scholarly journals [99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5093
Author(s):  
Berthold A. Nock ◽  
Aikaterini Kaloudi ◽  
Panagiotis Kanellopoulos ◽  
Barbara Janota ◽  
Barbara Bromińska ◽  
...  
Keyword(s):  
Tumor Imaging ◽  
Pharmacokinetic Profile ◽  
Diglycolic Acid ◽  
Preclinical Evaluation ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide ◽  
Specific Uptake ◽  
Grpr Antagonist

Diagnostic imaging and radionuclide therapy of prostate (PC) and breast cancer (BC) using radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists represents a promising approach. We herein propose the GRPR-antagonist based radiotracer [99mTc]Tc-DB15 ([99mTc]Tc-N4-AMA-DGA-DPhe6,Sar11,LeuNHEt13]BBN(6-13); N4: 6-carboxy-1,4,8,11-tetraazaundecane, AMA: aminomethyl-aniline, DGA: diglycolic acid) as a new diagnostic tool for GRPR-positive tumors applying SPECT/CT. The uptake of [99mTc]Tc-DB15 was tested in vitro in mammary (T-47D) and prostate cancer (PC-3) cells and in vivo in T-47D or PC-3 xenograft-bearing mice as well as in BC patients. DB15 showed high GRPR-affinity (IC50 = 0.37 ± 0.03 nM) and [99mTc]Tc-DB15 strongly bound to the cell-membrane of T-47D and PC-3 cells, according to a radiolabeled antagonist profile. In mice, the radiotracer showed high and prolonged GRPR-specific uptake in PC-3 (e.g., 25.56 ± 2.78 %IA/g vs. 0.72 ± 0.12 %IA/g in block; 4 h pi) and T-47D (e.g., 15.82 ± 3.20 %IA/g vs. 3.82 ± 0.30 %IA/g in block; 4 h pi) tumors, while rapidly clearing from background. In patients with advanced BC, the tracer could reveal several bone and soft tissue metastases on SPECT/CT. The attractive pharmacokinetic profile of [99mTc]DB15 in mice and its capability to target GRPR-positive BC lesions in patients highlight its prospects for a broader clinical use, an option currently being explored by ongoing clinical studies.

scholarly journals 68Ga-Radiolabeling and Pharmacological Characterization of a Kit-Based Formulation of the Gastrin-Releasing Peptide Receptor (GRP-R) Antagonist RM2 for Convenient Preparation of [68Ga]Ga-RM2

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1160
Author(s):  
Adrien Chastel ◽  
Delphine Vimont ◽  
Stephane Claverol ◽  
Marion Zerna ◽  
Sacha Bodin ◽  
...  
Keyword(s):  
Calcium Mobilization ◽  
Pharmacological Characterization ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide ◽  
Production Route ◽  
Membrane Bound ◽  
One Year ◽  
Calcium Mobilization Assay

Background: [68Ga]Ga-RM2 is a potent Gastrin-Releasing Peptide-receptor (GRP-R) antagonist for imaging prostate cancer and breast cancer, currently under clinical evaluation in several specialized centers around the world. Targeted radionuclide therapy of GRP-R-expressing tumors is also being investigated. We here report the characteristics of a kit-based formulation of RM2 that should ease the development of GRP-R imaging and make it available to more institutions and patients. Methods: Stability of the investigated kits over one year was determined using LC/MS/MS and UV-HPLC. Direct 68Ga-radiolabeling was optimized with respect to buffer (pH), temperature, reaction time and shaking time. Conventionally prepared [68Ga]Ga-RM2 using an automated synthesizer was used as a comparator. Finally, the [68Ga]Ga-RM2 product was assessed with regards to hydrophilicity, affinity, internalization, membrane bound fraction, calcium mobilization assay and efflux, which is a valuable addition to the in vivo literature. Results: The kit-based formulation, kept between 2 °C and 8 °C, was stable for over one year. Using acetate buffer pH 3.0 in 2.5–5.1 mL total volume, heating at 100 °C during 10 min and cooling down for 5 min, the [68Ga]Ga-RM2 produced by kit complies with the requirements of the European Pharmacopoeia. Compared with the module production route, the [68Ga]Ga-RM2 produced by kit was faster, displayed higher yields, higher volumetric activity and was devoid of ethanol. In in vitro evaluations, the [68Ga]Ga-RM2 displayed sub-nanomolar affinity (Kd = 0.25 ± 0.19 nM), receptor specific and time dependent membrane-bound fraction of 42.0 ± 5.1% at 60 min and GRP-R mediated internalization of 24.4 ± 4.3% at 30 min. The [natGa]Ga-RM2 was ineffective in stimulating intracellular calcium mobilization. Finally, the efflux of the internalized activity was 64.3 ± 6.5% at 5 min. Conclusion: The kit-based formulation of RM2 is suitable to disseminate GRP-R imaging and therapy to distant hospitals without complex radiochemistry equipment.

