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1. Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis

Author

Ahmad Chehaitly, Anne-Laure Guihot, Coralyne Proux, Linda Grimaud, Jade Aurrière, Benoit Legouriellec, Jordan Rivron, Emilie Vessieres, Clément Tétaud, Antonio Zorzano, Vincent Procaccio, Françoise Joubaud, Pascal Reynier, Guy Lenaers, Laurent Loufrani, and Daniel Henrion

Subjects
mitochondrial fusion, blood flow, shear stress, arteries, endothelial cell, atherosclerosis, Therapeutics. Pharmacology, RM1-950
Abstract

Flow (shear stress)-mediated dilation (FMD) of resistance arteries is a rapid endothelial response involved in tissue perfusion. FMD is reduced early in cardiovascular diseases, generating a major risk factor for atherosclerosis. As alteration of mitochondrial fusion reduces endothelial cells’ (ECs) sprouting and angiogenesis, we investigated its role in ECs responses to flow. Opa1 silencing reduced ECs (HUVECs) migration and flow-mediated elongation. In isolated perfused resistance arteries, FMD was reduced in Opa1+/− mice, a model of the human disease due to Opa1 haplo-insufficiency, and in mice with an EC specific Opa1 knock-out (EC-Opa1). Reducing mitochondrial oxidative stress restored FMD in EC-Opa1 mice. In isolated perfused kidneys from EC-Opa1 mice, flow induced a greater pressure, less ATP, and more H2O2 production, compared to control mice. Opa1 expression and mitochondrial length were reduced in ECs submitted in vitro to disturbed flow and in vivo in the atheroprone zone of the mouse aortic cross. Aortic lipid deposition was greater in Ldlr−/--Opa1+/- and in Ldlr−/--EC-Opa1 mice than in control mice fed with a high-fat diet. In conclusion, we found that reduction in mitochondrial fusion in mouse ECs altered the dilator response to shear stress due to excessive superoxide production and induced greater atherosclerosis development.

Published
2022
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2. Development and characterization of sorafenib-loaded lipid nanocapsules for the treatment of glioblastoma

Author

Anne Clavreul, Emilie Roger, Milad Pourbaghi-Masouleh, Laurent Lemaire, Clément Tétaud, and Philippe Menei

Subjects
drug delivery, glioblastoma, lipid nanocapsules, sorafenib, Therapeutics. Pharmacology, RM1-950
Abstract

Anticancer agents that target both tumor cells and angiogenesis are of potential interest for glioblastoma (GB) therapy. One such agent is sorafenib (SFN), a tyrosine kinase inhibitor. However, poor aqueous solubility and undesirable side effects limit its clinical application, including local treatment. We encapsulated SFN in lipid nanocapsules (LNCs) to overcome these drawbacks. LNCs are nanocarriers formulated according to a solvent-free process, using only components that have received regulatory approval. SFN-LNCs had a diameter of 54 ± 1 nm, high encapsulation efficiency (>90%), and a drug payload of 2.11 ± 0.03 mg/g of LNC dispersion. They inhibited in vitro angiogenesis and decreased human U87MG GB cell viability similarly to free SFN. In vivo studies showed that the intratumoral administration of SFN-LNCs or free SFN in nude mice bearing an orthotopic U87MG human GB xenograft decreased the proportion of proliferating cells in the tumor relative to control groups. SFN-LNCs were more effective than free SFN for inducing early tumor vascular normalization, characterized by increases in tumor blood flow and decreases in tumor vessel area. These results highlight the potential of LNCs as delivery systems for SFN. The vascular normalization induced by SFN-LNCs could be used to improve the efficacy of chemotherapy or radiotherapy for treating GB.

