Local Targeting of Malignant Gliomas by the Diffusible Peptidic Vector 1,4,7,10-Tetraazacyclododecane-1-Glutaric Acid-4,7,10-Triacetic Acid-Substance P

Kneifel, Stefan; Cordier, Dominik; Good, Stephan; Ionescu, Mihai C.S.; Ghaffari, Anthony; Höfer, Silvia; Kretzschmar, Martin; Tolnay, Markus; Apostolidis, Christos; Waser, Beatrice; Arnold, Marlène; Müeller-Brand, Jan; Maecke, Helmut R.; Reubi, Jean Claude; Merlo, Adrian

doi:10.1158/1078-0432.ccr-05-2820

Cited by 140 publications

(127 citation statements)

References 39 publications

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“…Figure 2D shows a case of glioblastoma coexpressing both receptors. Because of the blood-brain barrier, a successful targeting strategy with substance P analogs does not consist in a systemic application but in a local application into the tumor or in the cavity left by the resected tumor (31). Although substance P analogs were successfully applied in vivo in glioblastomas, NPY analogs have never been tested in glioblastomas.…”

Section: Glioblastomasmentioning

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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Section: Glioblastomasmentioning

confidence: 99%

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

Reubi

Maecke

2017

J Nucl Med

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“…At-MX35-F(ab') 2 Cancer des ovaires 9 patients traités ; aucune toxicité significative [31] 213 Bi-Substance P Glioblastome 5 patients traités ; 2 améliorations de l'index de Barthel [32,33] TIRÉS À PART J. Ménager …”

Section: Anticorps Radiomarquéunclassified

Radio-immunothérapie alpha

Ménager¹,

Gorin²,

Fichou³

et al. 2016

Med Sci (Paris)

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> La radioimmunothérapie alpha (RITα) est une thérapie anticancéreuse vectorisée utilisant généralement un anticorps monoclonal spécifique d'un antigène tumoral couplé à un émetteur de particules α. Les émetteurs α représentent un outil idéal pour éradiquer les tumeurs disséminées ou les métastases. De récentes données démontrent que les rayonnements ionisants, en plus de leur cytotoxicité directe, peuvent aussi induire une immunité antitumorale efficace. Les effets biologiques de l'irradiation pourraient donc être utilisés pour potentialiser la réponse à différents types d'immunothérapie, et ainsi ouvrir la voie au développement de nouvelles thérapies combinant RITα et immunothérapies. < radionucléide. Le choix du radionucléide repose sur des considérations pratiques (le coût, la disponibilité, le type de techniques de radiomarquage et la facilité d'utilisation), le type d'émission du radioélément, le transfert d'énergie linéique (TEL : quantité d'énergie transférée au milieu par la particule incidente, par unité de longueur de la trajectoire en keV 1 /µm) et la demi-vie physique du radioisotope (durée nécessaire pour que la moitié des noyaux radioactifs d'une source se soient désintégrés) [2]. Cette dernière doit être, autant que possible, en adéquation avec la pharmacocinétique du vecteur utilisé, afin de délivrer la plus grande dose possible de radioactivité à la tumeur après l'injection. Une demi-vie trop courte entraînera un nombre élevé de désintégrations avant d'atteindre la cible. À l'inverse, une demi-vie trop longue engendrera un grand nombre de désintégrations du radionucléide pendant la phase d'éli-mination du vecteur, rendant le radioimmunoconjugué plus toxique. La demi-vie doit également être compatible avec les applications cliniques et la prise en charge du patient. Ainsi, le temps nécessaire au transfert du radionucléide du site de production jusqu'à l'hôpital, 1 1 keV (kiloélectronvolts) = 10 3 eV ; 1 MeV (megaélectonvolts) = 10 6 eV.

