Design of Bimodal Ligands of Neurotensin Receptor 1 for Positron Emission Tomography Imaging and Fluorescence-Guided Surgery of Pancreatic Cancer

Renard, Emma; Dancer, Pierre-Alix; Portal, Christophe; Denat, Franck; Prignon, Aurélie; Gonçalves, Victor

doi:10.1021/acs.jmedchem.9b01407

Cited by 23 publications

(30 citation statements)

References 41 publications

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“…In another example, the bi-modal tracer [ 68 Ga]Ga-NODAGA-Lys(Cy5**)-AEEAc-[Me-Arg 8 ,Tle 12 ]NT(7−13) (NODAGA: 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid; Cy5**: tetrasulfonated cyanine 5.0; AEEAc: 8-amino-3,6-dioxaoctanoic acid) reached 2.56% ± 0.97% IA/g at 1 h in the same model, with quite elevated kidney values though (20% IA/g) [53]. However, such comparisons should be made with caution, in view of potential differences in protocols applied across labs.…”

Section: Discussionmentioning

confidence: 85%

Optimizing the Profile of [99mTc]Tc–NT(7–13) Tracers in Pancreatic Cancer Models by Means of Protease Inhibitors

Kanellopoulos

Nock

Krenning

et al. 2020

IJMS

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Background: The overexpression of neurotensin subtype 1 receptors (NTS1Rs) in human tumors may be elegantly exploited for directing neurotensin (NT)-based radionuclide carriers specifically to cancer sites for theranostic purposes. We have recently shown that [99mTc]Tc–DT1 ([99mTc]Tc–[N4–Gly7]NT(7–13)) and [99mTc]Tc–DT5 ([99mTc]Tc–[N4–βAla7,Dab9]NT(7–13)) show notably improved uptake in human colon adenocarcinoma WiDr xenografts in mice treated with neprilysin (NEP) inhibitors and/or angiotensin-converting enzyme (ACE) inhibitors compared with untreated controls. Aiming toward translation of this promising approach in NTS1R-positive pancreatic ductal adenocarcinoma (PDAC) patients, we now report on the impact of registered NEP/ACE inhibitors on the performance of [99mTc]Tc–DT1 and [99mTc]Tc–DT5 in pancreatic cancer models. Methods: The cellular uptake of [99mTc]Tc–DT1 and [99mTc]Tc–DT5 was tested in a panel of pancreatic cell lines, and their stability was assessed in mice treated or not treated with Entresto, lisinopril, or their combinations. Biodistribution was conducted in severe combined immunodeficiency (SCID) mice bearing pancreatic AsPC-1 xenografts. Results: The Entresto + lisinopril combination maximized the metabolic stability of the fast-internalizing [99mTc]Tc–DT1 in mice, resulting in notably enhanced tumor uptake (7.05 ± 0.80% injected activity (IA)/g vs. 1.25 ± 0.80% IA/g in non-treated controls at 4 h post-injection; p < 0.0001). Conclusions: This study has shown the feasibility of optimizing the uptake of [99mTc]Tc–DT1 in pancreatic cancer models with the aid of clinically established NEP/ACE inhibitors, in favor of clinical translation prospects.

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Section: Discussionmentioning

confidence: 85%

Optimizing the Profile of [99mTc]Tc–NT(7–13) Tracers in Pancreatic Cancer Models by Means of Protease Inhibitors

Kanellopoulos

Nock

Krenning

et al. 2020

IJMS

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“…Furthermore, the combination of PET/OI features certain important advantages over other imaging techniques. In fact, PET/OI offers the possibility of performing pre‐ and intra‐operative imaging [5a,b] . PET on the one hand shows extraordinary benefits in pre‐operative, whole‐body imaging as the gold‐standard [ 18 F]FDG and other PET nuclide‐labeled radiotracers demonstrate daily [8] .…”

Section: Introductionmentioning

confidence: 99%

Functional Hybrid Molecules for the Visualization of Cancer: PESIN‐Homodimers Combined with Multimodal Molecular Imaging Probes for Positron Emission Tomography and Optical Imaging: Suited for Tracking of GRPR‐Positive Malignant Tissue**

