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1. Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Promising Perspectives

Author

Nicolas Lepareur, Franck Lacœuille, Christelle Bouvry, François Hindré, Emmanuel Garcion, Michel Chérel, Nicolas Noiret, Etienne Garin, F. F. Russ Knapp, CRLCC Eugène Marquis (CRLCC), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Radiobiologie et d’Imageries EXpérimentale [SFR ICAT - UA] (PRIMEX), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA)-Université d'Angers (UA), Nuclear Oncology (CRCINA-ÉQUIPE 13), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Medical Radioisotopes Program [Oak Ridge, TN, USA] (Emeritus), Oak Ridge National Laboratory, French National Agency for Research called Investissements d'Avenir Labex IRONFrench National Research Agency (ANR) [ANR-11-LABX-0018], ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Plateforme de Radiobiologie et d’Imagerie EXperimentale - PRIMEX [Angers], Université d'Angers (UA), Bernardo, Elizabeth, Radiopharmaceutiques Innovants en Oncologie et Neurologie - - IRON2011 - ANR-11-LABX-0018 - LABX - VALID, and Lepareur, Nicolas

Subjects
radioembolization, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Therapeutic radioisotope, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [CHIM] Chemical Sciences, medicine, [CHIM]Chemical Sciences, In patient, radiopharmaceuticals, lcsh:R5-920, business.industry, Rhenium-188, Bone metastasis, THERAPEUTIC RADIOPHARMACEUTICALS, radionuclide therapy, bone pain palliation, oncology, peptides, General Medicine, medicine.disease, 3. Good health, Cancer treatment, Clinical trial, 030220 oncology & carcinogenesis, Radionuclide therapy, Medicine, Radiology, Early phase, business, lcsh:Medicine (General)
Abstract

International audience; Rhenium-188 (Re-188) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify Re-188 as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of Re-188 from the W-188/Re-188 generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA) Re-188. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a "theranostic pair." Thus, preparation and targeting of Re-188 agents for therapy is similar to imaging agents prepared with Tc-99m, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on Re-188-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these Re-188-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of Re-188-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that Re-188 represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.

Published
2019

2. Hybrid Gd 3+ /cisplatin cross-linked polymer nanoparticles enhance platinum accumulation and formation of DNA adducts in glioblastoma cell lines

Author

Clément Tétaud, Philippe Lecomte, Bénédicte Lelièvre, Christine Jérôme, Raphaël Riva, Hélène Lajous, Frank Boury, François Hindré, Emmanuel Garcion, Sylvie Avril, Bernardo, Elizabeth, Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Center for Education and Research on Macromolecules - CERM [Liège, Belgium], Université de Liège-CESAM RU [Liège, Belgium], Département de Pharmacologie-Toxicologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Plateforme de Radiobiologie et d’Imageries EXpérimentale [SFR ICAT - UA] (PRIMEX), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA)-Université d'Angers (UA), This work was supported by the 'Institut National de la Santé et de la Recherche Médicale' (INSERM), by the University ofAngers (Angers, France) and by the University of Liège (Liege, Belgium). H. L. was a Ph.D. student from the EuropeanCommunity in the framework of the Erasmus Mundus JointDoctorate Program NanoFar and received a fellowship from 'La Région Pays-de-la-Loire'. P. L. is Research Associate of the FRS-FNRS. F. H., C. T. and E. G. are members of the LabEx IRON 'Innovative Radiopharmaceuticals in Oncology and Neurology' funded by the ANR (French National Research Agency) as part of the French government 'Investissements d’Avenir' programme. The presented work is also related to the PL-BIO 2014-2020 INCA (Institut National du Cancer) project MARENGO – 'MicroRNA agonist and antagonist Nanomedicines for GliOblastoma treatment: from molecular programmation to preclinical validation' and to the 'Réseau Vectorisation and Radiothérapies' and 'Réseau Gliome (ReGGO)' of the 'Cancéropôle Grand-Ouest'., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Center for Education and Research on Macromolecules, Université de Liège, Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), Génétique Diversité et Ecophysiologie des Céréales (GDEC), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CESAM RU [Liège, Belgium]-Université de Liège, Plateforme de Radiobiologie et d’Imagerie EXperimentale - PRIMEX [Angers], Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA - Département NOHMAD - Equipe 17), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Groupe d'Etude des Interactions Hôte-Parasite (GEIHP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de la Recherche Agronomique (INRA), and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Recherche Agronomique (INRA)

