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

Autor: Séhédic, Delphine, Chourpa, Igor, Tétaud, Clément, Griveau, Audrey, Loussouarn, Claire, Avril, Sylvie, Legendre, Claire, Lepareur, Nicolas, Wion, Didier, Hindré, François, Davodeau, François, Garcion, Emmanuel
Přispěvatelé: 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), Université d'Angers (UA)-Université d'Angers (UA)
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Theranostics
Theranostics, Ivyspring International Publisher, 2017, 7 (18), pp.4517-4536. ⟨10.7150/thno.19403⟩
Theranostics, 2017, 7 (18), pp.4517-4536. ⟨10.7150/thno.19403⟩
ISSN: 1838-7640
Popis: 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.
Databáze: OpenAIRE
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