First-In-Human Study Demonstrating Tumor-Angiogenesis by PET/CT Imaging with (68)Ga-NODAGA-THERANOST, a High-Affinity Peptidomimetic for αvβ3 Integrin Receptor Targeting

Overview

Journal Cancer Biother Radiopharm

Specialties Oncology
Pharmacology
Radiology

Date 2015 May 7

PMID 25945808

Citations 10

Authors

Richard P Baum

Harshad R Kulkarni

Dirk Muller

Stanley Satz

Narasimhan Danthi

Young-Seung Kim

Martin W Brechbiel

Affiliations

Soon will be listed here.

Abstract

Unlabelled: (68)Ga-NODAGA-THERANOST™ is an αvβ3 integrin antagonist and the first radiolabeled peptidomimetic to reach clinical development for targeting integrin receptors. In this first-in-human study, the feasibility of integrin receptor peptidomimetic positron emission tomography/computed tomography (PET/CT) imaging was confirmed in patients with non-small-cell lung cancer and breast cancer.

Methods: Patients underwent PET/CT imaging with (68)Ga NODAGA-THERANOST. PET images were analyzed qualitatively and quantitatively and compared to 2-deoxy-2-((18)F) fluoro-d-glucose ((18)F-FDG) findings. Images were obtained 60 minutes postinjection of 300-500 MBq of (68)Ga-NODAGA-THERANOST.

Results: (68)Ga-NODAGA-THERANOST revealed high tumor-to-background ratios (SUVmax=4.8) and uptake at neoangiogenesis sites. Reconstructed fused images distinguished cancers with high malignancy potential and enabled enhanced bone metastasis detection. (18)F-FDG-positive lung and lymph node metastases did not show uptake, indicating the absence of neovascularization.

Conclusions: (68)Ga-NODAGA-THERANOST was found to be safe and effective, exhibiting in this study rapid blood clearance, stability, rapid renal excretion, favorable biodistribution and PK/PD, low irradiation burden (μSv/MBq/μg), and convenient radiolabeling. This radioligand might enable theranostics, that is, a combination of diagnostics followed by the appropriate therapeutics, namely antiangiogenic therapy, image-guided presurgical assessment, treatment response evaluation, prediction of pathologic response, neoadjuvant-peptidomimetic-radiochemotherapy, and personalized medicine strategies. Further clinical trials evaluating (68)Ga-NODAGA-THERANOST are warranted.

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References

Haubner R, Wester H, Reuning U, Senekowitsch-Schmidtke R, Diefenbach B, Kessler H . Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting. J Nucl Med. 1999; 40(6):1061-71. View

Xie J, Shen Z, Li K, Danthi N . Tumor angiogenic endothelial cell targeting by a novel integrin-targeted nanoparticle. Int J Nanomedicine. 2007; 2(3):479-85. PMC: 2676654. View

Smith J, Cheresh D . The Arg-Gly-Asp binding domain of the vitronectin receptor. Photoaffinity cross-linking implicates amino acid residues 61-203 of the beta subunit. J Biol Chem. 1988; 263(35):18726-31. View

Shin I, Maeng J, Jang B, You E, Cheng K, Li K . Tc-labeling of Peptidomimetic Antagonist to Selectively Target alpha(v)beta(3) Receptor-Positive Tumor: Comparison of PDA and EDDA as co-Ligands. Curr Radiopharm. 2010; 3(1):1-8. PMC: 2885802. DOI: 10.2174/1874471011003010001. View

Lewis M . Radiolabeled RGD peptides move beyond cancer: PET imaging of delayed-type hypersensitivity reaction. J Nucl Med. 2005; 46(1):2-4. View

McHugh B, Murdoch A, Haslett C, Sethi T . Loss of the integrin-activating transmembrane protein Fam38A (Piezo1) promotes a switch to a reduced integrin-dependent mode of cell migration. PLoS One. 2012; 7(7):e40346. PMC: 3390408. DOI: 10.1371/journal.pone.0040346. View