Hübner

Cheng

Wängler

et al. 2020

Chemistry A European J

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We describe multimodali maging probesf or gastrin-releasingp eptide receptor (GRPR)-specifict argeting suited for positrone mission tomographya nd opticali maging (PET/OI), consistingo fP ESIN (PEG 3-BBN 7-14)d imers connected to multimodali magingsubunits.T hese multimodal agents comprise af luorescentd ye for OI and the chelator ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutarica cid) (NODA-GA) for PET radiometali sotope labelling. Special focus was puto nt he influenceo ft he used dyes on the properties of the whole bioconjugates. For this, several compoundsw ith different fluorescent dyes and non-dye carrying subunits were synthesized and investigated.A sf luorescent dyes, dansyl, NBD, derivatives of fluorescein,c oumarin and rhodamine as well as three pyrilium-based dyes were employed. Considerable influence of the chargeo ft he colored unit on hydrophilicity as well as in vitro target receptor binding was observed and classified. High radiochemical yields and purities were found during radiolabeling of the multimodali maging subunits as well as their GRPR-specific bioconjugates with 68 Ga. Examinationso ft he photophysical properties of both molecule species displayedn ol oss or alteration of fluorescence characteristics.

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“…Fluorescence-guided surgery is of high interest for the visualization of malignant tissue as the accurate detection of tumor borders and small metastases near the primary as well as malignantly transformed sentinel lymph nodes is important to help spare healthy tissue during the surgical removal. The high spatial resolution provided by NIR-OI guarantees a clear visual contrast between healthy and cancerous tissue [ 8 , 9 , 10 ]. Furthermore, the precise removal of cancer by accurate discrimination between tumor and non-cancerous tissue minimizes the risk of tumor recurrence and maximizes the speed of recovery for the patients [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Hybrid Multimodal Imaging Synthons for Chemoselective and Efficient Biomolecule Modification with Chelator and Near-Infrared Fluorescent Cyanine Dye

et al. 2020

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The development of hybrid multimodal imaging synthons (MIS), carrying in addition to a chelator for radiometal labeling also a near-infrared (NIR) fluorescent cyanine dye was the aim of this work. The MIS should be introducible into biomolecules of choice via an efficient and chemoselective click chemistry reaction. After chemical optimization, a successful synthetic strategy towards such hybrid MIS was developed, based on solid phase-based synthesis techniques and applying different near-infrared fluorescent cyanine dyes. The developed hybrid agents were shown to be easily introducible into a model homobivalent peptidic gastrin-releasing peptide receptor- (GRPR)-specific carrier without forming any side products and the MIS as well as their bioconjugates were radiolabeled with the positron-emitter 68Ga3+. The hybrid multimodal agents were characterized with regard to their logDs, GRPR target affinities and photophysical characteristics. It could be shown that the properties of the bioconjugates were not per se affected by the introduction of the MIS but that the cyanine dye used and specifically the number of comprised negative charges per dye molecule can have a considerable influence on target receptor binding. Thus, the molecular toolbox described here enables the synthesis of tailored hybrid multimodal imaging synthons for biomolecule modification, meeting the specific need and envisioned application of the combined imaging agent.

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Design of Bimodal Ligands of Neurotensin Receptor 1 for Positron Emission Tomography Imaging and Fluorescence-Guided Surgery of Pancreatic Cancer

Cited by 23 publications

References 41 publications

Optimizing the Profile of [99mTc]Tc–NT(7–13) Tracers in Pancreatic Cancer Models by Means of Protease Inhibitors

Optimizing the Profile of [99mTc]Tc–NT(7–13) Tracers in Pancreatic Cancer Models by Means of Protease Inhibitors

Functional Hybrid Molecules for the Visualization of Cancer: PESIN‐Homodimers Combined with Multimodal Molecular Imaging Probes for Positron Emission Tomography and Optical Imaging: Suited for Tracking of GRPR‐Positive Malignant Tissue**

Hybrid Multimodal Imaging Synthons for Chemoselective and Efficient Biomolecule Modification with Chelator and Near-Infrared Fluorescent Cyanine Dye

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