Published
2018
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3. Development and characterization of sorafenib-loaded lipid nanocapsules for the treatment of glioblastoma

Author

Clément Tétaud, Emilie Roger, Laurent Lemaire, Philippe Menei, Anne Clavreul, Milad Pourbaghi-Masouleh, 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), Département de neurochirurgie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Division of Drug Delivery and Tissue Engineering [Nottingham, UK], University of Nottingham, UK (UON)-School of Pharmacy [Nottingham, UK], Plate-forme de Recherche en Imagerie et Spectroscopie Multi-modales [SFR ICAT - UA] (PRISM), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA)-Université d'Angers (UA), This research was supported by grants from the ‘Fondation de France,’‘Ligue contre le Cancer du Grand-Ouest, Comite Departemental duMaine-et-Loire,’ ‘Association en Avant la Vie,’ and the EuropeanCommission, Education, Audiovisual and Culture Executive Agency(EACEA), through the NanoFar Erasmus Mundus joint Doctoral program., Bernardo, Elizabeth, 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), School of Pharmacy [Nottingham, UK]-University of Nottingham, UK (UON), and Plate-forme de Recherche en Imagerie et Spectroscopie Multi-modales (PRISM [SFR ICAT - UA])

Subjects
Drug, Sorafenib, medicine.drug_class, Angiogenesis, media_common.quotation_subject, Drug Compounding, Pharmaceutical Science, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, 02 engineering and technology, Tyrosine-kinase inhibitor, 03 medical and health sciences, Mice, 0302 clinical medicine, Drug Delivery Systems, [SDV.CAN] Life Sciences [q-bio]/Cancer, Nanocapsules, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Viability assay, media_common, lipid nanocapsules, Chemistry, Brain Neoplasms, lcsh:RM1-950, glioblastoma, General Medicine, 021001 nanoscience & nanotechnology, Lipids, 3. Good health, lcsh:Therapeutics. Pharmacology, 030220 oncology & carcinogenesis, Drug delivery, Cancer research, Nanocarriers, 0210 nano-technology, medicine.drug, Research Article
Abstract

International audience; Anticancer agents that target both tumor cells and angiogenesis are of potential interest for glioblastoma (GB) therapy. One such agent is sorafenib (SFN), a tyrosine kinase inhibitor. However, poor aqueous solubility and undesirable side effects limit its clinical application, including local treatment. We encapsulated SFN in lipid nanocapsules (LNCs) to overcome these drawbacks. LNCs are nanocarriers formulated according to a solvent-free process, using only components that have received regulatory approval. SFN-LNCs had a diameter of 54 ± 1 nm, high encapsulation efficiency (>90%), and a drugpayload of 2.11 ± 0.03mg/g of LNC dispersion. They inhibited in vitro angiogenesis and decreased human U87MG GB cell viability similarly to free SFN. In vivo studies showed that the intratumoral administration of SFN-LNCs or free SFN in nude mice bearing an orthotopic U87MG human GB xenograft decreased the proportion of proliferating cells in the tumor relative to control groups. SFN-LNCs were more effective than free SFN for inducing early tumor vascular normalization, characterized by increases in tumor blood flow and decreases in tumor vessel area. These results highlight the potentialof LNCs as delivery systems for SFN. The vascular normalization induced by SFN-LNCs could be used to improve the efficacy of chemotherapy or radiotherapy for treating GB.

Published
2018
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4. Characterization of the distribution, retention, and efficacy of internal radiation of 188Re-lipid nanocapsules in an immunocompromised human glioblastoma model

Author

Nicolas Lepareur, Olivier Couturier, Philippe Menei, Anne Clavreul, Djamel Dabli, Francis Bouchet, François Hindré, Audrey Rousseau, Laurent Lemaire, Annabelle Cikankowitz, Clément Tétaud, Emmanuel Garcion, Animaux modèles pour la recherche en oncologie comparée (AMaROC), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), CIFAB-PRIMEX, Université d'Angers (UA), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), CRLCC Eugène Marquis (CRLCC), Nutrition, Métabolismes et Cancer (NuMeCan), 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 Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Médecine Nucléaire (Med Nuc - ANGERS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), 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), Service de neurochirurgie [CHU Angers], and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cancer Research, Lipid nanocapsules, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Immune system, Glioma, medicine, Convection-enhanced delivery, Human glioblastoma, Rhenium-188, business.industry, Internal radiotherapy, Internal radiation, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Human situation, 3. Good health, Radiation therapy, Neurology, Oncology, 030220 oncology & carcinogenesis, Immunology, Toxicity, Cancer research, Neurology (clinical), business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Glioblastoma
Abstract