Burnett C, Xie J, Quijano J, Shen Z, Hunter F, Bur M . Synthesis, in vitro, and in vivo characterization of an integrin alpha(v)beta(3)-targeted molecular probe for optical imaging of tumor. Bioorg Med Chem. 2005; 13(11):3763-71. DOI: 10.1016/j.bmc.2005.03.024. View

Liu Z, Wang F, Chen X . Integrin targeted delivery of radiotherapeutics. Theranostics. 2011; 1:201-10. PMC: 3086619. DOI: 10.7150/thno/v01p0201. View

Margolis D, Hoffman J, Herfkens R, Jeffrey R, Quon A, Gambhir S . Molecular imaging techniques in body imaging. Radiology. 2007; 245(2):333-56. DOI: 10.1148/radiol.2452061117. View

10.

Gaertner F, Kessler H, Wester H, Schwaiger M, Beer A . Radiolabelled RGD peptides for imaging and therapy. Eur J Nucl Med Mol Imaging. 2012; 39 Suppl 1:S126-38. DOI: 10.1007/s00259-011-2028-1. View

11.

Hanessian S, McNaughton-Smith G . Synthesis of a versatile peptidomimetic scaffold. Methods Mol Med. 2011; 23:161-74. DOI: 10.1385/0-89603-517-4:161. View

12.

Kim Y, Nwe K, Milenic D, Brechbiel M, Satz S, Baidoo K . Synthesis and characterization of αvβ₃-targeting peptidomimetic chelate conjugates for PET and SPECT imaging. Bioorg Med Chem Lett. 2012; 22(17):5517-22. PMC: 3423540. DOI: 10.1016/j.bmcl.2012.07.024. View

13.

Haubner R, Beer A, Wang H, Chen X . Positron emission tomography tracers for imaging angiogenesis. Eur J Nucl Med Mol Imaging. 2010; 37 Suppl 1:S86-103. PMC: 3629959. DOI: 10.1007/s00259-010-1503-4. View

14.

Reardon D, Neyns B, Weller M, Tonn J, Nabors L, Stupp R . Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies. Future Oncol. 2011; 7(3):339-54. DOI: 10.2217/fon.11.8. View

15.

Kurdziel K, Lindenberg L, Choyke P . Oncologic Angiogenesis Imaging in the clinic---how and why. Imaging Med. 2011; 3(4):445-457. PMC: 3224985. DOI: 10.2217/iim.11.31. View

16.

Knetsch P, Petrik M, Griessinger C, Rangger C, Fani M, Kesenheimer C . [68Ga]NODAGA-RGD for imaging αvβ3 integrin expression. Eur J Nucl Med Mol Imaging. 2011; 38(7):1303-12. DOI: 10.1007/s00259-011-1778-0. View

17.

Pytela R, Pierschbacher M, Ruoslahti E . Identification and isolation of a 140 kd cell surface glycoprotein with properties expected of a fibronectin receptor. Cell. 1985; 40(1):191-8. DOI: 10.1016/0092-8674(85)90322-8. View

18.

Beer A, Haubner R, Sarbia M, Goebel M, Luderschmidt S, Grosu A . Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man. Clin Cancer Res. 2006; 12(13):3942-9. DOI: 10.1158/1078-0432.CCR-06-0266. View

19.

Jeong J, Hong M, Chang Y, Lee Y, Kim Y, Cheon G . Preparation of a promising angiogenesis PET imaging agent: 68Ga-labeled c(RGDyK)-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid and feasibility studies in mice. J Nucl Med. 2008; 49(5):830-6. DOI: 10.2967/jnumed.107.047423. View

20.

Heroux J, Gharib A, Danthi N, Cecchini S, Ohayon J, Pettigrew R . High-affinity alphavbeta3 integrin targeted optical probe as a new imaging biomarker for early atherosclerosis: initial studies in Watanabe rabbits. Mol Imaging Biol. 2009; 12(1):2-8. PMC: 7103239. DOI: 10.1007/s11307-009-0242-z. View