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Molecules. 2017 Nov 11;22(11). pii: E1950. doi: 10.3390/molecules22111950.

NeoBOMB1, a GRPR-Antagonist for Breast Cancer Theragnostics: First Results of a Preclinical Study with [67Ga]NeoBOMB1 in T-47D Cells and Tumor-Bearing Mice.

Author information

1
Molecular Radiopharmacy, INRASTES/NCSR "Demokritos", 15310 Athens, Greece. katerinakaloudi@yahoo.gr.
2
Molecular Radiopharmacy, INRASTES/NCSR "Demokritos", 15310 Athens, Greece. mlymperis@hotmail.com.
3
Molecular Radiopharmacy, INRASTES/NCSR "Demokritos", 15310 Athens, Greece. athina.giarika@gmail.com.
4
Department of Radiology, Erasmus MC, 3015 CN Rotterdam, The Netherlands. s.dalm@erasmusmc.nl.
5
Advanced Accelerator Applications, 10010 Colleretto Giacosa TO, Italy. francesca.orlandi@adacap.com.
6
Advanced Accelerator Applications, 10010 Colleretto Giacosa TO, Italy. donato.barbato@adacap.com.
7
Advanced Accelerator Applications, 10010 Colleretto Giacosa TO, Italy. mattia.tedesco@adacap.com.
8
Molecular Radiopharmacy, INRASTES/NCSR "Demokritos", 15310 Athens, Greece. maina_thea@hotmail.com.
9
Department of Radiology, Erasmus MC, 3015 CN Rotterdam, The Netherlands. m.hendriks-dejong@erasmusmc.nl.
10
Molecular Radiopharmacy, INRASTES/NCSR "Demokritos", 15310 Athens, Greece. nock_berthold.a@hotmail.com.

Abstract

The GRPR-antagonist-based radioligands [67/68Ga/111In/177Lu]NeoBOMB1 have shown excellent theragnostic profiles in preclinical prostate cancer models, while [68Ga]NeoBOMB1 effectively visualized prostate cancer lesions in patients. We were further interested to explore the theragnostic potential of NeoBOMB1 in GRPR-positive mammary carcinoma, by first studying [67Ga]NeoBOMB1 in breast cancer models; Methods: We investigated the profile of [67Ga]NeoBOMB1, a [68Ga]NeoBOMB1 surrogate, in GRPR-expressing T-47D cells and animal models; Results: NeoBOMB1 (IC50s of 2.2 ± 0.2 nM) and [natGa]NeoBOMB1 (IC50s of 2.5 ± 0.2 nM) exhibited high affinity for the GRPR. At 37 °C [67Ga]NeoBOMB1 strongly bound to the T-47D cell-membrane (45.8 ± 0.4% at 2 h), internalizing poorly, as was expected for a radioantagonist. [67Ga]NeoBOMB1 was detected >90% intact in peripheral mouse blood at 30 min pi. In mice bearing T-47D xenografts, [67Ga]NeoBOMB1 specifically localized in the tumor (8.68 ± 2.9% ID/g vs. 0.6 ± 0.1% ID/g during GRPR-blockade at 4 h pi). The unfavorably high pancreatic uptake could be considerably reduced (206.29 ± 17.35% ID/g to 42.46 ± 1.31% ID/g at 4 h pi) by increasing the NeoBOMB1 dose from 10 pmol to 200 pmol, whereas tumor uptake remained unaffected. Notably, tumor values did not decline from 1 to 24 h pi; Conclusions: [67Ga]NeoBOMB1 can successfully target GRPR-positive breast cancer in animals with excellent prospects for clinical translation.

KEYWORDS:

GRPR-antagonist; PET-imaging; breast cancer; targeted tumor imaging; theragnostics

PMID:
29137110
PMCID:
PMC6150197
DOI:
10.3390/molecules22111950
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

F.O., D.B. and M.T., are AAA employees. T.M., B.A.N, and M.d.J. are co-inventors of an AAA-patent application (GRPR-Antagonists for detection, diagnosis and treatment of GRPR-positive cancer. WO 2014052471 A1); AAA funded this study and participated in the decision to publish the results. Funds for covering the costs to publish in open access were provided by AAA.

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