International audience; Internal radiation strategies hold great promise for glioblastoma (GB) therapy. We previously developed a nanovectorized radiotherapy that consists of lipid nanocapsules loaded with a lipophilic complex of Rhenium-188 (LNC(188)Re-SSS). This approach resulted in an 83 % cure rate in the 9L rat glioma model, showing great promise. The efficacy of LNC(188)Re-SSS treatment was optimized through the induction of a T-cell immune response in this model, as it is highly immunogenic. However, this is not representative of the human situation where T-cell suppression is usually encountered in GB patients. Thus, in this study, we investigated the efficacy of LNC(188)Re-SSS in a human GB model implanted in T-cell deficient nude mice. We also analyzed the distribution and tissue retention of LNC(188)Re-SSS. We observed that intratumoral infusion of LNCs by CED led to their complete distribution throughout the tumor and peritumoral space without leakage into the contralateral hemisphere except when large volumes were used. Seventy percent of the (188)Re-SSS activity was present in the tumor region 24 h after LNC(188)Re-SSS injection and no toxicity was observed in the healthy brain. Double fractionated internal radiotherapy with LNC(188)Re-SSS triggered survival responses in the immunocompromised human GB model with a cure rate of 50 %, which was not observed with external radiotherapy. In conclusion, LNC(188)Re-SSS can induce long-term survival in an immunosuppressive environment, highlighting its potential for GB therapy.

Published
2016
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5. Hybrid Gd

Author

Hélène, Lajous, Raphaël, Riva, Bénédicte, Lelièvre, Clément, Tétaud, Sylvie, Avril, François, Hindré, Frank, Boury, Christine, Jérôme, Philippe, Lecomte, and Emmanuel, Garcion

Subjects
Gadolinium DTPA, Polycarboxylate Cement, Cell Survival, Polyesters, Mice, Nude, Antineoplastic Agents, Polyethylene Glycols, DNA Adducts, Drug Liberation, Cell Line, Tumor, Animals, Nanoparticles, Female, Prodrugs, Cisplatin, Glioblastoma, Platinum
Abstract

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 nanoplatform biodistribution in the damaged parenchyma and its therapeutic benefit. For this purpose, a biocompatible amphiphilic triblock copolymer, made of degradable polyester and polycarbonate and bioeliminable polyethylene oxide (PEO), was synthesized by successive ring-opening polymerizations. After micellization 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 r2/r1 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 T2-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

6. 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
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7. Characterization of the distribution, retention, and efficacy of internal radiation of

Author

Annabelle, Cikankowitz, Anne, Clavreul, Clément, Tétaud, Laurent, Lemaire, Audrey, Rousseau, Nicolas, Lepareur, Djamel, Dabli, Francis, Bouchet, Emmanuel, Garcion, Philippe, Menei, Olivier, Couturier, and François, Hindré

Subjects
Radioisotopes, Brain Neoplasms, T-Lymphocytes, Mice, Nude, Xenograft Model Antitumor Assays, Mice, Rhenium, Treatment Outcome, Nanocapsules, Tumor Cells, Cultured, Animals, Autoradiography, Humans, Radiopharmaceuticals, Glioblastoma
Abstract

Internal radiation strategies hold great promise for glioblastoma (GB) therapy. We previously developed a nanovectorized radiotherapy that consists of lipid nanocapsules loaded with a lipophilic complex of Rhenium-188 (LNC

Published
2016

8. Automatisation de la production de nanocapsules lipidiques chargées en technétium-99 m

Author

Nicolas Lepareur, François Hindré, O. Couturier, Emmanuel Garcion, F. Lacoeuille, A. Contini, and Clément Tétaud

Subjects
Radiological and Ultrasound Technology, Biophysics, Radiology, Nuclear Medicine and imaging
Abstract