In vitro and in vivo evaluation of a 99mTc(I)-labeled bombesin analogue for imaging of gastrin releasing peptide receptor-positive tumors

2002 ◽  
Vol 29 (5) ◽  
pp. 553-560 ◽  
Author(s):  
Roberto La Bella ◽  
Elisa Garcia-Garayoa ◽  
Michael Langer ◽  
Peter Bläuenstein ◽  
Annette G Beck-Sickinger ◽  
...  
Keyword(s):  
In Vivo Evaluation ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide

scholarly journals In Vitro and In Vivo Application of Radiolabeled Gastrin-Releasing Peptide Receptor Ligands in Breast Cancer

2015 ◽  
Vol 56 (5) ◽  
pp. 752-757 ◽  
Author(s):  
S. U. Dalm ◽  
J. W. M. Martens ◽  
A. M. Sieuwerts ◽  
C. H. M. van Deurzen ◽  
S. J. Koelewijn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Receptor Ligands ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide

scholarly journals Bombesin receptor-targeted liposomes for enhanced delivery to lung cancer cells

2019 ◽  
Vol 10 ◽  
pp. 2553-2562
Author(s):  
Mohammad J Akbar ◽  
Pâmela C Lukasewicz Ferreira ◽  
Melania Giorgetti ◽  
Leanne Stokes ◽  
Christopher J Morris
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Storage Conditions ◽  
Lung Cancer Cells ◽  
Gastrin Releasing Peptide ◽  
Antagonist Peptides ◽  
Microscopic Studies ◽  
Grpr Antagonist

Background: Gastrin-releasing peptide is a member of the bombesin family of peptides. Its cognate receptor, gastrin releasing peptide receptor (GRPR), is widely expressed in cancers of the lung, pancreas and ovaries. Gastrin releasing peptide (GRP) is an autocrine growth factor in small cell lung cancer, which has very poor patient outcomes. High affinity antagonist peptides have been developed for in vivo cancer imaging. In this report we decorated pegylated liposomes with a GRPR antagonist peptide and studied its interaction with, and accumulation within, lung cancer cells. Results: An N-terminally cysteine modified GRPR antagonist (termed cystabn) was synthesised and shown to inhibit cell growth in vitro. Cystabn was used to prepare a targeted 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) lipid conjugate that was formulated into liposomes. The liposomes displayed desirable colloidal properties and good stability under storage conditions. Flow cytometric and microscopic studies showed that fluorescently labelled cystabn-decorated liposomes accumulated more extensively in GRPR over-expressing cells than matched liposomes that contained no cystabn targeting motif. Conclusion: The use of GRPR antagonistic peptides for nanoparticle targeting has potential for enhancing drug accumulation in resistant cancer cells.

scholarly journals In Vitro and In Vivo Evaluation of 64Cu-Labeled SarAr-Bombesin Analogs in Gastrin-Releasing Peptide Receptor-Expressing Prostate Cancer

2011 ◽  
Vol 52 (3) ◽  
pp. 470-477 ◽  
Author(s):  
K. A. Lears ◽  
R. Ferdani ◽  
K. Liang ◽  
A. Zheleznyak ◽  
R. Andrews ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
In Vivo Evaluation ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide

scholarly journals Effect of the Versatile Bifunctional Chelator AAZTA5 on the Radiometal Labelling properties and the in vitro performance of a Gastrin Releasing Peptide Receptor Antagonist

2020 ◽  
Author(s):  
Michael Hofstetter ◽  
Euy Sung Moon ◽  
Fabio D'Angelo ◽  
Lucien Geissbühler ◽  
Ian Alberts ◽  
...  
Keyword(s):  
Great Promise ◽  
Specific Cell ◽  
Binding Studies ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide ◽  
Pc3 Cells ◽  
Therapy Studies

