drug Administration. In 13 patients with prostate cancer diagnosed by biopsy, 68 Ga-BBN-RGD PET/CT detected 3 of 4 primary tumors, 14 metastatic lymph nodes, and 20 bone lesions with an SUV max of 4.46 6 0.50, 6.26 6 2.95, and 4.84 6 1.57, respectively. Only 2 of 4 primary tumors, 5 lymph nodes, and 12 bone lesions were positive on 68 Ga-BBN PET/CT, with the SUV max of 2.98 6 1.24, 4.17 6 1.89, and 3.61 6 1.85, respectively. Conclusion: This study indicates the safety and efficiency of a new type of dual integrin a v b 3 -and GRPR-targeting PET radiotracer in prostate cancer diagnosis and staging.

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Section: Discussionmentioning

confidence: 72%

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confidence: 86%

Clinical Translation of a Dual Integrin α_vβ₃– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, ⁶⁸Ga-BBN-RGD

et al. 2016

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“…This approach was chosen by different groups (38)(39)(40). The preferred "coligand" was the a V b 3 -targeting RGD motif.…”

Section: Development Of Heterobivalent Ligands With Short Linkersmentioning

confidence: 99%

Approaches to Multireceptor Targeting: Hybrid Radioligands, Radioligand Cocktails, and Sequential Radioligand Applications

Reubi

Maecke

2017

J Nucl Med

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Modern drug discovery highly depends on the identification and validation of the drug targets. Using the method of in vitro quantitative receptor autoradiography, we demonstrated that-for instance, in neuroendocrine tumors-up to 3 receptors can be coexpressed at a relatively high density. In addition, nonendocrine tumors such as breast, prostate, and brain tumors concomitantly express several G protein-coupled receptors at a high density. We propose 3 strategies for exploiting these findings for multireceptor targeting in vivo: use of heterobivalent or heteromultivalent ligands, which may bind simultaneously or monovalently to their different molecular targets; coinjection of a cocktail of radioligands; and sequential injection of different radioligands. Any of these strategies may help to remedy some of the major problems in cancer targeting: heterogeneity, change in phenotype during disease progression, and resistance.

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“…

While most studies have focused on optimizing ligands with a high affinity and selectivity to the cell surface targets, we envisioned a new imaging approach that utilized one high-and one low-affinity ligand targeted to independent receptors on a target cell surface.

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In Situ Ligation of High‐ and Low‐Affinity Ligands to Cell Surface Receptors Enables Highly Selective Recognition

et al. 2017

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molecules that are highly expressed in tumor vasculature [11] are widely used to image breast, [15] brain, [16] and lung [17] cancers in small animal models; however, RGD peptides often provide poor imaging contrast because the integrins are also expressed on other endothelial cells. The RGD peptides act as "strongly" interacting integrin ligands that nonselectively bind to the various integrins and are rapidly captured by the cells via receptor-mediated endocytosis, which decreases the tumor/ background signal ratio.While most studies have focused on optimizing ligands with a high affinity and selectivity to the cell surface targets, we envisioned a new imaging approach that utilized one high-and one low-affinity ligand targeted to independent receptors on a target cell surface. This approach was inspired by the pretargeted method used frequently in the molecular imaging field. [18][19][20][21][22][23] The concept is schematically presented in Figure 1.A simplified model was proposed in which various surface receptors are expressed on cells A and B. Cell A may be selectively visualized by applying the fluorescently labeled probe C, which shows a high affinity toward a receptor overexpressed on the surface of A, i.e., at K D of nano molar level ( Figure 1A). The same receptor could also be expressed more This paper reports an entirely unexplored concept of simultaneously recognizing two receptors using high-and low-affinity ligands through ligating them in situ on the target cell surface. This de novo approach is inspired by the pretargeting strategy frequently applied in molecular imaging, and has now evolved as the basis of a new paradigm for visualizing target cells with a high imaging contrast. A distinct advantage of using a labeled low-affinity ligand such as glycan is that the excess labeled ligand can be washed away from the cells, whereas the ligand bound to the cell, even at the milli molar affinity level, can be anchored by a bioorthogonal reaction with a pretargeted high-affinity ligand on the surface. Consequently, nonspecific background is minimized, leading to improved imaging contrast. Importantly, despite previously unexplored for molecular imaging, a notoriously weak glycan/lectin interaction can now be utilized as a highly selective ligand to the targets. Cell ImagingMolecular imaging research has focused on noninvasively analyzing the molecular kinetics in small animals for use in diagnostic applications. [1][2][3][4][5][6][7] In vivo information about biologically active small molecules and biomolecules, such as the localization or expression levels of target receptors, may be readily imaged using fluorescence or radionuclide-based detection. Although many promising tracers can target specific organs or tumors, [8][9][10][11][12][13] the selectivity and specificity of these tracers toward target cells must be improved. For example, RGD peptides, highaffinity ligands of α V β 3 integrins, [9,14] which are cell adhesion

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¹⁸F, ⁶⁴Cu, and ⁶⁸Ga Labeled RGD-Bombesin Heterodimeric Peptides for PET Imaging of Breast Cancer

Cited by 134 publications

References 44 publications

Clinical Translation of a Dual Integrin α_vβ₃– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, ⁶⁸Ga-BBN-RGD

Clinical Translation of a Dual Integrin α_vβ₃– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, ⁶⁸Ga-BBN-RGD

Approaches to Multireceptor Targeting: Hybrid Radioligands, Radioligand Cocktails, and Sequential Radioligand Applications

In Situ Ligation of High‐ and Low‐Affinity Ligands to Cell Surface Receptors Enables Highly Selective Recognition

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18F, 64Cu, and 68Ga Labeled RGD-Bombesin Heterodimeric Peptides for PET Imaging of Breast Cancer

Cited by 134 publications

References 44 publications

Clinical Translation of a Dual Integrin αvβ3– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, 68Ga-BBN-RGD

Clinical Translation of a Dual Integrin αvβ3– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, 68Ga-BBN-RGD

Approaches to Multireceptor Targeting: Hybrid Radioligands, Radioligand Cocktails, and Sequential Radioligand Applications

In Situ Ligation of High‐ and Low‐Affinity Ligands to Cell Surface Receptors Enables Highly Selective Recognition

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Product

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¹⁸F, ⁶⁴Cu, and ⁶⁸Ga Labeled RGD-Bombesin Heterodimeric Peptides for PET Imaging of Breast Cancer

Clinical Translation of a Dual Integrin α_vβ₃– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, ⁶⁸Ga-BBN-RGD

Clinical Translation of a Dual Integrin α_vβ₃– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, ⁶⁸Ga-BBN-RGD