Introduction L’utilisation de nanocapsules lipidiques chargees en rhenium-188 (188Re-SSS-LNC) pour la radiotherapie interne vectorisee du glioblastome constitue une alternative innovante qui a presente des resultats prometteurs. Le systeme nanocapsulaire lipidique utilise a montre une capacite a encapsuler le rhenium-188 sous forme d’un complexe, le bis(trithioperoxybenzoate)(dithiobenzoate) de rhenium. Deux programmes de recherche ont ete soutenus dans l’objectif du transfert a la clinique de cette nouvelle technologie. Dans cet objectif l’automatisation de la production et sa caracterisation constituent des etapes clefs. Les donnees presentees concernent l’automatisation de la production de nanocapsules lipidiques chargees en technetium-99 m (99mTc-SSS-LNC), utilisee comme modele du rhenium-188. Materiels et methodes Apres une etape de developpement et d’optimisation des conditions, 6 production (3 avec 0,5 GBq et 3 avec 5 GBq) ont ete realisees a l’aide d’un automate Synchrom R&D, Raytest® pilote par le logiciel Gynastar®, Raytest®. Chacune de ces productions a ete decrite par des indicateurs de procede et une caracterisation du produit final (activite et activite volumique, distribution en taille et potentiel zeta des particules et purete radiochimique PRC). En parallele, une methode de caracterisation de la PRC par chromatographie d’exclusion de taille a ete developpee (colonne ultrahydrogel, Waters®, injecteur pompe HPLC et detecteur UV Series 200, Perkin Elmer®, detecteur de radioactivite Radiomatic 150 TR, Perkin Elmer®). Resultats Un temps de production de 90 min ± (10) a ete observe. Les rendements de production ont ete de 44 % ± (1,7) pour les productions basse activite (0,5 GBq) et de 37 % ± (1,3) pour les productions haute activite (5 GBq). En fin de production, l’activite moyenne est comprise entre 291 MBq et 1501 MBq (activite volumique comprise entre 70 MBq/mL – 395 MBq/mL). Les nanoparticules obtenues presentent une taille de 64 nm ± (2), un PdI de 0,089 ± (0,019) et un potentiel zeta de -10 mV ± (2). Pour chaque production, une valeur de PRC superieure a 98 % a ete retrouvee. Conclusion La production automatisee en 99mTc-SSS-LNC developpee a presente un rendement, une distribution en taille et une PRC compatibles avec une utilisation en clinique. Les productions de nanocapsules chargees en rhenium-188 sont en cours d’optimisation et de caracterisation.

Published
2017
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9. Identification of two glioblastoma-associated stromal cell subtypes with different carcinogenic properties in histologically normal surgical margins

Author

Audrey Rousseau, Clément Tétaud, Amandine Etcheverry, Tony Avril, Jean Mosser, Philippe Menei, Cécile Henry, Anne Clavreul, Lecoupe-Grainville, Marie, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Service de neurochirurgie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Pontchaillou, Oncogenesis Stress Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by the Pays de la Loire and Bretagne regions and Ligue contre le cancer-49-Comite´ de Maine-et-Loire., Service de neurochirurgie [CHU Angers], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)

Subjects
Cancer Research, Pathology, medicine.medical_treatment, Apoptosis, Transcriptome, Mice, 0302 clinical medicine, Cell Movement, Tumor Cells, Cultured, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Brain Neoplasms, Brain, Flow Cytometry, 3. Good health, Cell Transformation, Neoplastic, Neurology, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Female, cancer-associated fibroblasts, medicine.medical_specialty, Stromal cell, Blotting, Western, Mice, Nude, Translational study, peritumoral brain zone, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Stroma, In vivo, Glioma, Biomarkers, Tumor, Human Umbilical Vein Endothelial Cells, medicine, Animals, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Proliferation, 030304 developmental biology, Gene Expression Profiling, glioblastoma, DNA Methylation, medicine.disease, Xenograft Model Antitumor Assays, Radiation therapy, Cancer-Associated Fibroblasts, Neurology (clinical), Stromal Cells
Abstract