Subjects
Cisplatin, Biodistribution, Chemistry, Gadolinium, [SDV]Life Sciences [q-bio], Biomedical Engineering, Nanoparticle, chemistry.chemical_element, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, Prodrug, 021001 nanoscience & nanotechnology, Micelle, 03 medical and health sciences, 0302 clinical medicine, Targeted drug delivery, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, medicine, Biophysics, Nanomedicine, General Materials Science, 0210 nano-technology, ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract

International audience; Glioblastoma is the most frequent and aggressive primary malignant tumor of the central nervous system with a gloomy prognosis. Platinum derivatives and one among them, cisplatin, exhibited promising results when locally administered into the brain of glioblastoma bearing rats. Nanovectorization of anticancer agents through polymeric nanoparticles may even promote drug accumulation within cells, thus concentrating the drug efficiently at its target. Anchorage of gadolinium complexes on the corona of such smart drug delivery systems could further allow magnetic resonance imaging (MRI) monitoring of the nanoplat-form biodistribution in the damaged parenchyma and its therapeutic benefit. For this purpose, a biocom-patible amphiphilic triblock copolymer, made of degradable polyester and polycarbonate and bioelimin-able polyethylene oxide (PEO), was synthesized by successive ring-opening polymerizations. After micelli-zation in water, gadolinium complexes were grafted onto the PEO micelle corona and the carboxylate functions, located at the surface of the micelle's core, were able to cross-link with Pt(II) complexes. A macromolecular prodrug was therefore recovered in which more than one third of the carboxylate functions were linked to a platinum atom. By this strategy, stable cisplatin cross-linked nanoparticles were formulated with a mean size in the range of 100.63 ± 12.04 nm consistent with biological investigations. Relaxometry measurements both in water and in plasma at 7 T, 25 °C, confirmed the intrinsic potential of these hybrid nanoparticles as alternative MRI contrast agents with a substantial increase in the r 2 /r 1 ratio by a factor of 3.3 and 2.7, respectively, compared to the conventional low molar mass Gd-DTPA. As a result, their infusion within the striatum of glioblastoma-bearing mice resulted in a hypersignal on T 2-weighted MR images that persisted over time. Ultimately, the formulated prodrug exhibited up to 50-fold increased accumulation in human glioblastoma cell lines and up to 32-fold enhanced subsequent Pt-DNA adduct formation in comparison with free cisplatin, thus supporting the potential of this innovative bimodal tool for further applications.

Published
2018

3. Locoregional Confinement and Major Clinical Benefit of 188 Re-Loaded CXCR4-Targeted Nanocarriers in an Orthotopic Human to Mouse Model of Glioblastoma