Abstract Background: Gastrin Releasing Peptide receptor (GRPr)-based radioligands, mainly antagonists, have shown great promise for diagnostic imaging of GRPr-positive cancers, such as prostate and breast.The present study aims at developing and evaluating a versatile GRPr-based probe for both PET / SPECT imaging as well as intraoperative and therapeutic applications. The influence of the versatile chelator AAZTA5 on the radiometal labelling properties and the in vitro performance of the generated radiotracers were thoroughly investigated.The GRPr-based antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was functionalized with the chelator 6-[Bis(carboxymethyl)amino]-1,4-bis(carboyxmethyl)-6-methyl-1,4-diazepane (AAZTA5) through the spacer 4-amino-1-carboxymethyl-piperidine (Pip) to obtain AAZTA5-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (LF1). LF1 was radiolabelled with 68Ga (PET), 111In (SPECT, intraoperative applications) and 177Lu (therapy, SPECT). In vitro evaluation included stability studies, determination of lipophilicity, protein-binding studies, determination of Kd and Bmax as well as internalization studies using the epithelial human prostate cancer cell line PC3. In vitro monotherapy as well as combination therapy studies were further performed to assess its applicability as a theranostic compound.Results: LF1 was labelled with 68Ga, 111In and 177Lu within 5 min at room temperature (RT). The molar activities (Am) were ranging between 50-60 MBq/nmol for 68Ga-LF1, 10-20 MBq/nmol for 111In-LF1 and 177Lu-LF1. The radiotracers were found to be stable for a period of 4 h post labeling exhibiting a hydrophilic profile with an average of a LogDoctanol/PBS of -3, while the bound activity to the human serum protein was approximately 10%. 68/natGa-LF1, 177/natLu-LF1 and 111/natIn-LF1 exhibited high affinity for the PC3 cells, with Kd values of 16.27±2.45 nM, 10.25±2.73 nM and 5.16±1.94 nM, respectively, and the required concentration of the radiotracers to saturate the receptors (Bmax) was between 0.5 and 0.8 nM which corresponds to approximately 4 x 105 receptors per cell. Low specific internalization rate was found in cell culture, while the total specific cell surface bound uptake always exceeded the internalized activity. In vitro therapy studies showed that combination of 177Lu-LF1 with rapamycin inhibit the growth of PC3 cells more efficiently compared to 177Lu-LF1 alone.Conclusion: Encouraged by these promising in vitro data, preclinical evaluation of the LF1 precursor are planned in tumour models in vivo.

scholarly journals In vitro and in vivo evaluation of a 64Cu-labeled NOTA-Bn-SCN-Aoc-bombesin analogue in gastrin-releasing peptide receptor expressing prostate cancer

2012 ◽  
Vol 39 (5) ◽  
pp. 609-616 ◽  
Author(s):  
Jeffrey M. Craft ◽  
Ravindra A. De Silva ◽  
Kimberly A. Lears ◽  
Rebecca Andrews ◽  
Kexian Liang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
In Vivo Evaluation ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide

Patients with fever of unknown origin (FUO): diagnosis by nuclear medicine imaging

2001 ◽  
Vol 40 (03) ◽  
pp. 59-70 ◽  
Author(s):  
W. Becker ◽  
J. Meiler
Keyword(s):  
Nuclear Medicine ◽  
Fever Of Unknown Origin ◽  
Tumor Imaging ◽  
White Blood Cells ◽  
Unknown Origin ◽  
Final Diagnosis ◽  
Recurrent Fever ◽  
Nuclear Medicine Imaging

SummaryFever of unknown origin (FUO) in immunocompetent and non neutropenic patients is defined as recurrent fever of 38,3° C or greater, lasting 2-3 weeks or longer, and undiagnosed after 1 week of appropriate evaluation. The underlying diseases of FUO are numerous and infection accounts for only 20-40% of them. The majority of FUO-patients have autoimmunity and collagen vascular disease and neoplasm, which are responsible for about 50-60% of all cases. In this respect FOU in its classical definition is clearly separated from postoperative and neutropenic fever where inflammation and infection are more common. Although methods that use in-vitro or in-vivo labeled white blood cells (WBCs) have a high diagnostic accuracy in the detection and exclusion of granulocytic pathology, they are only of limited value in FUO-patients in establishing the final diagnosis due to the low prevalence of purulent processes in this collective. WBCs are more suited in evaluation of the focus in occult sepsis. Ga-67 citrate is the only commercially available gamma emitter which images acute, chronic, granulomatous and autoimmune inflammation and also various malignant diseases. Therefore Ga-67 citrate is currently considered to be the tracer of choice in the diagnostic work-up of FUO. The number of Ga-67-scans contributing to the final diagnosis was found to be higher outside Germany than it has been reported for labeled WBCs. F-l 8-2’-deoxy-2-fluoro-D-glucose (FDG) has been used extensively for tumor imaging with PET. Inflammatory processes accumulate the tracer by similar mechanisms. First results of FDG imaging demonstrated, that FDG may be superior to other nuclear medicine imaging modalities which may be explained by the preferable tracer kinetics of the small F-l 8-FDG molecule and by a better spatial resolution of coincidence imaging in comparison to a conventional gamma camera.

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