International audience; Glioblastoma (GB) is a highly infiltrative tumor recurring within a few centimeters of the resection cavity in 90% of cases, even in cases of complete tumor resection and adjuvant chemo/radiotherapy. We recently isolated GB-associated stromal cells (GASCs) from the GB peritumoral zone, with phenotypic and functional properties similar to those of the cancer-associated fibroblasts (CAFs) present in the stroma of carcinomas. In particular, GASCs promote blood vessel development and have tumor-promoting effects on glioma cells in vitro and in vivo. In this study, we characterized these cells further, by analyzing the transcriptome and methylome of 14 GASC and five control stromal cell preparations derived from non-GB peripheral brain tissues. We identified two subtypes of GASCs in surgical margins in GB patients: GASC-A and GASC-B. GASC-B promoted the development of tumors and endothelium, whereas GASC-A did not. A difference in DNA methylation may underlie these two subtypes. We identified various proteins as being produced in the procarcinogenic GASC-B. Some of these proteins may serve as prognostic factors for GB and/or targets for anti-glioma treatment. In conclusion, in this era of personalized therapy, the status of GASCs in GB-free surgical margins should be taken into account, to improve treatment and the prevention of recurrence.

Published
2015
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10. Targeting and treatment of glioblastomas with human mesenchymal stem cells carrying ferrociphenol lipid nanocapsules

Author

Anne-Laure Lainé, Claudia N. Montero-Menei, Florence Franconi, Philippe Menei, Clément Tétaud, Anne Clavreul, Catherine Passirani, Nolwenn Lautram, Angélique Montagu, Anne Vessières, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CIFAB-PRIMEX, Université d'Angers (UA), Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ), Université d'Angers ( UA ), 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
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cell, Pharmaceutical Science, Endogeny, 02 engineering and technology, Mice, International Journal of Nanomedicine, Drug Discovery, Medicine, Cells, Cultured, media_common, Original Research, 0303 health sciences, nanoparticle, General Medicine, Stem-cell therapy, 021001 nanoscience & nanotechnology, Lipids, 3. Good health, medicine.anatomical_structure, Drug delivery, 0210 nano-technology, Drug, Cell Survival, media_common.quotation_subject, Biophysics, Bioengineering, Nanotechnology, Antineoplastic Agents, Mesenchymal Stem Cell Transplantation, Biomaterials, 03 medical and health sciences, Nanocapsules, Cell Line, Tumor, Distribution (pharmacology), Animals, Humans, Viability assay, Ferrous Compounds, targeting, 030304 developmental biology, [ SDV ] Life Sciences [q-bio], business.industry, Organic Chemistry, Mesenchymal stem cell, Mesenchymal Stem Cells, Xenograft Model Antitumor Assays, drug delivery, Cancer research, business, Glioblastoma
Abstract

Anne Clavreul,1 Angélique Montagu,2 Anne-Laure Lainé,2 Clément Tétaud,2 Nolwenn Lautram,2 Florence Franconi,3 Catherine Passirani,2 Anne Vessières,4 Claudia N Montero-Menei,2 Philippe Menei1 1Département de Neurochirurgie, Centre Hospitalier Universitaire, Angers, France; 2INSERM UMR-S 1066, Université d’Angers, LUNAM Université, Angers, France; 3CIFAB-PRIMEX, Université d’Angers, LUNAM Université, Angers, France; 4CNRS-UMR 7223, ENSCP, Paris, France Abstract: Recently developed drug delivery nanosystems, such as lipid nanocapsules (LNCs), hold great promise for the treatment of glioblastomas (GBs). In this study, we used a subpopulation of human mesenchymal stem cells, “marrow-isolated adult multilineage inducible” (MIAMI) cells, which have endogenous tumor-homing activity, to deliver LNCs containing an organometallic complex (ferrociphenol or Fc-diOH), in the orthotopic U87MG GB model. We determined the optimal dose of Fc-diOH-LNCs that can be carried by MIAMI cells and compared the efficacy of Fc-diOH-LNC-loaded MIAMI cells with that of the free-standing Fc-diOH-LNC system. We showed that MIAMI cells entrapped an optimal dose of about 20 pg Fc-diOH per cell, with no effect on cell viability or migration capacity. The survival of U87MG-bearing mice was longer after the intratumoral injection of Fc-diOH-LNC-loaded MIAMI cells than after the injection of Fc-diOH-LNCs alone. The greater effect of the Fc-diOH-LNC-loaded MIAMI cells may be accounted for by their peritumoral distribution and a longer residence time of the drug within the tumor. These results confirm the potential of combinations of stem cell therapy and nanotechnology to improve the local tissue distribution of anticancer drugs in GB.Keywords: glioblastoma, mesenchymal stem cells, nanoparticle, drug delivery, targeting&nbsp

