Temporary blood–brain barrier disruption by low intensity pulsed ultrasound increases carboplatin delivery and efficacy in preclinical models of glioblastoma
Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. Few cytotoxic chemotherapies have been shown to be effective against GBM, due in part to the presence of the blood–brain barrier (BBB), which reduces the penetration of chemotherapies from the blood to the brain. Ultrasound-induced BBB opening (US-BBB) has been shown to increase the penetration of multiple chemotherapeutic agents in the brain in animal models. In the current study, the anti-tumor activity of carboplatin chemotherapy with and without US-BBB was investigated in several GBM mouse models.
First, the IC50 of two commercial (U87 and U251) and six patient-derived GBM cell lines (PDCL) to carboplatin was measured. Next, U87 was subcutaneously grafted to a nude mouse model to test the in vivo response of the tumor to carboplatin in the absence of the BBB. Lastly, nude mice bearing orthotopically xenografted GBM cell lines (U87 or a PDCL) were randomized to four experimental groups: (i) untreated, (ii) US-BBB alone, (iii) carboplatin alone and, (iv) carboplatin + US-BBB. Mice were treated once weekly for 4 weeks and monitored for toxicity, tumor growth, and survival.
Carboplatin plus US-BBB enhanced survival (p = 0.03) and delayed tumor growth (p < 0.05) of GBM-bearing mice compared to carboplatin alone, with a 4.2-fold increase of carboplatin penetration in the brain, without evidence of significant neurological or systemic toxicity.
Carboplatin efficacy was enhanced in GBM mouse models with US-BBB and appears to be a promising chemotherapy for this approach.
KeywordsGlioblastoma Blood–brain barrier Ultrasound Carboplatin
This research was funded in part by: Investissements d’avenir ANR-10-IAIHU-06, Institut Universitaire de Cancérologie, Fondation ARC pour la recherche sur le cancer, Association pour la Recherche sur les Tumeurs Cérébrales, Ligue Nationale Contre le Cancer, and support from CarThera (Paris, France). INCA-DGOS-Inserm_12560 SiRIC CURAMUS is financially supported by the French National Cancer Institute, the French Ministry of Solidarity and Health and INSERM and CarThera.
Compliance with ethical standards
Conflict of interest
Ahmed Idbaih reports receiving travel funding from CarThera (June 2018); Guillaume Bouchoux, Charlotte Schmitt, Michael Canney, and Frédéric Sottilini are employees of CarThera. Michael Canney and Alexandre Carpentier are paid consultants of CarThera. Alexandre Carpentier, Michael Canney, and Frédéric Sottilini have ownership interest in CarThera.
All protocols involving live animals were reviewed and approved by a local animal ethics committee for welfare of animals (Ministère de l’Enseignement Supérieur et de la Recherche, Paris, France, Protocol #0113.02). PDCLs were obtained with signed patient consent form and stored in the certified OncoNeuroTek tissue bank.
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