Author

Séhédic, Delphine, Chourpa, Igor, Tétaud, Clément, Griveau, Audrey, Loussouarn, Claire, Avril, Sylvie, Legendre, Claire, Lepareur, Nicolas, Wion, Didier, Hindré, François, Davodeau, François, Garcion, Emmanuel, Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Nanomédicaments et Nanosondes, EA 6295 (NMNS), Université de Tours, Plateforme de Radiobiologie et d’Imagerie EXperimentale - PRIMEX [Angers], Université d'Angers (UA), Département d'oncologie médicale [Rennes], CRLCC Eugène Marquis (CRLCC), BrainTech Laboratory [CHU Grenoble Alpes - Inserm U1205] (Brain Tech Lab ), CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Nuclear Oncology (CRCINA-ÉQUIPE 13), Plateforme d’Analyses Cellulaires et Moléculaires - PACeM [Angers], This work was supported by 'La Région Pays-de-la-Loire' through the Nuclear Technology for Health project (NucSan), by the 'Institut National de la Santé et de la Recherche Médicale' (INSERM), by 'La Ligue Nationale Contre le Cancer' through an 'Equipe Labellisée 2012' grant and by the 'Axe Vectorisation and Radiothérapies of the Cancéropôle Grand-Ouest'. Delphine Séhédic was a Ph.D. student from the NucSan project and received a fellowship from 'La Région Pays-de-la-Loire'. N.L., F.H., F.D. and E.G. are also member of the LabEx IRON 'Innovative Radiopharmaceuticals in Oncology and Neurology' as part of the French government 'Investissements d’Avenir' program. The presented work is also related to the PL-BIO 2014-2020 INCA (Institut National du Cancer) project MARENGO - 'MicroRNA agonist and antagonist Nanomedicines for GliOblastoma treatment: from molecular programmation to preclinical validation', to the ANR (French National Research Agency) program RADIOHEAD 'Nanocapsules for Selective Internal RadioTherapy of glioblastoma, and to the 'Région Pays-de-la-Loire' project IRAD' Pre-clinical validation of an innovative Internal RADiotherapy of glioma in a large spontaneous animal model'. C.Lo., and C.Le. were posdoctoral fellows Inca and Fondation ARC, respectively., Université de Tours (UT), Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Plateforme de Radiobiologie et d’Imageries EXpérimentale [SFR ICAT - UA] (PRIMEX), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), and Université d'Angers (UA)-Université d'Angers (UA)

Subjects
CXCR4, nanoparticle, [SDV.CAN] Life Sciences [q-bio]/Cancer, glioblastoma, immuno-targeting, spectral imaging, [SDV.CAN]Life Sciences [q-bio]/Cancer, macrophage, radiation therapy
Abstract

International audience; Purpose: Gold standard beam radiation for glioblastoma (GBM) treatment is challenged by resistance phenomena occurring in cellular populations well prepared to survive or to repair damage caused by radiation. Among signals that have been linked with radio-resistance, the SDF1/CXCR4 axis, associated with cancer stem-like cell, may be an opportune target. To avoid the problem of systemic toxicity and blood-brain barrier crossing, the relevance and efficacy of an original system of local brain internal radiation therapy combining a radiopharmaceutical with an immuno-nanoparticle was investigated.Experiment design: The nanocarrier combined lipophilic thiobenzoate complexes of rhenium-188 loaded in the core of a lipid nanocapsule (LNC188Re) with a function-blocking antibody, 12G5 directed at the CXCR4, on its surface. The efficiency of 12G5-LNC188Re was investigated in an orthotopic and xenogenic GBM model of CXCR4-positive U87MG cells implanted in the striatum of Scid mice.Results: We demonstrated that 12G5-LNC188Re single infusion treatment by convection-enhanced delivery resulted in a major clinical improvement in median survival that was accompanied by locoregional effects on tumor development including hypovascularization and stimulation of the recruitment of bone marrow derived CD11b- or CD68-positive cells as confirmed by immunohistochemistry analysis. Interestingly, thorough analysis by spectral imaging in a chimeric U87MG GBM model containing CXCR4-positive/red fluorescent protein (RFP)-positive- and CXCR4-negative/RFP-negative-GBM cells revealed greater confinement of DiD-labeled 12G5-LNCs than control IgG2a-LNCs in RFP compartments. Main conclusion: These findings on locoregional impact and targeting of disseminated cancer cells in tumor margins suggest that intracerebral active targeting of nanocarriers loaded with radiopharmaceuticals may have considerable benefits in clinical applications.

Published
2017

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