Published
2015
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11. Inhibition of ectopic glioma tumor growth by a potent ferrocenyl drug loaded into stealth lipid nanocapsules

Author

Anne-Laure Lainé, Emmanuel Garcion, Anne Vessières, Clément Tétaud, Gérard Jaouen, Robert-Alain Toillon, Anne Clavreul, Léo Aubert, Matthieu Guilbert, Jean-Pierre Benoit, Catherine Passirani, Audrey Rousseau, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Service de neurochirurgie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), PRES Université Nantes Angers Le Mans (UNAM), Chimie et biochimie des complexes moléculaires (CBCM), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Chemical Biology (CHEMBIO), Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Charles Friedel, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Signalisation des facteurs de croissance dans le cancer du sein. Protéomique fonctionnelle, Institut National de la Santé et de la Recherche Médicale (INSERM), Plasticité Cellulaire et Cancer - U908 (CPAC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Pôle de recheche et d'enseignement supérieur (UNAM), Service de neurochirurgie, and Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Drug, Materials science, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Biomedical Engineering, Brain tumor, Pharmaceutical Science, Medicine (miscellaneous), Bioengineering, 02 engineering and technology, Pharmacology, 010402 general chemistry, medicine.disease_cause, 01 natural sciences, Nanocapsules, Cell Line, Tumor, Glioma, medicine, Animals, [CHIM]Chemical Sciences, General Materials Science, Ferrous Compounds, IC50, ComputingMilieux_MISCELLANEOUS, media_common, Drug Carriers, Cell Cycle, Cell cycle, 021001 nanoscience & nanotechnology, medicine.disease, Rats, Inbred F344, In vitro, Rats, 0104 chemical sciences, 3. Good health, Nanomedicine, Cancer cell, Molecular Medicine, Female, Reactive Oxygen Species, 0210 nano-technology, Oxidative stress
Abstract

In this work, a novel ferrocenyl complex (ansa-FcdiOH) was assessed for brain tumor therapy through stealth lipid nanocapsules (LNCs). Stealth LNCs, prepared according to a one-step process, showed rapid uptake by cancer cells and extended blood circulation time. The ferrocenyl complex was successfully encapsulated into these LNCs measuring 40nm with a high loading capacity (6.4%). In vitro studies showed a potent anticancer effect of ansa-FcdiOH on 9L cells with a low IC50 value (0.1μM) associated with an oxidative stress and a dose-dependent alteration of the cell cycle. Repeated intravenous injections of stealth ansa-FcdiOH LNCs in ectopic glioma bearing rats induced a significant tumor growth inhibition, supported by a reduced number of proliferative cells in tumors compared to control group. Additionally, no liver damage was observed in treated animals. These results indicated that stealth ansa-FcdiOH LNCs might be considered as a potential new approach for cancer chemotherapy. From the Clinical Editor In this study, a novel ferrocenyl complex was assessed for brain tumor therapy through stealth lipid nanocapsules, demonstrating no liver damage, and superior tumor volume reduction compared to saline and stealth lipid nanocapsules alone in an ectopic glioma model.

