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

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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 (LNC188Re-SSS). This approach resulted in an 83 % cure rate in the 9L rat glioma model, showing great promise. The efficacy of LNC188Re-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 LNC188Re-SSS in a human GB model implanted in T-cell deficient nude mice. We also analyzed the distribution and tissue retention of LNC188Re-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 188Re-SSS activity was present in the tumor region 24 h after LNC188Re-SSS injection and no toxicity was observed in the healthy brain. Double fractionated internal radiotherapy with LNC188Re-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, LNC188Re-SSS can induce long-term survival in an immunosuppressive environment, highlighting its potential for GB therapy.

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Abbreviations

BSA:

Bovine serum albumin

CED:

Convection enhanced-delivery

DMEM:

Dulbecco’s modified Eagle’s medium

Ext RT:

External radiotherapy

FCS:

Fetal calf serum

GB:

Glioblastoma

HBSS:

Hepes buffered saline solution

IST:

Increase in median survival time

LB:

B lymphocyte

LNCs:

Lipid nanocapsules

LNC188Re-SSS:

Lipid nanocapsules loaded with Rhenium-188

mAb:

Monoclonal antibody

MRI:

Magnetic resonance imaging

NK:

Natural killer

PBS:

Phosphate buffered saline

Vi:

Volume of injection

Vd:

Volume of distribution

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Ackowledgements

We thank neurosurgeons from CHU Angers for providing the Lab1 tumor sample. We also thank Dr Catherine Ibisch and Dr Jérôme Abadie (AMaROC, ONIRIS, Nantes), Pierre Legras and Jérôme Roux (Service Commun d’Animalerie Hospitalo-Universitaire, Angers), Pr Jean-Pierre Benoit and Aurélien Contini (INSERM U1066-MINT, Angers), Dr Florence Franconi (PRIMEX, Angers) and Dr Franck Lacoeuille (Médecine Nucléaire et Biophysique, CHU d'Angers) for allowing us to use their facilities. This work was supported by the French National Research Agency through the RADIOHEAD program (ANR-12-EMMA-0033-01), “La Région Pays-de-la-Loire” through the Nuclear Technology for Health project (NucSan) and IRAD programs, “La Ligue Nationale Contre le Cancer” through an “Equipe Labellisée 2012” grant, the “Institut National de la Santé et de la Recherche Médicale” (INSERM), the “Axe Vectorisation et Radiothérapies”, and the “Réseau Gliome Grand Ouest” (ReGGO) of the “Cancéropôle Grand-Ouest”. The co-authors of this manuscript are also members of the Labex IRON “Innovative Radiopharmaceuticals in Oncology and Neurology” as part of the French government program “Investissements d’Avenir”. A. Ci. received a fellowship from the NucSan program.

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Authors and Affiliations

  1. INSERM U1066 MINT (Micro et Nanomédecines Biomimétiques), Université d’Angers, Angers, France

    Annabelle Cikankowitz, Anne Clavreul, Clément Tétaud, Laurent Lemaire, Emmanuel Garcion, Philippe Menei, Olivier Couturier & François Hindré

  2. AMaROC, ONIRIS, Ecole Nationale Véterinaire de Nantes, Nantes, France

    Annabelle Cikankowitz

  3. Service de Neurochirurgie, CHU d’Angers, Angers, France

    Anne Clavreul & Philippe Menei

  4. Laboratoire de Pathologie Cellulaire et Tissulaire, CHU d’Angers, Angers, France

    Audrey Rousseau

  5. Centre Régional de Lutte Contre le Cancer (CRLCC) Eugène Marquis, Rennes, France

    Nicolas Lepareur

  6. Médecine Nucléaire et Biophysique, CHU d’Angers, Angers, France

    Djamel Dabli, Francis Bouchet & Olivier Couturier

  7. PRIMEX (Plateforme de Radiobiologie et d’Imagerie Expérimentale), Université d’Angers, Angers, France

    Annabelle Cikankowitz, Clément Tétaud & François Hindré

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  1. Annabelle Cikankowitz
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  2. Anne Clavreul
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  3. Clément Tétaud
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  4. Laurent Lemaire
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  5. Audrey Rousseau
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  6. Nicolas Lepareur
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  7. Djamel Dabli
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  9. Emmanuel Garcion
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  10. Philippe Menei
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Correspondence to Anne Clavreul.

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11060_2016_2289_MOESM1_ESM.tif

Experimental design to analyze the LNC distribution in the orthotopic GB Lab1 model by fluorescence (LNC-DID) and autoradiography (LNC188Re-SSS). (TIF 931 KB)

11060_2016_2289_MOESM2_ESM.tif

Biodistribution of LNC188Re-SSS. A distribution study was carried out using two female nude-NMRI mice on D19 following Lab1 cell injection. A Vi of 5 µL LNC188Re-SSS was performed at a flow-rate of 0.5 µL/min. The animals were sacrificed 1 h (n = 1) and 24 h (n = 1) after injection. The organs were removed, washed, and weighed. The activity content of each organ was determined using a gamma counter (Packard Auto-Gamma 5000 series). Results are expressed as the percentage of the injected dose. (n = number of mice analyzed). (TIF 581 KB)

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Cikankowitz, A., Clavreul, A., Tétaud, C. et al. Characterization of the distribution, retention, and efficacy of internal radiation of 188Re-lipid nanocapsules in an immunocompromised human glioblastoma model. J Neurooncol 131, 49–58 (2017). https://doi.org/10.1007/s11060-016-2289-4

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