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“…Internalization of substance P conjugated to the chelator 1-(1-carboxy-3-carboxypropyl)-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid (DOTAGA) was found to be specific, and in a first clinical study using 90 Y-and 213 Bilabeled DOTATAGA-substance P, 20 patients have been enrolled (116). Patients with high-grade lesions (n 5 16) were included after progression of disease or denial of conventional treatment options.…”

Section: Radiolabeled Substance P and Chloratoxinmentioning

confidence: 99%

“…On the basis of these encouraging results, 2 further studies were initiated with radiolabeled substance P. The previous study (116) showed that from a surgical point of view, resectability was facilitated by improved demarcation and by the radiation-induced antiangiogenic effect in these patients who had been treated up front with locoregional radiopeptide therapy. Therefore, a study (118) analyzed whether neoadjuvant treatment before tumor resection is also a valid concept for improved therapy of malignant brain tumors.…”

Section: Radiolabeled Substance P and Chloratoxinmentioning

confidence: 99%

Radiopeptide Imaging and Therapy in Europe

Ambrosini¹,

Fani²,

Fanti³

et al. 2011

J Nucl Med

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183

116

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Receptor targeting with radiolabeled peptides has become an important topic, particularly in nuclear oncology. Strong research efforts are under way in radiopharmaceutical science laboratories and in nuclear medicine departments in Europe. The target receptors belong to the large family of G-proteincoupled receptors. The prototypes of these radiopeptides are based on analogs of somatostatin targeting somatostatin receptor-positive tumors, particularly well-differentiated neuroendocrine tumors. These radiopeptides have an important impact not only on diagnosis but also on targeted radionuclide therapy of these tumors. Besides the registered radiopeptide 111 In-pentetreotide, efficient SPECT tracers labeled with 99m Tc and PET agents based on generator-produced 68 Ga have been developed and used in the clinic. In parallel to the development of diagnostic agents, radiopeptides labeled with the b 2 emitters 90 Y and 177 Lu are also widely used. Because the same chelators and therefore the same conjugates can be used in diagnosis and therapy, they constitute ideal theranostic pairs. This progress is driven not only by scientists and clinicians but also by patient interest groups. New radiopeptides targeting other G-protein-coupled receptors are entering the clinic, among them glucagon-like peptide 1 receptor-targeting molecules. This receptor is overexpressed on literally all benign insulinomas. 111 In-labeled derivatives of the insulinotropic 39-mer peptide exendin-4 were beneficial in the pre-and perioperative localization of these benign lesions. In contrast, lack of localization may indicate malignant insulinoma. The bombesin-and gastrin-releasing peptide receptor family is potentially important because these receptors are overexpressed on major human tumors such as prostate tumors, breast tumors, gastrointestinal stromal tumors, and vessels of ovarian cancer. 99m Tc-labeled peptides for SPECT and 68 Ga-, as well as 64 Cu-labeled agonists or antagonists, have been studied in breast tumors, prostate tumors, gastrointestinal stromal tumors, and gliomas with considerable success. A phase I therapeutic study with a 177 Lu-labeled agonist has been completed. There are not enough clinical data available to reveal the significance of these new modalities in patient care, but several phase I studies are under way in larger patient cohorts using PET agents. Another G-protein-coupled receptor with high overexpression on human tumors is the gastrin/ cholecystokinin-2 receptor. It is overexpressed in more than 90% of cases of medullary thyroid cancer, in small cell lung cancer, and in a subgroup of neuroendocrine tumors. Correlating with in vitro receptor localization using autoradiography of 27 patients with metastasized medullary thyroid cancer, SPECT or planar imaging of these patients resulted in a 95% sensitivity of tumor localization. Finally, another G-protein-coupled receptor is found in brain tumors and peritumoral vessels. Literally all cases of glioblastoma multiforme overexpress the neurokinin type 1 receptor; th...

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Local Targeting of Malignant Gliomas by the Diffusible Peptidic Vector 1,4,7,10-Tetraazacyclododecane-1-Glutaric Acid-4,7,10-Triacetic Acid-Substance P

Cited by 140 publications

References 39 publications

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

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

Radio-immunothérapie alpha

Radiopeptide Imaging and Therapy in Europe

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