Published
2014
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12. Glioblastoma-associated stromal cells (GASCs) from histologically normal surgical margins have a myofibroblast phenotype and angiogenic properties

Author

Anne Clavreul, Clément Tétaud, Tony Avril, Philippe Menei, Catherine Guette, Olivier Coqueret, Rogatien Faguer, Alice Boissard, Laurent Lemaire, Cécile Henry, Audrey Rousseau, Service de neurochirurgie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Substances d'Origine Naturelle et Analogues Structuraux (SONAS), Université d'Angers (UA), Ingénierie de la vectorisation particulaire, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme d'Ingénierie et d'Analyses Moléculaires (PIAM), Service de neuro-pathologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de neurochirurgie [CHU Angers], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Proteomics, Pathology, Neoplasm, Residual, Angiogenesis, Biopsy, Cell Communication, Cell Separation, Neovascularization, Tandem Mass Spectrometry, Tumor Cells, Cultured, Myofibroblasts, Tumor Markers, education.field_of_study, Cultured, Neovascularization, Pathologic, Blotting, Brain Neoplasms, Hepatocyte Growth Factor, Flow Cytometry, Tumor Cells, 3. Good health, Phenotype, Residual, Hepatocyte growth factor, medicine.symptom, Western, Myofibroblast, medicine.drug, medicine.medical_specialty, Stromal cell, Population, Blotting, Western, Primary Cell Culture, Biology, Pathology and Forensic Medicine, Glioma, medicine, Biomarkers, Tumor, Matrix-Assisted Laser Desorption-Ionization, Humans, education, Pathologic, [SDV.GEN]Life Sciences [q-bio]/Genetics, Wound Healing, Spectrometry, Reproducibility of Results, Mass, Biological, medicine.disease, Chemokine CXCL12, Coculture Techniques, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Neoplasm, Stromal Cells, Wound healing, Glioblastoma
Abstract

International audience; Glioblastoma (GB) displays diffusely infiltrative growth patterns. Dispersive cells escape surgical resection and contribute to tumour recurrence within a few centimeters of the resection cavity in 90% of cases. We know that the non-neoplastic stromal compartment, in addition to infiltrative tumour cells, plays an active role in tumour recurrence. We isolated a new stromal cell population from the histologically normal surgical margins of GB by computer-guided stereotaxic biopsies and primary culture. These GB-associated stromal cells (GASCs) share phenotypic and functional properties with the cancer-associated fibroblasts (CAFs) described in the stroma of carcinomas. In particular, GASCs have tumour-promoting effects on glioma cells in vitro and in vivo. Here, we describe a quantitative proteomic analysis, using iTRAQ labelling and mass spectrometry, to compare GASCs with control stromal cells derived from non-GB peripheral brain tissues. A total of 1077 proteins were quantified and 67 proteins were found to differ between GASCs and control stromal cells. Several proteins changed in GASCs are related to a highly motile myofibroblast phenotype, and to wound healing and angiogenesis. The results for several selected proteins were validated by western blotting or flow cytometry. Furthermore, the effect of GASCs on angiogenesis was confirmed using the orthotopic U87MG glioma model. In conclusion, GASCs, isolated from GB histologically normal surgical margins and found mostly near blood vessels, could be a vascular niche constituent establishing a permissive environment, facilitating angiogenesis and possibly colonization of recurrence-initiating cells. We identify various proteins as being expressed in GASCs: some of these proteins may serve as prognostic factors for GB and/or targets for anti-glioma treatment.

Published
2013
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13. Rhenium-188: application for glioblastoma internal radiotherapy

Author

Annabelle Cikankowitz, Clément Tétaud, Camille Belloche, Elise Verger, Olivier-François Couturier, Franck Lacœuille, Dabli, D., Francis Bouchet, Audrey Rousseau, Nicolas Lepareur, Jean-Pierre Benoit, Philippe Menei, Anne Clavreul, Ibisch, C., François Hindré, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Microenvironnement et remodelage, Foie, métabolismes et cancer, 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-CRLCC Eugène Marquis (CRLCC), Univ Angers, Okina, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-CRLCC Eugène Marquis (CRLCC)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

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