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

Delphine Séhédic; Igor Chourpa; Clément Tétaud; Audrey Griveau; Claire Loussouarn; Sylvie Avril; Claire Legendre; Nicolas Lepareur; Didier Wion; François Hindré; François Davodeau; Emmanuel Garcion

doi:10.7150/thno.19403

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

Delphine Séhédic ¹ Igor Chourpa ² Clément Tétaud ^{1, 3} Audrey Griveau ¹ Claire Loussouarn ¹ Sylvie Avril ¹ Claire Legendre ¹ Nicolas Lepareur ⁴ Didier Wion ⁵ François Hindré ^{1, 3} François Davodeau ⁶ Emmanuel Garcion ^{1, 3, 7, *}

* Auteur correspondant

1 CRCINA - Département NOHMAD - Equipe 13 - Oncologie nucléaire

CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers

2 NMNS - Nanomédicaments et Nanosondes - EA 6295 [Tours]

3 Plateforme de Radiobiologie et d’Imagerie EXperimentale - PRIMEX [Angers]

4 Département d'oncologie médicale [Rennes]

5 BrainTech Laboratory [CHU Grenoble Alpes - Inserm U1205]

6 CRCINA - Département NOHMAD - Equipe 17 - Design and Application of Innovative Local Treatments in Glioblastoma

CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers

7 Plateforme d’Analyses Cellulaires et Moléculaires - PACeM [Angers]

Abstract : 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.

Keywords : CXCR4 glioblastoma radiation therapy immuno-targeting spectral imaging macrophage nanoparticle.

Type de document :

Article dans une revue

Theranostics, Ivyspring International Publisher, 2017, 7 (18), pp.4517 - 4536. 〈10.7150/thno.19403〉

Domaine :

Sciences du Vivant [q-bio] / Cancer

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http://www.hal.inserm.fr/inserm-01631431
Contributeur : Elizabeth Bernardo <>
Soumis le : jeudi 9 novembre 2017 - 11:28:15
Dernière modification le : jeudi 5 avril 2018 - 10:37:03

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

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